New Approaches in International Guidelines for Genetic Toxicology Assays: Latest Updates on OECD Guidelines

EPA Science Inventory

In March 2010, the 22nd meeting of the Working Group of National Coordinators of the OECD Test Guidelines Programme (WNT) approved a project for updating the Test Guidelines on genotoxicity, with Canada, the Netherlands, France and the USA identified as lead countries for this wo...

Pharmacogenomic Testing for Neuropsychiatric Drugs: Current Status of Drug Labeling, Guidelines for Using Genetic Information, and Test Options

PubMed Central

Drozda, Katarzyna; Müller, Daniel J.; Bishop, Jeffrey R.

2014-01-01

Advancements in pharmacogenomics have introduced an increasing number of opportunities to bring personalized medicine into clinical practice. Understanding how and when to use this technology to help guide pharmacotherapy used to treat neuropsychiatric conditions remains a challenge for many clinicians. Currently, guidelines exist to assist clinicians in the use of genetic information for drug selection and/or dosing for the tricyclic antidepressants, carbamazepine, and phenytoin. Additional language in the product labeling suggests that genetic information may also be useful for assessing the starting and target doses, as well as drug interaction potential, for a number of other medications used to treat psychiatric and neurological conditions. In this review, we outline the current status of pharmacogenomic testing for neuropsychiatric drugs as it pertains to information contained in drug labeling, consensus guidelines, and test panels, as well as considerations related to obtaining tests for patients. PMID:24523097

[Latest international guidelines for screening, prevention and treatment of familial breast cancer - implications for the relevant practice in Hungary].

PubMed

Romics, László; Kocsis, Judit; Ormándi, Katalin; Molnár, Béla Ákos

2016-07-01

Screening, prevention and treatment of familial breast cancer require a multidisciplinary approach. New guidelines were published in the United Kingdom for the management of familial breast cancer. The authors summarise these new guidelines and analyse the relevant practice in Hungary. Relevant guidelines of the National Institute for Health and Care Excellence and Familial Breast Cancer Report (NHS Scotland) are described. New guidelines will increase the number of genetic tests as well as genetic counselling. An increase in the number of breast magnetic resonance imaging is expected, too. Chemoprevention can be offered for individuals with medium risk and above. Promising trials are underway with platinum based chemotherapy and polyADP-ribose polimerase inhibitors for the systemic treatment of familial breast cancer. The increase in the number of genetic tests, counselling, and breast magnetic resonance imaging may have a significant impact on health care budget. These guidelines will change some aspects of the current management of familial breast cancer. Orv. Hetil., 2016, 157(28), 1117-1125.

"Would you test your children without their consent?" and other sticky dilemmas in the field of cancer genetic testing.

PubMed

Brierley, Karina L; Bonadies, Danielle C; Moyer, Anne; Matloff, Ellen T

2014-09-01

Cancer genetic testing is surrounded by myriad ethical, legal, and psychosocial implications which are being revisited as testing expands into an everyday practice and into more complicated areas like whole exome and direct-to-consumer testing. We chose to survey cancer genetic counselors and physicians from a wide range of non-genetics specialties to determine what they would do if faced with the complex decisions associated with cancer genetic testing, how their views compare, and how they align with current guidelines and data. Genetic counselors were significantly more likely than non-genetics physicians to bill their insurance for testing (94.9 vs. 86.8 %; p = 0.001) and purchase life insurance before testing (86.6 vs. 68.6 %; p = 0.000) and were less likely to use an alias (3.2 vs. 13.2 %; p = 0.000) or order testing on their own DNA (15.3 vs. 24.2 %; p = 0.004). They were also less likely to test their minor children (0.9 vs. 33.1 %; p = 0.000) or test their children without their knowledge and consent/assent (1.4 vs.11.5 %; p = 0.000). The results of our study indicate that there is wide variation regarding what clinicians predict they would do in the areas of ethical, legal and psychosocial issues in cancer genetic testing. Cancer genetic counselors' choices are more aligned with professional guidelines, likely due to their experience in the field and awareness of current guidelines. These data are a starting point for a broader discussion of who should offer cancer genetic counseling and testing to patients, particularly as the complexity of the available testing options and associated issues increase with whole exome sequencing.

Presymptomatic ALS genetic counseling and testing

PubMed Central

Stanislaw, Christine; Reyes, Eliana; Hussain, Sumaira; Cooley, Anne; Fernandez, Maria Catalina; Dauphin, Danielle D.; Michon, Sara-Claude; Andersen, Peter M.; Wuu, Joanne

2016-01-01

Remarkable advances in our understanding of the genetic contributions to amyotrophic lateral sclerosis (ALS) have sparked discussion and debate about whether clinical genetic testing should routinely be offered to patients with ALS. A related, but distinct, question is whether presymptomatic genetic testing should be offered to family members who may be at risk for developing ALS. Existing guidelines for presymptomatic counseling and testing are mostly based on small number of individuals, clinical judgment, and experience from other neurodegenerative disorders. Over the course of the last 8 years, we have provided testing and 317 genetic counseling sessions (including predecision, pretest, posttest, and ad hoc counseling) to 161 first-degree family members participating in the Pre-Symptomatic Familial ALS Study (Pre-fALS), as well as testing and 75 posttest counseling sessions to 63 individuals with familial ALS. Based on this experience, and the real-world challenges we have had to overcome in the process, we recommend an updated set of guidelines for providing presymptomatic genetic counseling and testing to people at high genetic risk for developing ALS. These recommendations are especially timely and relevant given the growing interest in studying presymptomatic ALS. PMID:27194384

Consumerism in prenatal diagnosis: a challenge for ethical guidelines

PubMed Central

Henn, W.

2000-01-01

The ethical guidelines for prenatal diagnosis proposed by the World Health Organisation (WHO), as well as by national regulations, only refer to paternity and gender of the fetus as unacceptable, disease-unrelated criteria for prenatal selection, as no other such parameters are at hand so far. This perspective is too narrow because research on complex genetic systems such as cognition and ageing is about to provide clinically applicable tests for genetic constituents of potentially desirable properties such as intelligence or longevity which could be misused as parameters for prenatal diagnosis. Moreover, there is an increasing number of prenatally testable genetic traits, such as heritable deafness, which are generally regarded as pathological but desired by some prospective parents and taken into account as parameters for pro-disability selection. To protect prenatal diagnosis from ethically unacceptable genetic consumerism, guidelines must be clarified as soon as possible and updated towards a worldwide restriction of prenatal genetic testing to immediately disease-determining traits. Key Words: Genetics • prenatal diagnosis • ethics • consumerism PMID:11129845

ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes.

PubMed

Syngal, Sapna; Brand, Randall E; Church, James M; Giardiello, Francis M; Hampel, Heather L; Burt, Randall W

2015-02-01

This guideline presents recommendations for the management of patients with hereditary gastrointestinal cancer syndromes. The initial assessment is the collection of a family history of cancers and premalignant gastrointestinal conditions and should provide enough information to develop a preliminary determination of the risk of a familial predisposition to cancer. Age at diagnosis and lineage (maternal and/or paternal) should be documented for all diagnoses, especially in first- and second-degree relatives. When indicated, genetic testing for a germline mutation should be done on the most informative candidate(s) identified through the family history evaluation and/or tumor analysis to confirm a diagnosis and allow for predictive testing of at-risk relatives. Genetic testing should be conducted in the context of pre- and post-test genetic counseling to ensure the patient's informed decision making. Patients who meet clinical criteria for a syndrome as well as those with identified pathogenic germline mutations should receive appropriate surveillance measures in order to minimize their overall risk of developing syndrome-specific cancers. This guideline specifically discusses genetic testing and management of Lynch syndrome, familial adenomatous polyposis (FAP), attenuated familial adenomatous polyposis (AFAP), MUTYH-associated polyposis (MAP), Peutz-Jeghers syndrome, juvenile polyposis syndrome, Cowden syndrome, serrated (hyperplastic) polyposis syndrome, hereditary pancreatic cancer, and hereditary gastric cancer.

ACG Clinical Guideline: Genetic Testing and Management of Hereditary Gastrointestinal Cancer Syndromes

PubMed Central

Syngal, Sapna; Brand, Randall E.; Church, James M.; Giardiello, Francis M.; Hampel, Heather L.; Burt, Randall W.

2015-01-01

This guideline presents recommendations for the management of patients with hereditary gastrointestinal cancer syndromes. The initial assessment is the collection of a family history of cancers and premalignant gastrointestinal conditions and should provide enough information to develop a preliminary determination of the risk of a familial predisposition to cancer. Age at diagnosis and lineage (maternal and/or paternal) should be documented for all diagnoses, especially in first- and second-degree relatives. When indicated, genetic testing for a germline mutation should be done on the most informative candidate(s) identified through the family history evaluation and/or tumor analysis to confirm a diagnosis and allow for predictive testing of at-risk relatives. Genetic testing should be conducted in the context of pre- and post-test genetic counseling to ensure the patient's informed decision making. Patients who meet clinical criteria for a syndrome as well as those with identified pathogenic germline mutations should receive appropriate surveillance measures in order to minimize their overall risk of developing syndrome-specific cancers. This guideline specifically discusses genetic testing and management of Lynch syndrome, familial adenomatous polyposis (FAP), attenuated familial adenomatous polyposis (AFAP), MUTYH-associated polyposis (MAP), Peutz–Jeghers syndrome, juvenile polyposis syndrome, Cowden syndrome, serrated (hyperplastic) polyposis syndrome, hereditary pancreatic cancer, and hereditary gastric cancer. PMID:25645574

Ethical dimensions of genetics in pediatric neurology: a look into the future.

PubMed

Avard, Denise M; Knoppers, Bartha M

2002-03-01

Health care providers and families with children who participate in genetic research or who need specialized genetic services, including genetic testing, will encounter not only medical but difficult social, ethical, and legal questions surrounding pediatric genetic neurology. Children are often at the center of much of the genetic revolution and their unique needs raise special concerns about the risks and benefits associated with genetic research, particularly the issues of consent, the use of genetic databases, and gene therapy. Moreover, genetic research and testing raise important psychosocial risks. In this article we discuss some of the benefits and consequences of genetic technologies for children in relation to national and international guidelines. In particular, physicians, policy-makers, and families should be knowledgeable about the guidelines and have a good understanding of the psychosocial and ethical issues associated with genetics in pediatric neurology.

Genetics Home Reference: inclusion body myopathy with early-onset Paget disease and frontotemporal dementia

MedlinePlus

... condition damages parts of the brain that control reasoning, personality, social skills, speech, and language. Personality changes, ... Clearinghouse: Paget's Disease of Bone: An Endocrine Society Clinical Practice Guideline Genetic Testing (1 link) Genetic Testing ...

Ethical issues in neurogenetics.

PubMed

Uhlmann, Wendy R; Roberts, J Scott

2018-01-01

Many neurogenetic conditions are inherited and therefore diagnosis of a patient will have implications for the patient's relatives and can raise ethical issues. Predictive genetic testing offers asymptomatic relatives the opportunity to determine their risk status for a neurogenetic condition, and professional guidelines emphasize patients' autonomy and informed, voluntary decision making. Beneficence and nonmaleficence both need to be considered when making decisions about disclosure and nondisclosure of genetic information and test results. There can be disclosure concerns and challenges in determining whose autonomy to prioritize when a patient makes a genetic testing decision that can reveal the genetic status of a relative (e.g., testing an adult child when the at-risk parent has not been tested). Ethical issues are prominent when genetic testing for neurogenetic conditions is requested prenatally, on minors, adoptees, adult children at 25% risk, and for individuals with psychiatric issues or cognitive impairment. Neurogenetic conditions can result in cognitive decline which can affect decisional capacity and lead to ethical challenges with decision making, informed consent, and determining the patient's ability to comprehend test results. The ethical implications of genetic testing and emerging issues, including direct-to-consumer genetic testing, disclosure of secondary findings from genomic sequencing, and use of apolipoprotein E testing in clinical and research settings, are also discussed. Resources for information about genetic testing practice guidelines, insurance laws, and directories of genetics clinics are included. Copyright © 2018 Elsevier B.V. All rights reserved.

Ethical Issues in Neurogenetics

PubMed Central

Uhlmann, Wendy R.; Roberts, J. Scott

2018-01-01

Many neurogenetic conditions are inherited and therefore diagnosis of a patient will have implications for their relatives and can raise ethical issues. Predictive genetic testing offers asymptomatic relatives the opportunity to determine their risk status for a neurogenetic condition, and professional guidelines emphasize patients’ autonomy and informed, voluntary decision-making. Beneficence and non-maleficence both need to be considered when making decisions about disclosure and nondisclosure of genetic information and test results. There can be disclosure concerns and issues of determining whose autonomy to prioritize when a patient makes a genetic testing decision that can reveal the genetic status of a relative (e.g. testing an adult child when the at-risk parent has not been tested). Ethical issues are prominent when genetic testing for neurogenetic conditions is requested prenatally, on minors, adoptees, adult children at 25% risk, and for individuals with psychiatric issues or cognitive impairment. Neurogenetic conditions can result in cognitive decline which can affect decisional capacity and lead to ethical challenges with decision-making, informed consent and determining the patient’s ability to comprehend test results. The ethical implications of genetic testing and emerging issues, including direct-to-consumer genetic testing, disclosure of secondary findings from genomic sequencing, and use of APOE testing in clinical and research settings, are also discussed. Resources for information about genetic testing practice guidelines, insurance laws and directories of genetics clinics are included. PMID:29325614

Improved access to life insurance after genetic diagnosis of familial hypercholesterolaemia: cross-sectional postal questionnaire study

PubMed Central

Huijgen, Roeland; Homsma, Sietske JM; Hutten, Barbara A; Kindt, Iris; Vissers, Maud N; Kastelein, John JP; van Rijckevorsel, Jan LA

2012-01-01

A decade ago, in the initial stage of genetic testing for familial hypercholesterolaemia (FH) in The Netherlands, it was reported that such screening decreased access to affordable life insurance for mutation carriers. In 2003, in order to improve access to insurance for FH mutation carriers, insurers agreed to underwrite according to a set of guidelines. In this cross-sectional study, we assessed whether access to insurance has improved since the advent of these guidelines. We approached 2825 subjects that had participated in the genetic testing for FH between 1998 and 2003. We compared unconditional acceptance rates before and after FH diagnosis and before and after the guidelines were issued by means of logistic regression analysis. Our study outcome pertains to 414 FH patients who applied for life insurance. Unconditional acceptance of a policy before DNA diagnosis and before the issue of guidelines occurred in 182 out of 255 (71%) cases, versus 27 out of 35 (77%) cases after DNA diagnosis, but before the issue of guidelines. De facto, 107 out of 124 (86%) patients received unconditional acceptance after DNA diagnosis and after the issue of guidelines (P for trend=0.002). Access to life insurance improved for FH patients after molecular diagnosis and it improved even further after the guidelines were issued. Therefore, we argue that limited access to life insurance on the basis of ‘DNA discrimination' is no longer a valid argument against genetic cascade testing for FH, at least not in our country. PMID:22293687

Laboratory diagnosis of creatine deficiency syndromes: a technical standard and guideline of the American College of Medical Genetics and Genomics.

PubMed

Sharer, J Daniel; Bodamer, Olaf; Longo, Nicola; Tortorelli, Silvia; Wamelink, Mirjam M C; Young, Sarah

2017-02-01

Disclaimer: These ACMG Standards and Guidelines are intended as an educational resource for clinical laboratory geneticists to help them provide quality clinical laboratory genetic services. Adherence to these standards and guidelines is voluntary and does not necessarily assure a successful medical outcome. These Standards and Guidelines should not be considered inclusive of all proper procedures and tests or exclusive of others that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, clinical laboratory geneticists should apply their professional judgment to the specific circumstances presented by the patient or specimen. Clinical laboratory geneticists are encouraged to document in the patient's record the rationale for the use of a particular procedure or test, whether or not it is in conformance with these Standards and Guidelines. They also are advised to take notice of the date any particular guideline was adopted, and to consider other relevant medical and scientific information that becomes available after that date. It also would be prudent to consider whether intellectual property interests may restrict the performance of certain tests and other procedures.Cerebral creatine deficiency syndromes are neurometabolic conditions characterized by intellectual disability, seizures, speech delay, and behavioral abnormalities. Several laboratory methods are available for preliminary and confirmatory diagnosis of these conditions, including measurement of creatine and related metabolites in biofluids using liquid chromatography-tandem mass spectrometry or gas chromatography-mass spectrometry, enzyme activity assays in cultured cells, and DNA sequence analysis. These guidelines are intended to standardize these procedures to help optimize the diagnosis of creatine deficiency syndromes. While biochemical methods are emphasized, considerations for confirmatory molecular testing are also discussed, along with variables that influence test results and interpretation.Genet Med 19 2, 256-263.

Genetic counseling and testing for Alzheimer disease: joint practice guidelines of the American College of Medical Genetics and the National Society of Genetic Counselors.

PubMed

Goldman, Jill S; Hahn, Susan E; Catania, Jennifer Williamson; LaRusse-Eckert, Susan; Butson, Melissa Barber; Rumbaugh, Malia; Strecker, Michelle N; Roberts, J Scott; Burke, Wylie; Mayeux, Richard; Bird, Thomas

2011-06-01

Alzheimer disease is the most common cause of dementia. It occurs worldwide and affects all ethnic groups. The incidence of Alzheimer disease is increasing due, in part, to increased life expectancy and the aging baby boomer generation. The average lifetime risk of developing Alzheimer disease is 10-12%. This risk at least doubles with the presence of a first-degree relative with the disorder. Despite its limited utility, patients express concern over their risk and, in some instances, request testing. Furthermore, research has demonstrated that testing individuals for apolipoprotein E can be valuable and safe in certain contexts. However, because of the complicated genetic nature of the disorder, few clinicians are prepared to address the genetic risks of Alzheimer disease with their patients. Given the increased awareness in family history thanks to family history campaigns, the increasing incidence of Alzheimer disease, and the availability of direct to consumer testing, patient requests for information is increasing. This practice guideline provides clinicians with a framework for assessing their patients' genetic risk for Alzheimer disease, identifying which individuals may benefit from genetic testing, and providing the key elements of genetic counseling for AD.

[Genetic diseases:recent scientific findings and health and ethical problems].

PubMed

Taruscio, D; D'Agnolo, G

1999-01-01

Genetic diseases are very numerous, even though rare as single conditions: therefore, overall they represent a significant portion of morbidity at population level. The improvement of molecular genetic techniques has brought a great increase in the diagnostic potential toward genetic diseases, concerning either symptomatic or pre-symptomatic individuals and healthy carriers. However, this has frequently unforeseen consequences, such as a discrepancy between diagnostic and therapeutic potentials. Moreover, the development of genetic tests has raised a number of questions regarding ethical, legal e social problems. The Italian guidelines for genetic tests (available on the Internet site of Istituto Superiore di Sanità: http:@www.iss.it) have been elaborated in 1998 to define general principles for performing and managing genetic tests as well as for programming and promoting genetic testing within the public health system. In accordance with recommendations by international bodies (WHO, EU), the Guidelines give emphasis to the appropriate use of both safe and efficacious tests, the performance in laboratories with high quality standards. A further crucial point is the relationship between the health system and individuals: authonomy of decision, psychological and social assistance, as well as adequate attention to ethical and privacy problems should be guaranteed.

Mutation Detection in Patients With Advanced Cancer by Universal Sequencing of Cancer-Related Genes in Tumor and Normal DNA vs Guideline-Based Germline Testing.

PubMed

Mandelker, Diana; Zhang, Liying; Kemel, Yelena; Stadler, Zsofia K; Joseph, Vijai; Zehir, Ahmet; Pradhan, Nisha; Arnold, Angela; Walsh, Michael F; Li, Yirong; Balakrishnan, Anoop R; Syed, Aijazuddin; Prasad, Meera; Nafa, Khedoudja; Carlo, Maria I; Cadoo, Karen A; Sheehan, Meg; Fleischut, Megan H; Salo-Mullen, Erin; Trottier, Magan; Lipkin, Steven M; Lincoln, Anne; Mukherjee, Semanti; Ravichandran, Vignesh; Cambria, Roy; Galle, Jesse; Abida, Wassim; Arcila, Marcia E; Benayed, Ryma; Shah, Ronak; Yu, Kenneth; Bajorin, Dean F; Coleman, Jonathan A; Leach, Steven D; Lowery, Maeve A; Garcia-Aguilar, Julio; Kantoff, Philip W; Sawyers, Charles L; Dickler, Maura N; Saltz, Leonard; Motzer, Robert J; O'Reilly, Eileen M; Scher, Howard I; Baselga, Jose; Klimstra, David S; Solit, David B; Hyman, David M; Berger, Michael F; Ladanyi, Marc; Robson, Mark E; Offit, Kenneth

2017-09-05

Guidelines for cancer genetic testing based on family history may miss clinically actionable genetic changes with established implications for cancer screening or prevention. To determine the proportion and potential clinical implications of inherited variants detected using simultaneous sequencing of the tumor and normal tissue ("tumor-normal sequencing") compared with genetic test results based on current guidelines. From January 2014 until May 2016 at Memorial Sloan Kettering Cancer Center, 10 336 patients consented to tumor DNA sequencing. Since May 2015, 1040 of these patients with advanced cancer were referred by their oncologists for germline analysis of 76 cancer predisposition genes. Patients with clinically actionable inherited mutations whose genetic test results would not have been predicted by published decision rules were identified. Follow-up for potential clinical implications of mutation detection was through May 2017. Tumor and germline sequencing compared with the predicted yield of targeted germline sequencing based on clinical guidelines. Proportion of clinically actionable germline mutations detected by universal tumor-normal sequencing that would not have been detected by guideline-directed testing. Of 1040 patients, the median age was 58 years (interquartile range, 50.5-66 years), 65.3% were male, and 81.3% had stage IV disease at the time of genomic analysis, with prostate, renal, pancreatic, breast, and colon cancer as the most common diagnoses. Of the 1040 patients, 182 (17.5%; 95% CI, 15.3%-19.9%) had clinically actionable mutations conferring cancer susceptibility, including 149 with moderate- to high-penetrance mutations; 101 patients tested (9.7%; 95% CI, 8.1%-11.7%) would not have had these mutations detected using clinical guidelines, including 65 with moderate- to high-penetrance mutations. Frequency of inherited mutations was related to case mix, stage, and founder mutations. Germline findings led to discussion or initiation of change to targeted therapy in 38 patients tested (3.7%) and predictive testing in the families of 13 individuals (1.3%), including 6 for whom genetic evaluation would not have been initiated by guideline-based testing. In this referral population with selected advanced cancers, universal sequencing of a broad panel of cancer-related genes in paired germline and tumor DNA samples was associated with increased detection of individuals with potentially clinically significant heritable mutations over the predicted yield of targeted germline testing based on current clinical guidelines. Knowledge of these additional mutations can help guide therapeutic and preventive interventions, but whether all of these interventions would improve outcomes for patients with cancer or their family members requires further study. clinicaltrials.gov Identifier: NCT01775072.

Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-Society Task Force on colorectal cancer.

PubMed

Giardiello, Francis M; Allen, John I; Axilbund, Jennifer E; Boland, C Richard; Burke, Carol A; Burt, Randall W; Church, James M; Dominitz, Jason A; Johnson, David A; Kaltenbach, Tonya; Levin, Theodore R; Lieberman, David A; Robertson, Douglas J; Syngal, Sapna; Rex, Douglas K

2014-08-01

The Multi-Society Task Force, in collaboration with invited experts, developed guidelines to assist health care providers with the appropriate provision of genetic testing and management of patients at risk for and affected with Lynch syndrome as follows: Figure 1 provides a colorectal cancer risk assessment tool to screen individuals in the office or endoscopy setting; Figure 2 illustrates a strategy for universal screening for Lynch syndrome by tumor testing of patients diagnosed with colorectal cancer; Figures 3-6 provide algorithms for genetic evaluation of affected and at-risk family members of pedigrees with Lynch syndrome; Table 10 provides guidelines for screening at-risk and affected persons with Lynch syndrome; and Table 12 lists the guidelines for the management of patients with Lynch syndrome. A detailed explanation of Lynch syndrome and the methodology utilized to derive these guidelines, as well as an explanation of, and supporting literature for, these guidelines are provided. Copyright © 2014 American Gastroenterological Association, American College of Gastroenterology, the American Society of Colon and Rectal Surgeons, and the American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.

Diagnostic Yield of Chromosomal Microarray Analysis in an Autism Primary Care Practice: Which Guidelines to Implement?

ERIC Educational Resources Information Center

McGrew, Susan G.; Peters, Brittany R.; Crittendon, Julie A.; Veenstra-VanderWeele, Jeremy

2012-01-01

Genetic testing is recommended for patients with ASD; however specific recommendations vary by specialty. American Academy of Pediatrics and American Academy of Neurology guidelines recommend G-banded karyotype and Fragile X DNA. The American College of Medical Genetics recommends Chromosomal Microarray Analysis (CMA). We determined the yield of…

Best practice guidelines for molecular genetic diagnosis of cystic fibrosis and CFTR-related disorders--updated European recommendations.

PubMed

Dequeker, Els; Stuhrmann, Manfred; Morris, Michael A; Casals, Teresa; Castellani, Carlo; Claustres, Mireille; Cuppens, Harry; des Georges, Marie; Ferec, Claude; Macek, Milan; Pignatti, Pier-Franco; Scheffer, Hans; Schwartz, Marianne; Witt, Michal; Schwarz, Martin; Girodon, Emmanuelle

2009-01-01

The increasing number of laboratories offering molecular genetic analysis of the CFTR gene and the growing use of commercial kits strengthen the need for an update of previous best practice guidelines (published in 2000). The importance of organizing regional or national laboratory networks, to provide both primary and comprehensive CFTR mutation screening, is stressed. Current guidelines focus on strategies for dealing with increasingly complex situations of CFTR testing. Diagnostic flow charts now include testing in CFTR-related disorders and in fetal bowel anomalies. Emphasis is also placed on the need to consider ethnic or geographic origins of patients and individuals, on basic principles of risk calculation and on the importance of providing accurate laboratory reports. Finally, classification of CFTR mutations is reviewed, with regard to their relevance to pathogenicity and to genetic counselling.

[Survey on the attitude toward genetic testing of neurologists certified by the Japanese Society of Neurology].

PubMed

Yoshida, Kunihiro; Ohata, Takako; Muto, Kaori; Tsuchiya, Atsushi; Sawada, Jinichi; Hazama, Takanori; Ikeda, Shu-Ichi; Toda, Tatsushi

2013-01-01

To clarify the attitude toward genetic testing for neuromuscular diseases, a questionnaire was sent to 4,762 neurologists certified by the Japanese Society of Neurology. By December 21, 2011, 1,493 questionnaires (31.4%) were returned. Of these, 1,233 (82.6%) had experienced genetic testing, but only 396 (26.5%) had referred to the guideline for genetic testing of the Japanese Society of Neurology (2009). The numbers of respondents who were positive, or more positive than negative for genetic testing for myotonic dystrophy type 1 (DM1), Huntington's disease (HD), and familial amyloid polyneuropathy (FAP) were 753 (50.4%), 915 (61.3%), and 980 (65.6%), respectively. The predominant reason for a positive attitude toward genetic testing was to confirm or exclude the diagnosis. Conversely, the predominant reason for a negative attitude toward genetic testing differed between the diseases. For DM1, it was to confirm the diagnosis without genetic testing. For HD, it was that genetic testing would not result in effective prevention or therapy. In FAP, it was that post-testing psychosocial support for the patient and their family was difficult. Common to DM1, HD, and FAP, a significant number of respondents (approximately 60%) felt it difficult to explain the negative aspects that might occur after the disclosure of test results. Concerning predictive or prenatal genetic testing, most respondents referred at-risk individuals to specialized genetic counseling clinics. In general, neurologists are likely to conduct genetic testing properly in consideration not only of the characteristics of the diseases but also of the circumstances of each patient and his or her family. To support neurologists who are involved in genetic testing, the guidelines should be more easily accessible. Many respondents wanted information on the institutions that provide genetic counseling and testing; however, financial support to such institutions is indispensable for fulfilling this requirement.

Genetic counseling and testing for Alzheimer disease: Joint practice guidelines of the American College of Medical Genetics and the National Society of Genetic Counselors

PubMed Central

Goldman, Jill S.; Hahn, Susan E.; Catania, Jennifer Williamson; LaRusse-Eckert, Susan; Butson, Melissa Barber; Rumbaugh, Malia; Strecker, Michelle N.; Roberts, J. Scott; Burke, Wylie; Mayeux, Richard; Bird, Thomas

2012-01-01

Alzheimer disease is the most common cause of dementia. It occurs worldwide and affects all ethnic groups. The incidence of Alzheimer disease is increasing due, in part, to increased life expectancy and the aging baby boomer generation. The average lifetime risk of developing Alzheimer disease is 10–12%. This risk at least doubles with the presence of a first-degree relative with the disorder. Despite its limited utility, patients express concern over their risk and, in some instances, request testing. Furthermore, research has demonstrated that testing individuals for apoli-poprotein E can be valuable and safe in certain contexts. However, because of the complicated genetic nature of the disorder, few clinicians are prepared to address the genetic risks of Alzheimer disease with their patients. Given the increased awareness in family history thanks to family history campaigns, the increasing incidence of Alzheimer disease, and the availability of direct to consumer testing, patient requests for information is increasing. This practice guideline provides clinicians with a framework for assessing their patients’ genetic risk for Alzheimer disease, identifying which individuals may benefit from genetic testing, and providing the key elements of genetic counseling for AD. PMID:21577118

Inherited mutations in BRCA1 and BRCA2 in an unselected multiethnic cohort of Asian patients with breast cancer and healthy controls from Malaysia

PubMed Central

Wen, Wei Xiong; Allen, Jamie; Lai, Kah Nyin; Mariapun, Shivaani; Hasan, Siti Norhidayu; Ng, Pei Sze; Lee, Daphne Shin-Chi; Lee, Sheau Yee; Yoon, Sook-Yee; Lim, Joanna; Lau, Shao Yan; Decker, Brennan; Pooley, Karen; Dorling, Leila; Luccarini, Craig; Baynes, Caroline; Conroy, Don M; Harrington, Patricia; Simard, Jacques; Yip, Cheng Har; Mohd Taib, Nur Aishah; Ho, Weang Kee; Antoniou, Antonis C; Dunning, Alison M; Easton, Douglas F

2018-01-01

Background Genetic testing for BRCA1 and BRCA2 is offered typically to selected women based on age of onset and family history of cancer. However, current internationally accepted genetic testing referral guidelines are built mostly on data from cancer genetics clinics in women of European descent. To evaluate the appropriateness of such guidelines in Asians, we have determined the prevalence of germ line variants in an unselected cohort of Asian patients with breast cancer and healthy controls. Methods Germ line DNA from a hospital-based study of 2575 unselected patients with breast cancer and 2809 healthy controls were subjected to amplicon-based targeted sequencing of exonic and proximal splice site junction regions of BRCA1 and BRCA2 using the Fluidigm Access Array system, with sequencing conducted on a Illumina HiSeq2500 platform. Variant calling was performed with GATK UnifiedGenotyper and were validated by Sanger sequencing. Results Fifty-five (2.1%) BRCA1 and 66 (2.6%) BRCA2 deleterious mutations were identified among patients with breast cancer and five (0.18%) BRCA1 and six (0.21%) BRCA2 mutations among controls. One thousand one hundred and eighty-six (46%) patients and 97 (80%) carriers fulfilled the National Comprehensive Cancer Network guidelines for genetic testing. Conclusion Five per cent of unselected Asian patients with breast cancer carry deleterious variants in BRCA1 or BRCA2. While current referral guidelines identified the majority of carriers, one in two patients would be referred for genetic services. Given that such services are largely unavailable in majority of low-resource settings in Asia, our study highlights the need for more efficient guidelines to identify at-risk individuals in Asia. PMID:28993434

American College of Medical Genetics guideline on the cytogenetic evaluation of the individual with developmental delay or mental retardation

PubMed Central

Shaffer, Lisa G.

2005-01-01

The following are the recommendations of the American College of Medical Genetics (ACMG) Professional Practice and Guidelines Committee, which was convened to assist health care professionals in making decisions regarding cytogenetic diagnostic testing and counseling for mental retardation (MR) and developmental delay (DD). This document reviews available evidence concerning the value of conventional and molecular cytogenetic testing for the identification of chromosomal anomalies that play a role in the etiology of MR/DD, and, based on this evidence, specific recommendations for each method of testing are provided. PMID:16301868

Genetic heterogeneity in HER2 testing may influence therapy eligibility.

PubMed

Bernasconi, Barbara; Chiaravalli, Anna Maria; Finzi, Giovanna; Milani, Katia; Tibiletti, Maria Grazia

2012-05-01

Prospective studies have demonstrated that approximately 20% of HER2 testing may be inaccurate. When carefully validated testing is conducted, available data do not clearly demonstrate the superiority of either IHC or fluorescence in situ hybridization (FISH) as a predictor of benefit from anti-HER2 therapy. In addition, the interpretation of the findings of HER2 tests according to international guidelines is not uniform. The American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) recently published practice guidelines for a definition of HER2 amplification heterogeneity that can give rise to discrepant results between IHC and FISH assays for HER2. In this article, we compare the HER2 status of 291 non consecutive breast cancers. The status is determined by both IHC and FISH approaches, using a specific FISH strategy to investigate genetic heterogeneity. Our data demonstrate that HER2 amplified cells may be found as diffuse, clustered in a specific area or section, intermingled with non-amplified cells or confined to metastatic nodules. The correct evaluation of ratio value in the presence of genetic heterogeneity and of polysomy contributes to the accurate assessment of HER2 status and potentially affects the selection of appropriate anti-HER2 therapy. By taking into account the presence of different genetic cell populations, the immunotherapy eligibility criteria for HER2 FISH scoring proposed in the CAP (2009) and SIGU guidelines identify an additional subset of cases for trastuzumab or lapatinib therapy compared to the ASCO/CAP (2007) guidelines.

Assessing the cost of implementing the 2011 Society of Obstetricians and Gynecologists of Canada and Canadian College of Medical Genetics practice guidelines on the detection of fetal aneuploidies.

PubMed

Lilley, Margaret; Hume, Stacey; Karpoff, Nina; Maire, Georges; Taylor, Sherry; Tomaszewski, Robert; Yoshimoto, Maisa; Christian, Susan

2017-09-01

The Society of Obstetricians and Gynecologists of Canada and the Canadian College of Medical Genetics published guidelines, in 2011, recommending replacement of karyotype with quantitative fluorescent polymerase chain reaction when prenatal testing is performed because of an increased risk of a common aneuploidy. This study's objective is to perform a cost analysis following the implementation of quantitative fluorescent polymerase chain reaction as a stand-alone test. A total of 658 samples were received between 1 April 2014 and 31 August 2015: 576 amniocentesis samples and 82 chorionic villi sampling. A chromosome abnormality was identified in 14% (93/658) of the prenatal samples tested. The implementation of the 2011 Society of Obstetricians and Gynecologists of Canada and the Canadian College of Medical Genetics guidelines in Edmonton and Northern Alberta resulted in a cost savings of $46 295.80. The replacement of karyotype with chromosomal microarray for some indications would be associated with additional costs. The implementation of new test methods may provide cost savings or added costs. Cost analysis is important to consider during the implementation of new guidelines or technologies. © 2017 John Wiley & Sons, Ltd. © 2017 John Wiley & Sons, Ltd.

A Novel Approach to Improving Utilization of Laboratory Testing.

PubMed

Zhou, Yaolin; Procop, Gary W; Riley, Jacquelyn D

2018-02-01

- The incorporation of best practice guidelines into one's institution is a challenging goal of utilization management, and the successful adoption of such guidelines depends on institutional context. Laboratorians who have access to key clinical data are well positioned to understand existing local practices and promote more appropriate laboratory testing. - To apply a novel approach to utilization management by reviewing international clinical guidelines and current institutional practices to create a reliable mechanism to improve detection and reduce unnecessary tests in our patient population. - We targeted a frequently ordered genetic test for HFE-related hereditary hemochromatosis, a disorder of low penetrance. After reviewing international practice guidelines, we evaluated 918 HFE tests and found that all patients with new diagnoses had transferrin saturation levels that were significantly higher than those of patients with nonrisk genotypes (72% versus 42%; P < .001). - Our "one-button" order that restricts HFE genetic tests to patients with transferrin saturation greater than 45% is consistent with published practice guidelines and detected 100% of new patients with HFE-related hereditary hemochromatosis. - Our proposed algorithm differs from previously published approaches in that it incorporates both clinical practice guidelines and local physician practices, yet requires no additional hands-on effort from pathologists or clinicians. This novel approach to utilization management embraces the role of pathologists as leaders in promoting high-quality patient care in local health care systems.

Consensus and controversies in best practices for molecular genetic testing of spinocerebellar ataxias

PubMed Central

Sequeiros, Jorge; Seneca, Sara; Martindale, Joanne

2010-01-01

Many laboratories worldwide are offering molecular genetic testing for spinocerebellar ataxias (SCAs). This is essential for differential diagnosis and adequate genetic counselling. The European Molecular Genetics Quality Network (EMQN) started an SCA external quality assessment scheme in 2004. There was a clear need for updated laboratory guidelines. EMQN and EuroGentest organized a Best Practice (BP) meeting to discuss current practices and achieve consensus. A pre-meeting survey showed that 36 laboratories (20 countries) conducted nearly 18 000 SCA tests the year before, and identified issues to discuss. Draft guidelines were produced immediately after the meeting and discussed online for several months. The final version was endorsed by EMQN, and harmonized with guidelines from other oligonucleotide repeat disorders. We present the procedures taken to organize the survey, BP meeting, as well as drafting and approval of BP guidelines. We emphasize the most important recommendations on (1) pre-test requirements, (2) appropriate methodologies and (3) interpretation and reporting, and focus on the discussion of controversial issues not included in the final document. In addition, after an extensive review of scientific literature, and responding to recommendations made, we now produce information that we hope will facilitate the activities of diagnostic laboratories and foster quality SCA testing. For the main loci, this includes (1) a list of repeat sequences, as originally published; (2) primers in use; and (3) an evidence-based description of the normal and pathogenic repeat-size ranges, including those of reduced penetrance and those in which there is still some uncertainty. This information will be maintained and updated in http://www.scabase.eu. PMID:20179748

Effects of Cancer Genetic Panel Testing on at-Risk Individuals.

PubMed

Frost, Anja S; Toaff, Miriam; Biagi, Tara; Stark, Elizabeth; McHenry, Allison; Kaltman, Rebecca

2018-06-01

To evaluate the role of screening patients at increased risk for hereditary cancer syndromes with an extended panel of cancer predisposition genes to identify actionable genetic mutations. A retrospective chart review was conducted of all patients presenting to a multidisciplinary cancer program for genetic counseling and testing from January 2015 to December 2016. Individuals presenting to the program were identified as at-risk by a personal or family history of cancer, by their health care provider, or by self-referral. All participants met current National Comprehensive Cancer Network criteria for genetic risk evaluation for hereditary cancer. The results of testing and its implications for management, based on National Comprehensive Cancer Network guidelines, were recorded. Of 670 at-risk patients who underwent genetic testing, 66 (9.9%) had BRCA-limited testing; of these, 26 of 670 (3.9%) had a deleterious or likely pathogenic mutation. Expanded panel testing was done for 560 of the 670 patients (83.4%), and abnormal results were found in 65 of 670 (9.7%); non-BRCA mutations (predominantly CHEK2) were found in 49 of the 65 (75%). Abnormal genetic testing was associated with increased surveillance in 96% of those with deleterious mutations, whereas negative testing for a known familial mutation in 45 patients was associated with a downgrade of their risk and reduction of subsequent surveillance and management. Guideline-based management is frequently altered by genetic testing, including panel testing, in patients at risk for cancer. We recommend that obstetrics and gynecology providers routinely refer at-risk patients for genetic counseling and testing when clinically appropriate.

Let the consumer decide? The regulation of commercial genetic testing

PubMed Central

Levitt, D. M.

2001-01-01

Objectives—The development of predictive genetic tests provides a new area where consumers can gain knowledge of their health status and commercial opportunities. "Over-the-counter" or mail order genetic tests are most likely to provide information on carrier status or the risk of developing a multifactorial disease. The paper considers the social and ethical implications of individuals purchasing genetic tests and whether genetic information is different from other types of health information which individuals can obtain for themselves. Design—The discussion is illustrated by findings from a questionnaire survey of university students as potential consumers. Topics covered included what health tests they had already used, expectations of genetic tests, willingness to pay, who should have access to the results and whether there need to be restrictions on such tests. Sample—Six hundred and fifteen first-year students in the universities of Leuven, Cardiff, Central Lancashire, Vienna and Nijmegen studying either medicine or a non-science subject. Results—Students were enthusiastic about genetic tests and had high expectations of their accuracy and usefulness but most thought they should be available through the health service and a minority thought that some tests, for example for sex selection, should not be available at all. There were few differences in responses by sex or subject of study but some by country. The paper also considers ethical and social issues outside the scope of a questionnaire survey of this type. Conclusion—To address some of these issues the sale of genetic tests to individuals can be made subject to ethical guidelines or codes of practice, for example to protect vulnerable groups, but there are fundamental social and ethical questions which such guidelines cannot address. Key Words: Genetic tests • European • commercialisation PMID:11731604

Genetics Evaluation Guidelines for the Etiologic Diagnosis of Congenital Hearing Loss

PubMed Central

2002-01-01

The advent of hearing screening in newborns in many states has led to an increase in the use of genetic testing and related genetic services in the follow-up of infants with hearing loss. A significant proportion of those with congenital hearing loss have genetic etiologies underlying their hearing loss. To ensure that those identified with congenital hearing loss receive the genetic services appropriate to their conditions, the Maternal and Child Health Bureau of the Health Resources and Services Administration funded the American College of Medical Genetics to convene an expert panel to develop guidelines for the genetic evaluation of congential hearing loss. After a brief overview of the current knowledge of hearing loss, newborn screening, and newborn hearing screening, we provide an overview of genetic services and a guideline that describes how best to ensure that patients receive appropriate genetic services. The significant contribution of genetic factors to these conditions combined with the rapid evolution of knowledge about the genetics of these conditions overlaid with the inherently multidisciplinary nature of genetic services provides an example of a condition for which a well-integrated multidisciplinary approach to care is clearly needed. PMID:12180152

Genetic Testing Integration Panels (GTIPs): A novel approach for considering integration of direct-to-consumer and other new genetic tests into patient care

PubMed Central

Uhlmann, Wendy R.; Sharp, Richard R.

2014-01-01

There has been a dramatic increase in the number of genetic tests available but few tests have practice guidelines. In addition, many tests have become available outside of genetics clinics through direct-to-consumer (DTC) companies and several offer tests not considered standard of care. To address several practical challenges associated with the rapid introduction of clinical and DTC genetic tests, we propose that genetic counselors and geneticists organize expert panels in their institutions to discuss the integration of new tests into patient care. We propose the establishment of Genetic Testing Integration Panels (GTIPs) to bring together local experts in medical genetics, genetic counseling, bioethics and law, health communication and clinical laboratory genetics. We describe key features of this approach and consider some of the potential advantages and limitations of using a GTIP to address the many clinical challenges raised by rapidly emerging clinical and DTC genetic tests. PMID:22246561

Let the consumer decide? The regulation of commercial genetic testing.

PubMed

Levitt, D M

2001-12-01

The development of predictive genetic tests provides a new area where consumers can gain knowledge of their health status and commercial opportunities. "Over-the-counter" or mail order genetic tests are most likely to provide information on carrier status or the risk of developing a multifactorial disease. The paper considers the social and ethical implications of individuals purchasing genetic tests and whether genetic information is different from other types of health information which individuals can obtain for themselves. The discussion is illustrated by findings from a questionnaire survey of university students as potential consumers. Topics covered included what health tests they had already used, expectations of genetic tests, willingness to pay, who should have access to the results and whether there need to be restrictions on such tests. SAMPLE-Six hundred and fifteen first-year students in the universities of Leuven, Cardiff, Central Lancashire, Vienna and Nijmegen studying either medicine or a non-science subject. Students were enthusiastic about genetic tests and had high expectations of their accuracy and usefulness but most thought they should be available through the health service and a minority thought that some tests, for example for sex selection, should not be available at all. There were few differences in responses by sex or subject of study but some by country. The paper also considers ethical and social issues outside the scope of a questionnaire survey of this type. To address some of these issues the sale of genetic tests to individuals can be made subject to ethical guidelines or codes of practice, for example to protect vulnerable groups, but there are fundamental social and ethical questions which such guidelines cannot address.

The ethical implications of genetic testing in the classroom.

PubMed

Taylor, Ann T S; Rogers, Jill Cellars

2011-07-01

The development of classroom experiments where students examine their own DNA is frequently described as an innovative teaching practice. Often these experiences involve students analyzing their genes for various polymorphisms associated with disease states, like an increased risk for developing cancer. Such experiments can muddy the distinction between classroom investigation and medical testing. Although the goals and issues surrounding classroom genotyping do not directly align with those of clinical testing, instructors can use the guidelines and standards established by the medical genetics community when evaluating the ethics of human genotyping. We developed a laboratory investigation and discussion which allowed undergraduate science students to explore current DNA manipulation techniques to isolate their p53 gene, followed by a dialogue probing the ethical implications of examining their sample for various polymorphisms. Students never conducted genotyping on their samples because of the ethical concerns presented in this paper, so the discussion replaced the actual genetic testing in the class. A science faculty member led the laboratory portion, while a genetic counselor facilitated the discussion of the ethical concepts underlying genetic counseling: autonomy, beneficence, confidentiality, and justice. In their final papers, students demonstrated an understanding of the practice guidelines established by the genetics community and acknowledged the ethical considerations inherent in p53 genotyping. Given the burgeoning market for personalized medicine, teaching undergraduates about the psychosocial and ethical dimensions of human genetic testing is important and timely. Moreover, incorporating a genetic counselor in the classroom discussion provided a rich and dynamic discussion of human genetic testing. Copyright © 2011 Wiley Periodicals, Inc.

Inherited mutations in BRCA1 and BRCA2 in an unselected multiethnic cohort of Asian patients with breast cancer and healthy controls from Malaysia.

PubMed

Wen, Wei Xiong; Allen, Jamie; Lai, Kah Nyin; Mariapun, Shivaani; Hasan, Siti Norhidayu; Ng, Pei Sze; Lee, Daphne Shin-Chi; Lee, Sheau Yee; Yoon, Sook-Yee; Lim, Joanna; Lau, Shao Yan; Decker, Brennan; Pooley, Karen; Dorling, Leila; Luccarini, Craig; Baynes, Caroline; Conroy, Don M; Harrington, Patricia; Simard, Jacques; Yip, Cheng Har; Mohd Taib, Nur Aishah; Ho, Weang Kee; Antoniou, Antonis C; Dunning, Alison M; Easton, Douglas F; Teo, Soo Hwang

2018-02-01

Genetic testing for BRCA1 and BRCA2 is offered typically to selected women based on age of onset and family history of cancer. However, current internationally accepted genetic testing referral guidelines are built mostly on data from cancer genetics clinics in women of European descent. To evaluate the appropriateness of such guidelines in Asians, we have determined the prevalence of germ line variants in an unselected cohort of Asian patients with breast cancer and healthy controls. Germ line DNA from a hospital-based study of 2575 unselected patients with breast cancer and 2809 healthy controls were subjected to amplicon-based targeted sequencing of exonic and proximal splice site junction regions of BRCA1 and BRCA2 using the Fluidigm Access Array system, with sequencing conducted on a Illumina HiSeq2500 platform. Variant calling was performed with GATK UnifiedGenotyper and were validated by Sanger sequencing. Fifty-five (2.1%) BRCA1 and 66 (2.6%) BRCA2 deleterious mutations were identified among patients with breast cancer and five (0.18%) BRCA1 and six (0.21%) BRCA2 mutations among controls. One thousand one hundred and eighty-six (46%) patients and 97 (80%) carriers fulfilled the National Comprehensive Cancer Network guidelines for genetic testing. Five per cent of unselected Asian patients with breast cancer carry deleterious variants in BRCA1 or BRCA2 . While current referral guidelines identified the majority of carriers, one in two patients would be referred for genetic services. Given that such services are largely unavailable in majority of low-resource settings in Asia, our study highlights the need for more efficient guidelines to identify at-risk individuals in Asia. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

The strains recommended for use in the bacterial reverse mutation test (OECD guideline 471) can be certified as non-genetically modified organisms.

PubMed

Sugiyama, Kei-Ichi; Yamada, Masami; Awogi, Takumi; Hakura, Atsushi

2016-01-01

The bacterial reverse mutation test, commonly called Ames test, is used worldwide. In Japan, the genetically modified organisms (GMOs) are regulated under the Cartagena Domestic Law, and organisms obtained by self-cloning and/or natural occurrence would be exempted from the law case by case. The strains of Salmonella typhimurium and Escherichia coli recommended for use in the bacterial reverse mutation test (OECD guideline 471), have been considered as non-GMOs because they can be constructed by self-cloning or naturally occurring bacterial strains, or do not disturb the biological diversity. The present article explains the reasons why these tester strains should be classified as non-GMOs.

[Practical guidelines for genetic testing in cardiovascular diseases].

PubMed

Reinhard, W; Trenkwalder, T; Schunkert, H

2017-08-01

In the last decade, genetic testing for cardiovascular disorders has become more and more relevant. Progress in molecular genetics has led to new opportunities for diagnostics, improved risk prediction and could lead to novel therapeutic approaches. Genetic diagnostic testing is relevant for both confirming a diagnosis as well as deciding on therapeutic consequences, if applicable. Furthermore, predictive testing in family members for specific cardiovascular diseases is now a standard procedure in holistic patient management. The process of genetic testing as well as documentation requirements and discussion of test results with patients are subject to legal regulations. These regulations might be confusing for clinical practitioners/cardiologists. The aim of this article is to provide a clinical framework for genetic testing. First, we explain the legal and ethical background. Second, we illustrate the process of genetic testing step by step and present updates on remuneration. Finally, we discuss the significance of genetic testing and specific disease indications in cardiology.

EMQN best practice guidelines for the molecular genetic diagnosis of hereditary hemochromatosis (HH).

PubMed

Porto, Graça; Brissot, Pierre; Swinkels, Dorine W; Zoller, Heinz; Kamarainen, Outi; Patton, Simon; Alonso, Isabel; Morris, Michael; Keeney, Steve

2016-04-01

Molecular genetic testing for hereditary hemochromatosis (HH) is recognized as a reference test to confirm the diagnosis of suspected HH or to predict its risk. The vast majority (typically >90%) of patients with clinically characterized HH are homozygous for the p.C282Y variant in the HFE gene, referred to as HFE-related HH. Since 1996, HFE genotyping was implemented in diagnostic algorithms for suspected HH, allowing its early diagnosis and prevention. However, the penetrance of disease in p.C282Y homozygotes is incomplete. Hence, homozygosity for p.C282Y is not sufficient to diagnose HH. Neither is p.C282Y homozygosity required for diagnosis as other rare forms of HH exist, generally referred to as non-HFE-related HH. These pose significant challenges when defining criteria for referral, testing protocols, interpretation of test results and reporting practices. We present best practice guidelines for the molecular genetic diagnosis of HH where recommendations are classified, as far as possible, according to the level and strength of evidence. For clarification, the guidelines' recommendations are preceded by a detailed description of the methodology and results obtained with a series of actions taken in order to achieve a wide expert consensus, namely: (i) a survey on the current practices followed by laboratories offering molecular diagnosis of HH; (ii) a systematic literature search focused on some identified controversial topics; (iii) an expert Best Practice Workshop convened to achieve consensus on the practical recommendations included in the guidelines.

EMQN best practice guidelines for the molecular genetic diagnosis of hereditary hemochromatosis (HH)

PubMed Central

Porto, Graça; Brissot, Pierre; Swinkels, Dorine W; Zoller, Heinz; Kamarainen, Outi; Patton, Simon; Alonso, Isabel; Morris, Michael; Keeney, Steve

2016-01-01

Molecular genetic testing for hereditary hemochromatosis (HH) is recognized as a reference test to confirm the diagnosis of suspected HH or to predict its risk. The vast majority (typically >90%) of patients with clinically characterized HH are homozygous for the p.C282Y variant in the HFE gene, referred to as HFE-related HH. Since 1996, HFE genotyping was implemented in diagnostic algorithms for suspected HH, allowing its early diagnosis and prevention. However, the penetrance of disease in p.C282Y homozygotes is incomplete. Hence, homozygosity for p.C282Y is not sufficient to diagnose HH. Neither is p.C282Y homozygosity required for diagnosis as other rare forms of HH exist, generally referred to as non-HFE-related HH. These pose significant challenges when defining criteria for referral, testing protocols, interpretation of test results and reporting practices. We present best practice guidelines for the molecular genetic diagnosis of HH where recommendations are classified, as far as possible, according to the level and strength of evidence. For clarification, the guidelines' recommendations are preceded by a detailed description of the methodology and results obtained with a series of actions taken in order to achieve a wide expert consensus, namely: (i) a survey on the current practices followed by laboratories offering molecular diagnosis of HH; (ii) a systematic literature search focused on some identified controversial topics; (iii) an expert Best Practice Workshop convened to achieve consensus on the practical recommendations included in the guidelines. PMID:26153218

EMQN best practice guidelines for the molecular genetic testing and reporting of chromosome 11p15 imprinting disorders: Silver–Russell and Beckwith–Wiedemann syndrome

PubMed Central

Eggermann, Katja; Bliek, Jet; Brioude, Frédéric; Algar, Elizabeth; Buiting, Karin; Russo, Silvia; Tümer, Zeynep; Monk, David; Moore, Gudrun; Antoniadi, Thalia; Macdonald, Fiona; Netchine, Irène; Lombardi, Paolo; Soellner, Lukas; Begemann, Matthias; Prawitt, Dirk; Maher, Eamonn R; Mannens, Marcel; Riccio, Andrea; Weksberg, Rosanna; Lapunzina, Pablo; Grønskov, Karen; Mackay, Deborah JG; Eggermann, Thomas

2016-01-01

Molecular genetic testing for the 11p15-associated imprinting disorders Silver–Russell and Beckwith–Wiedemann syndrome (SRS, BWS) is challenging because of the molecular heterogeneity and complexity of the affected imprinted regions. With the growing knowledge on the molecular basis of these disorders and the demand for molecular testing, it turned out that there is an urgent need for a standardized molecular diagnostic testing and reporting strategy. Based on the results from the first external pilot quality assessment schemes organized by the European Molecular Quality Network (EMQN) in 2014 and in context with activities of the European Network of Imprinting Disorders (EUCID.net) towards a consensus in diagnostics and management of SRS and BWS, best practice guidelines have now been developed. Members of institutions working in the field of SRS and BWS diagnostics were invited to comment, and in the light of their feedback amendments were made. The final document was ratified in the course of an EMQN best practice guideline meeting and is in accordance with the general SRS and BWS consensus guidelines, which are in preparation. These guidelines are based on the knowledge acquired from peer-reviewed and published data, as well as observations of the authors in their practice. However, these guidelines can only provide a snapshot of current knowledge at the time of manuscript submission and readers are advised to keep up with the literature. PMID:27165005

Recommendations regarding the genetic and immunological study of reproductive dysfunction.

PubMed

Alonso-Cerezo, María Concepción; Calero Ruiz, Mercedes; Chantada-Abal, Venancio; de la Fuente-Hernández, Luis Alfonso; García-Cobaleda, Inmaculada; García-Ochoa, Carlos; García-Sagredo, José Miguel; Nuñez, Rocío; Oliva, Rafael; Orera-Clemente, María; Pintado-Vera, David; Sanchez-Ramon, Silvia

2018-04-19

In this article several members of diverse scientific associations and reproduction experts from Spain have updated different genetic and immunological procedure recommendations in couples affected by reproductive dysfunction with the goal of providing a set of useful guidelines for the clinic. The laboratory test has been considered as highly recommendable for making clinical decisions when the result of the diagnostic test is relevant, moderately recommendable when the results are of limited evidence because they are inconsistent, and low when the benefit of the test is uncertain. It is expected that these recommendations will provide some useful guidelines for the diagnosis, prognosis and treatment of couples presenting reproductive dysfunction. Copyright © 2018 Elsevier España, S.L.U. All rights reserved.

Teaching about genetic testing issues in the undergraduate classroom: a case study.

PubMed

Rogers, Jill Cellars; Taylor, Ann T S

2011-06-01

Educating undergraduates about current genetic testing and genomics can involve novel and creative teaching practices. The higher education literature describes numerous pedagogical approaches in the laboratory designed to engage science and liberal arts students. Often these experiences involve students analyzing their own genes for various polymorphisms, some of which are associated with disease states such as an increased risk for developing cancer. While the literature acknowledges possible ethical ramifications of such laboratory exercises, authors do not present recommendations or rubrics for evaluating whether or not the testing is, in fact, ethical. In response, we developed a laboratory investigation and discussion which allowed undergraduate science students to explore current DNA manipulation techniques to isolate their p53 gene, followed by a dialogue probing the ethical implications of examining their sample for various polymorphisms. Students never conducted genotyping on their samples because of ethical concerns, so the discussion served to replace actual genetic testing in the class. A basic scientist led the laboratory portion of the assignment. A genetic counselor facilitated the discussion, which centered around existing ethical guidelines for clinical genetic testing and possible challenges of human genotyping outside the medical setting. In their final papers, students demonstrated an understanding of the practice guidelines established by the genetics community and acknowledged the ethical considerations inherent in p53 genotyping. Given the burgeoning market for personalized medicine, teaching undergraduates about the psychosocial and ethical dimensions of human gene testing seems important and timely, and introduces an additional role genetic counselors can play in educating consumers about genomics.

Genetic Testing in Clinical Settings.

PubMed

Franceschini, Nora; Frick, Amber; Kopp, Jeffrey B

2018-04-11

Genetic testing is used for screening, diagnosis, and prognosis of diseases consistent with a genetic cause and to guide drug therapy to improve drug efficacy and avoid adverse effects (pharmacogenomics). This In Practice review aims to inform about DNA-related genetic test availability, interpretation, and recommended clinical actions based on results using evidence from clinical guidelines, when available. We discuss challenges that limit the widespread use of genetic information in the clinical care setting, including a small number of actionable genetic variants with strong evidence of clinical validity and utility, and the need for improving the health literacy of health care providers and the public, including for direct-to-consumer tests. Ethical, legal, and social issues and incidental findings also need to be addressed. Because our understanding of genetic factors associated with disease and drug response is rapidly increasing and new genetic tests are being developed that could be adopted by clinicians in the short term, we also provide extensive resources for information and education on genetic testing. Copyright © 2018 National Kidney Foundation, Inc. All rights reserved.

The role of genetic testing in epilepsy diagnosis and management.

PubMed

Weber, Yvonne G; Biskup, Saskia; Helbig, Katherine L; Von Spiczak, Sarah; Lerche, Holger

2017-08-01

Epilepsy is a common neurological disorder characterized by recurrent unprovoked seizures. More than 500 epilepsy-associated genes have been described in the literature. Most of these genes play an important role in neuronal excitability, cortical development or synaptic transmission. A growing number of genetic variations have implications on diagnosis and prognostic or therapeutic advice in terms of a personalized medicine. Area covered: The review presents the different forms of genetic epilepsies with respect to their underlying genetic and functional pathophysiology and aims to give advice for recommended genetic testing. Moreover, it discusses ethical and legal guidelines, costs and technical limitations which should be considered. Expert commentary: Genetic testing is an important component in the diagnosis and treatment of many forms of epilepsy.

Creation and Implementation of an Environmental Scan to Assess Cancer Genetics Services at Three Oncology Care Settings.

PubMed

Bednar, Erica M; Walsh, Michael T; Baker, Ellen; Muse, Kimberly I; Oakley, Holly D; Krukenberg, Rebekah C; Dresbold, Cara S; Jenkinson, Sandra B; Eppolito, Amanda L; Teed, Kelly B; Klein, Molly H; Morman, Nichole A; Bowdish, Elizabeth C; Russ, Pauline; Wise, Emaline E; Cooper, Julia N; Method, Michael W; Henson, John W; Grainger, Andrew V; Arun, Banu K; Lu, Karen H

2018-05-16

An environmental scan (ES) is an efficient mixed-methods approach to collect and interpret relevant data for strategic planning and project design. To date, the ES has not been used nor evaluated in the clinical cancer genetics setting. We created and implemented an ES to inform the design of a quality improvement (QI) project to increase the rates of adherence to national guidelines for cancer genetic counseling and genetic testing at three unique oncology care settings (OCS). The ES collected qualitative and quantitative data from reviews of internal processes, past QI efforts, the literature, and each OCS. The ES used a data collection form and semi-structured interviews to aid in data collection. The ES was completed within 6 months, and sufficient data were captured to identify opportunities and threats to the QI project's success, as well as potential barriers to, and facilitators of guideline-based cancer genetics services at each OCS. Previously unreported barriers were identified, including inefficient genetic counseling appointment scheduling processes and the inability to track referrals, genetics appointments, and genetic test results within electronic medical record systems. The ES was a valuable process for QI project planning at three OCS and may be used to evaluate genetics services in other settings.

Are the kids really all right? Direct-to-consumer genetic testing in children: are company policies clashing with professional norms?

PubMed

Howard, Heidi Carmen; Avard, Denise; Borry, Pascal

2011-11-01

The genetic testing of minors within the direct-to-consumer (DTC) genetic testing (GT) context has been given relatively little attention. The issue of testing healthy children for diseases that would only develop in adulthood raises many important ethical, legal and social issues. As genetic testing is now available outside of the traditional health care system, often without even the intermediate of a health care professional, we surveyed 37 DTC GT companies regarding their policies for testing in children. Although the response rate is relatively low (35%, 13/37), our findings reveal that a clear majority of companies do perform genetic testing in minors. As such, companies testing for adult onset diseases are acting in contradiction of established professional guidelines, which state, among others, that, for predictive genetic testing, the availability of therapeutic or preventive measures is necessary for testing to be performed in asymptomatic minors. The community of stakeholders in children's health care and genetic testing should, therefore, decide which standards need to be upheld by DTC GT companies and ensure that these are met.

Knowledge of genetic testing for hereditary kidney cancer in Canada is lacking: The results of the Canadian national hereditary kidney cancer needs assessment survey

PubMed Central

Violette, Philippe D.; Kamel-Reid, Suzanne; Graham, Gail E.; Reaume, M. Neil; Jewett, Michael A.; Care, Melanie; Basiuk, Joan; Pautler, Stephen E.

2014-01-01

Introducton: Treatment of hereditary renal cell carcinoma (HRCC) requires a multidisciplinary approach that may involve medical oncologists, geneticists, genetic counsellors, and urologists. The objective of our survey was to obtain current and representative information about the use and perceived importance of genetic testing for HRCC in Canada. Methods: A self-administered web-based survey was provided to Canadian medical oncologists, geneticists, genetic counsellors, and urologists in collaboration with their respective associations. The survey was created through an iterative process in consultation with the Kidney Cancer Research Network of Canada and contained both quantitative and qualitative components. The survey was designed to be exploratory and results were compared across regions. Results: The overall response was low (6.6%). Of the respondents, 42%, 33%, 19%, 5% were genetic counsellors, urologists, medical oncologists and medical geneticists, respectively. Of the respondents, 62.7% described their practice as academic, and 37.3% described it as non-academic. Non-academic respondents tended to refer for genetic counselling less frequently than academic (48.6% vs. 67.2%). Most respondents believed that genetic testing for HRCC was available (82.8%), although 47.7% did not know which tests were available. This observation was consistent across provinces. Testing for Von Hippel-Lindau syndrome was given the highest priority among respondents. Limited provider knowledge, clinical guidelines, institutional funding, access, and poor coordination between disciplines were cited as barriers to testing. Interpretation: There is a need to increase provider knowledge of genetic testing for HRCC. These findings support the development of practice guidelines and national strategies to improve coordination of specialists and access to genetics services. Limitations of the present study include low survey response which did not allow for inferential analysis by geographic region or respondent specialty. PMID:25485012

Identification, genetic testing, and management of hereditary melanoma.

PubMed

Leachman, Sancy A; Lucero, Olivia M; Sampson, Jone E; Cassidy, Pamela; Bruno, William; Queirolo, Paola; Ghiorzo, Paola

2017-03-01

Several distinct melanoma syndromes have been defined, and genetic tests are available for the associated causative genes. Guidelines for melanoma genetic testing have been published as an informal "rule of twos and threes," but these guidelines apply to CDKN2A testing and are not intended for the more recently described non-CDKN2A melanoma syndromes. In order to develop an approach for the full spectrum of hereditary melanoma patients, we have separated melanoma syndromes into two types: "melanoma dominant" and "melanoma subordinate." Syndromes in which melanoma is a predominant cancer type are considered melanoma dominant, although other cancers, such as mesothelioma or pancreatic cancers, may also be observed. These syndromes are associated with defects in CDKN2A, CDK4, BAP1, MITF, and POT1. Melanoma-subordinate syndromes have an increased but lower risk of melanoma than that of other cancer(s) seen in the syndrome, such as breast and ovarian cancer or Cowden syndrome. Many of these melanoma-subordinate syndromes are associated with well-established predisposition genes (e.g., BRCA1/2, PTEN). It is likely that these predisposition genes are responsible for the increased susceptibility to melanoma as well but with lower penetrance than that observed for the dominant cancer(s) in those syndromes. In this review, we describe our extension of the "rule of twos and threes" for melanoma genetic testing. This algorithm incorporates an understanding of the spectrum of cancers and genes seen in association with melanoma to create a more comprehensive and tailored approach to genetic testing.

Pathways from Autism Spectrum Disorder (ASD) Diagnosis to Genetic Testing

PubMed Central

Barton, Krysta S.; Tabor, Holly K.; Starks, Helene; Garrison, Nanibaa’ A.; Laurino, Mercy; Burke, Wylie

2017-01-01

Purpose This study examines challenges faced by families and health providers related to genetic testing for autism spectrum disorder (ASD). Methods This qualitative study of 14 parents and 15 health providers identified an unstandardized three-step process for families who pursue ASD genetic testing. Results Step 1 is the clinical diagnosis of ASD, confirmed by providers practicing alone or in a team. Step 2 is the offer of genetic testing to find an etiology. For those offered testing, step 3 involves the parents’ decision whether to pursue testing. Despite professional guidelines and recommendations, interviews describe considerable variability in approaches to genetic testing for ASD, a lack of consensus among providers, and questions about clinical utility. Many families in our study were unaware of the option for genetic testing; testing decisions by parents appear to be influenced by both provider recommendations and insurance coverage. Conclusion Consideration of genetic testing for ASD should take into account different views about the clinical utility of testing and variability in insurance coverage. Ideally, policy makers from the range of clinical specialties involved in ASD care should revisit policies to clarify the purpose of genetic testing for ASD and promote consensus about its appropriate use. PMID:29048417

Pharmacogenetic tests: the need for a level playing field.

PubMed

Pirmohamed, Munir; Hughes, Dyfrig A

2013-01-01

The delivery of more personalized medicinecould be accelerated by addressing the substantial differences in the level of evidence required for the inclusion of pharmacogenetic tests in treatment guidelines, drug labelling and reimbursement schemes compared with that needed for non-genetic diagnostic tests.

Patient Education and Informed Consent for Preimplantation Genetic Diagnosis: Health Literacy for Genetics and Assisted Reproductive Technology

PubMed Central

McGowan, Michelle L.; Burant, Chris; Moran, Rocio; Farrell, Ruth

2013-01-01

Introduction Innovative applications of genetic testing have emerged within the field of assisted reproductive technology through preimplantation genetic diagnosis (PGD). As in all forms of genetic testing, adequate genetic counseling and informed consent are critical. Despite the growing recognition of the role of informed consent in genetic testing, there is little data available about how this process occurs in the setting of PGD. Methods A cross sectional study of IVF clinics offering PGD in the U.S. was conducted to assess patient education and informed consent practices. Descriptive data were collected with a self-administered survey instrument. Results More than half of the clinics offering PGD required genetic counseling prior to PGD (56%). Genetic counseling was typically performed by certified genetic counselors (84 %). Less than half (37%) of the clinics required a separate informed consent process for genetic testing of embryonic cells. At a majority of those clinics requiring a separate informed consent for genetic testing (54%), informed consent for PGD and genetic testing took place as a single event before beginning IVF procedures. Conclusions The results suggest that patient education and informed consent practices for PGD have yet to be standardized. These findings warrant the establishment of professional guidelines for patient education and informed consent specific to embryonic genetic testing. PMID:19652605

Prevention and Screening in Hereditary Breast and Ovarian Cancer.

PubMed

Zeichner, Simon B; Stanislaw, Christine; Meisel, Jane L

2016-10-15

In recent years, we have learned a great deal about pathogenic mutations that increase the risk of breast and ovarian cancer, particularly mutations in the BRCA1 and BRCA2 genes. Here we review current guidelines on breast and ovarian cancer screening, prophylactic surgery, and other risk-reduction strategies in patients with these mutations, and we detail the data that drive these recommendations. We also discuss guidelines on screening and management for other cancers associated with BRCA1 and BRCA2, such as male breast cancer, pancreatic cancer, and prostate cancer. Discussions about genetic testing have become more complex with the advent of panel testing, which often allows for testing of a more comprehensive panel of genes than traditional BRCA1 and BRCA2 testing, but which is also associated with a higher likelihood of obtaining results with less clear data to inform management. It is difficult to come to a consensus on how best to address the varied and potentially challenging situations that may arise from genetic testing. The complexity inherent in managing these cases makes a multidisciplinary team-including medical oncologists, surgical oncologists, genetic counselors, reproductive endocrinologists, and medical ethicists-critical to optimization of care.

Community Involvement in Developing Policies for Genetic Testing: Assessing the Interests and Experiences of Individuals Affected by Genetic Conditions

PubMed Central

Gollust, Sarah E.; Apse, Kira; Fuller, Barbara P.; Miller, Paul Steven; Biesecker, Barbara B.

2005-01-01

Because the introduction of genetic testing into clinical medicine and public health creates concerns for the welfare of individuals affected with genetic conditions, those individuals should have a role in policy decisions about testing. Mechanisms for promoting participation range from membership on advisory committees to community dialogues to surveys that provide evidence for supporting practice guidelines. Surveys can assess the attitudes and the experiences of members of an affected group and thus inform discussions about that community’s concerns regarding the appropriate use of a genetic test. Results of a survey of individuals affected with inherited dwarfism show how data can be used in policy and clinical-practice contexts. Future research of affected communities’ interests should be pursued so that underrepresented voices can be heard. PMID:15623855

Multi-disciplinary summit on genetics services for women with gynecologic cancers: A Society of Gynecologic Oncology White Paper.

PubMed

Randall, Leslie M; Pothuri, Bhavana; Swisher, Elizabeth M; Diaz, John P; Buchanan, Adam; Witkop, Catherine T; Bethan Powell, C; Smith, Ellen Blair; Robson, Mark E; Boyd, Jeff; Coleman, Robert L; Lu, Karen

2017-08-01

To assess current practice, advise minimum standards, and identify educational gaps relevant to genetic screening, counseling, and testing of women affected by gynecologic cancers. The Society of Gynecologic Oncology (SGO) organized a multidisciplinary summit that included representatives from the American College of Obstetricians and Gynecologists (ACOG), the American Society Clinical Oncology (ASCO), the National Society of Genetic Counselors (NSGC), and patient advocacy groups, BrightPink and Facing our Risk of Cancer Empowered (FORCE). Three subject areas were discussed: care delivery models for genetic testing, barriers to genetic testing, and educational opportunities for providers of genetic testing. The group endorsed current SGO, National Comprehensive Cancer Network (NCCN), and NSGC genetic testing guidelines for women affected with ovarian, tubal, peritoneal cancers, or DNA mismatch repair deficient endometrial cancer. Three main areas of unmet need were identified: timely and universal genetic testing for women with ovarian, fallopian tube, and peritoneal cancers; education regarding minimum standards for genetic counseling and testing; and barriers to implementation of testing of both affected individuals as well as cascade testing of family members. Consensus building among all stakeholders resulted in an action plan to address gaps in education of gynecologic oncology providers and delivery of cancer genetics care. Copyright © 2017. Published by Elsevier Inc.

Lysosomal storage diseases: diagnostic confirmation and management of presymptomatic individuals.

PubMed

Wang, Raymond Y; Bodamer, Olaf A; Watson, Michael S; Wilcox, William R

2011-05-01

To develop educational guidelines for the diagnostic confirmation and management of individuals identified by newborn screening, family-based testing after proband identification, or carrier testing in at-risk populations, and subsequent prenatal or postnatal testing of those who are presymptomatic for a lysosomal storage disease. Review of English language literature and discussions in a consensus development panel comprised an international group of experts in the clinical and laboratory diagnosis, treatment and management, newborn screening, and genetic aspects of lysosomal storage diseases. Although clinical trial and longitudinal data were used when available, the evidence in the literature is limited and consequently the recommendations must be considered as expert opinion. Guidelines were developed for Fabry, Gaucher, and Niemann-Pick A/B diseases, glycogen storage type II (Pompe disease), globoid cell leukodystrophy (Krabbe disease), metachromatic leukodystrophy, and mucopolysaccharidoses types I, II, and VI. These guidelines serve as an educational resource for confirmatory testing and subsequent clinical management of presymptomatic individuals suspected to have a lysosomal storage disease; they also help to define a research agenda for longitudinal studies such as the American College of Medical Genetics/National Institutes of Health Newborn Screening Translational Research Network.

Health-related direct-to-consumer genetic testing: a review of companies' policies with regard to genetic testing in minors.

PubMed

Borry, Pascal; Howard, Heidi C; Sénécal, Karine; Avard, Denise

2010-03-01

More and more companies are advertising and selling genetic tests directly to consumers. Considering the ethical, legal, and psychological concerns surrounding genetic testing in minors, a study of companies' websites was performed in order to describe and analyze their policies with respect to this issue. Of the 29 companies analyzed, 13 did not provide any information about this matter, eight companies allowed genetic testing upon parental request, four companies stated that their website is not directed to children under 18 years, and four companies suggested that in order to be tested, applicants should have reached the age of legal majority. If private companies offer genetic tests which are also offered in a clinical setting, can they be expected to adhere to the existing clinical guidelines with regard to these tests? If so, a certain ambiguity exists. Many companies are emphasizing in their disclaimers that their services are not medical services and should not be used as a basis for making medical decisions. Nonetheless, it remains debatable whether genetic testing in minors would be appropriate in this context. In line with the Advisory Committee on Genetic Testing, the Human Genetics Commission addressed the problem of non-consensual testing and recommended not to supply genetic testing services directly to those under the age of 16 or to those not able to make a competent decision regarding testing.

40 CFR 798.5200 - Mouse visible specific locus test.

Code of Federal Regulations, 2010 CFR

2010-07-01

... control groups. (4) Control groups—(i) Concurrent controls. The use of positive or spontaneous controls is... control groups. (ii) Test chemical vehicle, doses used and rationale for dose selection, toxicity data... SUBSTANCES CONTROL ACT (CONTINUED) HEALTH EFFECTS TESTING GUIDELINES Genetic Toxicity § 798.5200 Mouse...

40 CFR 798.5200 - Mouse visible specific locus test.

Code of Federal Regulations, 2013 CFR

2013-07-01

... control groups. (4) Control groups—(i) Concurrent controls. The use of positive or spontaneous controls is... control groups. (ii) Test chemical vehicle, doses used and rationale for dose selection, toxicity data... SUBSTANCES CONTROL ACT (CONTINUED) HEALTH EFFECTS TESTING GUIDELINES Genetic Toxicity § 798.5200 Mouse...

40 CFR 798.5200 - Mouse visible specific locus test.

Code of Federal Regulations, 2012 CFR

2012-07-01

... control groups. (4) Control groups—(i) Concurrent controls. The use of positive or spontaneous controls is... control groups. (ii) Test chemical vehicle, doses used and rationale for dose selection, toxicity data... SUBSTANCES CONTROL ACT (CONTINUED) HEALTH EFFECTS TESTING GUIDELINES Genetic Toxicity § 798.5200 Mouse...

40 CFR 798.5200 - Mouse visible specific locus test.

Code of Federal Regulations, 2014 CFR

2014-07-01

... control groups. (4) Control groups—(i) Concurrent controls. The use of positive or spontaneous controls is... control groups. (ii) Test chemical vehicle, doses used and rationale for dose selection, toxicity data... SUBSTANCES CONTROL ACT (CONTINUED) HEALTH EFFECTS TESTING GUIDELINES Genetic Toxicity § 798.5200 Mouse...

40 CFR 798.5200 - Mouse visible specific locus test.

Code of Federal Regulations, 2011 CFR

2011-07-01

... control groups. (4) Control groups—(i) Concurrent controls. The use of positive or spontaneous controls is... control groups. (ii) Test chemical vehicle, doses used and rationale for dose selection, toxicity data... SUBSTANCES CONTROL ACT (CONTINUED) HEALTH EFFECTS TESTING GUIDELINES Genetic Toxicity § 798.5200 Mouse...

Recommendations for the use of microarrays in prenatal diagnosis.

PubMed

Suela, Javier; López-Expósito, Isabel; Querejeta, María Eugenia; Martorell, Rosa; Cuatrecasas, Esther; Armengol, Lluis; Antolín, Eugenia; Domínguez Garrido, Elena; Trujillo-Tiebas, María José; Rosell, Jordi; García Planells, Javier; Cigudosa, Juan Cruz

2017-04-07

Microarray technology, recently implemented in international prenatal diagnosis systems, has become one of the main techniques in this field in terms of detection rate and objectivity of the results. This guideline attempts to provide background information on this technology, including technical and diagnostic aspects to be considered. Specifically, this guideline defines: the different prenatal sample types to be used, as well as their characteristics (chorionic villi samples, amniotic fluid, fetal cord blood or miscarriage tissue material); variant reporting policies (including variants of uncertain significance) to be considered in informed consents and prenatal microarray reports; microarray limitations inherent to the technique and which must be taken into account when recommending microarray testing for diagnosis; a detailed clinical algorithm recommending the use of microarray testing and its introduction into routine clinical practice within the context of other genetic tests, including pregnancies in families with a genetic history or specific syndrome suspicion, first trimester increased nuchal translucency or second trimester heart malformation and ultrasound findings not related to a known or specific syndrome. This guideline has been coordinated by the Spanish Association for Prenatal Diagnosis (AEDP, «Asociación Española de Diagnóstico Prenatal»), the Spanish Human Genetics Association (AEGH, «Asociación Española de Genética Humana») and the Spanish Society of Clinical Genetics and Dysmorphology (SEGCyD, «Sociedad Española de Genética Clínica y Dismorfología»). Copyright © 2017 Elsevier España, S.L.U. All rights reserved.

Pulmonary arterial hypertension: Specialists’ knowledge, practices, and attitudes of genetic counseling and genetic testing in the USA

PubMed Central

Jacher, Joseph E.; Martin, Lisa J.; Chung, Wendy K.; Loyd, James E.; Nichols, William C.

2017-01-01

Pulmonary arterial hypertension (PAH) is characterized by obstruction of pre-capillary pulmonary arteries, which leads to sustained elevation of pulmonary arterial pressure. Identifying those at risk through early interventions, such as genetic testing, may mitigate disease course. Current practice guidelines recommend genetic counseling and offering genetic testing to individuals with heritable PAH, idiopathic PAH, and their family members. However, it is unclear if PAH specialists follow these recommendations. Thus, our research objective was to determine PAH specialists’ knowledge, utilization, and perceptions about genetic counseling and genetic testing. A survey was designed and distributed to PAH specialists who primarily work in the USA to assess their knowledge, practices, and attitudes about the genetics of PAH. Participants’ responses were analyzed using parametric and non-parametric statistics and groups were compared using the Wilcoxon rank sum test. PAH specialists had low perceived and actual knowledge of the genetics of PAH, with 13.2% perceiving themselves as knowledgeable and 27% actually being knowledgeable. Although these specialists had positive or ambivalent attitudes about genetic testing and genetic counseling, they had poor utilization of these genetic services, with almost 80% of participants never or rarely ordering genetic testing or referring their patients with PAH for genetic counseling. Physicians were more knowledgeable, but had lower perceptions of the value of genetic testing and genetic counseling compared to non-physicians (P < 0.05). The results suggest that increased education and awareness is needed about the genetics of PAH as well as the benefits of genetic testing and genetic counseling for individuals who treat patients with PAH. PMID:28597770

[Quality of genetic services--analysis of medical genetic expert opinions solicited by private health insurance companies].

PubMed

Nippert, Reinhardt Peter; Schmidtke, Jörg

2012-01-01

Service quality for patients with genetic conditions can be assessed through the analysis of clinical genetic data sets, as was the case in this study. It represents a secondary analysis of a compilation of a single genetic expert's medical opinions covering the years 2000 to 2009, solicited by private health insurance companies with the intention of probing into medical necessity and adequacy of genetic testing ordered by physicians. Genetic testing has become an increasingly important part of clinical diagnostic services. Controlling these services does not only reduce costs but also saves patients from unwarranted over-utilisation. Therefore, the reasons given by doctors when ordering genetic tests are part of the quality of service delivery. The study revealed that more than 30% of the molecular genetic tests ordered lack sound medical reasoning and 30% of the cases studied show violation or neglect of guidelines and recommendations for diagnostic procedures with respect to genetic testing. In essence, the findings indicate a need for human genetic information among physicians. Their professional organisations are called upon to design and offer CME/CPD programmes in medical genetics to maintain and continually improve the quality of medical genetic care for patients with genetic conditions. Copyright © 2012. Published by Elsevier GmbH.

Patients with Amyotrophic Lateral Sclerosis Have High Interest in and Limited Access to Genetic Testing.

PubMed

Wagner, Karin N; Nagaraja, Haikady; Allain, Dawn C; Quick, Adam; Kolb, Stephen; Roggenbuck, Jennifer

2017-06-01

Although genetic testing for amyotrophic lateral sclerosis (ALS) is widely available, it is unknown what proportion of patients with ALS have access to genetic counseling and testing, and patient attitudes towards ALS genetic testing have not been studied. We conducted a national survey of ALS patients enrolled in the Agency for Toxic Substances and Disease Registry, which consisted of multiple choice questions and two 12 item Likert scale series assessing respondents' experience with and attitude toward genetic testing. The survey had an 8 % response rate, with 449 completed responses. Genetic testing was offered to 33.4 % and completed by 67.1 % of those offered. A minority of respondents (12.5 %) saw a genetic counselor, and were much more likely to be offered genetic testing (p = 0.0001). Respondents with a family history of ALS (8.4 %) were more likely to be offered testing (p = 0.0001) and complete testing (p = 0.05). Respondents with a family history of ALS were more likely to report a favorable attitude towards genetic testing (p = 0.0003), as were respondents who saw a genetic counselor (p = 0.02). The majority of respondents (82.7 %) felt that genetic testing should be offered to all patients with ALS. Our results indicate that ALS patients may have limited access to genetic testing, but perceive benefit from this service. Development of practice guidelines for genetic testing in ALS, to include the routine offer of genetic counseling, may result in broader and more consistent access to these services.

High burden of genetic conditions diagnosed in a cardiac neurodevelopmental clinic.

PubMed

Goldenberg, Paula C; Adler, Betsy J; Parrott, Ashley; Anixt, Julia; Mason, Karen; Phillips, Jannel; Cooper, David S; Ware, Stephanie M; Marino, Bradley S

2017-04-01

There is a known high prevalence of genetic and clinical syndrome diagnoses in the paediatric cardiac population. These disorders often have multisystem effects, which may have an important impact on neurodevelopmental outcomes. Taken together, these facts suggest that patients and families may benefit from consultation by genetic specialists in a cardiac neurodevelopmental clinic. This study assessed the burden of genetic disorders and utility of genetics evaluation in a cardiac neurodevelopmental clinic. A retrospective chart review was conducted of patients evaluated in a cardiac neurodevelopmental clinic from 6 December, 2011 to 16 April, 2013. All patients were seen by a cardiovascular geneticist with genetic counselling support. A total of 214 patients were included in this study; 64 of these patients had a pre-existing genetic or syndromic diagnosis. Following genetics evaluation, an additional 19 were given a new clinical or laboratory-confirmed genetic diagnosis including environmental such as teratogenic exposures, malformation associations, chromosomal disorders, and single-gene disorders. Genetic testing was recommended for 112 patients; radiological imaging to screen for congenital anomalies for 17 patients; subspecialist medical referrals for 73 patients; and non-genetic clinical laboratory testing for 14 patients. Syndrome-specific guidelines were available and followed for 25 patients with known diagnosis. American Academy of Pediatrics Red Book asplenia guideline recommendations were given for five heterotaxy patients, and family-based cardiac screening was recommended for 23 families affected by left ventricular outflow tract obstruction. Genetics involvement in a cardiac neurodevelopmental clinic is helpful in identifying new unifying diagnoses and providing syndrome-specific care, which may impact the patient's overall health status and neurodevelopmental outcome.

Statement of the ESHG on direct-to-consumer genetic testing for health-related purposes

PubMed Central

2010-01-01

Many private companies offer direct-to-consumer (DTC) genetic testing services. Some tests may detect severe and highly penetrant monogenic disorders, while other tests are for genetic variants found associated with increased susceptibility for common and complex diseases in large-scale population studies. Through its Public and Professional Policy committee followed by member and expert consultation, the European Society of Human Genetics has developed the following policy on advertising and provision of predictive genetic tests by such DTC companies: (1) clinical utility of a genetic test shall be an essential criterion for deciding to offer this test to a person or a group of persons; (2) laboratories providing genetic tests should comply with accepted quality standards, including those regarding laboratory personnel qualifications; (3) information about the purpose and appropriateness of testing should be given before the test is done; (4) genetic counselling appropriate to the type of test and disease should be offered; and for some tests psychosocial evaluation and follow-up should be available; (5) privacy and confidentiality of sensitive genetic information should be secured and the data safely guarded; (6) special measures should be taken to avoid inappropriate testing of minors and other legally incapacitated persons; (7) all claims regarding genetic tests should be transparent; advertisement should be unbiased and marketing of genetic tests should be fair; (8) in biomedical research, health care and marketing, respect should be given to relevant ethical principles, as well as international treaties and recommendations regarding genetic testing; and (9) nationally approved guidelines considering all the above-mentioned aspects should be made and followed. PMID:20736974

Joint SOGC-CCMG Opinion for Reproductive Genetic Carrier Screening: An Update for All Canadian Providers of Maternity and Reproductive Healthcare in the Era of Direct-to-Consumer Testing.

PubMed

Wilson, R Douglas; De Bie, Isabelle; Armour, Christine M; Brown, Richard N; Campagnolo, Carla; Carroll, June C; Okun, Nan; Nelson, Tanya; Zwingerman, Rhonda; Audibert, Francois; Brock, Jo-Ann; Brown, Richard N; Campagnolo, Carla; Carroll, June C; De Bie, Isabelle; Johnson, Jo-Ann; Okun, Nan; Pastruck, Melanie; Vallée-Pouliot, Karine; Wilson, R Douglas; Zwingerman, Rhonda; Armour, Christine; Chitayat, David; De Bie, Isabelle; Fernandez, Sara; Kim, Raymond; Lavoie, Josee; Leonard, Norma; Nelson, Tanya; Taylor, Sherry; Van Allen, Margot; Van Karnebeek, Clara

2016-08-01

This guideline was written to update Canadian maternity care and reproductive healthcare providers on pre- and postconceptional reproductive carrier screening for women or couples who may be at risk of being carriers for autosomal recessive (AR), autosomal dominant (AD), or X-linked (XL) conditions, with risk of transmission to the fetus. Four previous SOGC- Canadian College of Medical Geneticists (CCMG) guidelines are updated and merged into the current document. All maternity care (most responsible health provider [MRHP]) and paediatric providers; maternity nursing; nurse practitioner; provincial maternity care administrator; medical student; and postgraduate resident year 1-7. Fertile, sexually active females and their fertile, sexually active male partners who are either planning a pregnancy or are pregnant (preferably in the first trimester of pregnancy, but any gestational age is acceptable). Women and their partners will be able to obtain appropriate genetic carrier screening information and possible diagnosis of AR, AD, or XL disorders (preferably pre-conception), thereby allowing an informed choice regarding genetic carrier screening and reproductive options (e.g., prenatal diagnosis, preimplantation genetic diagnosis, egg or sperm donation, or adoption). Informed reproductive decisions related to genetic carrier screening and reproductive outcomes based on family history, ethnic background, past obstetrical history, known carrier status, or genetic diagnosis. SOGC REPRODUCTIVE CARRIER SCREENING SUMMARY STATEMENT (2016): Pre-conception or prenatal education and counselling for reproductive carrier screening requires a discussion about testing within the three perinatal genetic carrier screening/diagnosis time periods, which include pre-conception, prenatal, and neonatal for conditions currently being screened for and diagnosed. This new information should be added to the standard reproductive carrier screening protocols that are already being utilized by the most responsible maternity provider through the informed consent process with the patient. (III-A; GRADE low/moderate) SOGC OVERVIEW OF RECOMMENDATIONS QUALITY AND GRADE: There was a strong observational/expert opinion (quality and grade) for the genetic carrier literature with randomized controlled trial evidence being available only for the invasive testing. Both the Canadian Task Force on Preventive Health Care quality and classification and the GRADE evidence quality and grade are provided. MEDLINE; PubMed; government neonatal screening websites; key words/common reproductive genetic carrier screened diseases/previous SOGC Guidelines/medical academic societies (Society of Maternal-Fetal Medicine [SMFM]; American College of Medical Genetics and Genomics; American College of Obstetricians and Gynecologists [ACOG]; CCMG; Royal College Obstetrics and Gynaecology [RCOG] [UK]; American Society of Human Genetics [ASHG]; International Society of Prenatal Diagnosis [ISPD])/provincial neonatal screening policies and programs; search terms (carrier screening, prenatal screening, neonatal genetic/metabolic screening, cystic fibrosis (CF), thalassemia, hemoglobinopathy, hemophilia, Fragile X syndrome (FXS), spinal muscular atrophy, Ashkenazi Jewish carrier screening, genetic carrier screening protocols, AR, AD, XL). 10 years (June 2005-September 2015); initial search dates June 30, 2015 and September 15, 2015; completed final search January 4, 2016. Validation of articles was completed by primary authors RD Wilson and I De Bie. Benefits are to provide an evidenced based reproductive genetic carrier screening update consensus based on international opinions and publications for the use of Canadian women, who are planning a pregnancy or who are pregnant and have been identified to be at risk (personal or male partner family or reproductive history) for the transmission of a clinically significant genetic condition to their offspring with associated morbidity and/or mortality. Harm may arise from having counselling and informed testing of the carrier status of the mother, their partner, or their fetus, as well as from declining to have this counselling and informed testing or from not having the opportunity for counselling and informed testing. Costs will ensue both from the provision of opportunities for counselling and testing, as well as when no such opportunities are offered or are declined and the birth of a child with a significant inherited condition and resulting morbidity/mortality occurs; these comprise not only the health care costs to the system but also the social/financial/psychological/emotional costs to the family. These recommendations are based on expert opinion and have not been subjected to a health economics assessment and local or provincial implementation will be required. This guideline is an update of four previous joint SOGC-CCMG Genetic Screening Guidelines dated 2002, 2006, 2008, and 2008 developed by the SOGC Genetic Committee in collaboration with the CCMG Prenatal Diagnosis Committee (now Clinical Practice Committee). 2016 CARRIER SCREENING RECOMMENDATIONS. Copyright © 2016 The Society of Obstetricians and Gynaecologists of Canada/La Société des obstétriciens et gynécologues du Canada. Published by Elsevier Inc. All rights reserved.

Molecular Testing of Brain Tumor

PubMed Central

Park, Sung-Hye; Won, Jaekyung; Kim, Seong-Ik; Lee, Yujin; Park, Chul-Kee; Kim, Seung-Ki; Choi, Seung-Hong

2017-01-01

The World Health Organization (WHO) classification of central nervous system (CNS) tumors was revised in 2016 with a basis on the integrated diagnosis of molecular genetics. We herein provide the guidelines for using molecular genetic tests in routine pathological practice for an accurate diagnosis and appropriate management. While astrocytomas and IDH-mutant (secondary) glioblastomas are characterized by the mutational status of IDH, TP53, and ATRX, oligodendrogliomas have a 1p/19q codeletion and mutations in IDH, CIC, FUBP1, and the promoter region of telomerase reverse transcriptase (TERTp). IDH-wildtype (primary) glioblastomas typically lack mutations in IDH, but are characterized by copy number variations of EGFR, PTEN, CDKN2A/B, PDGFRA, and NF1 as well as mutations of TERTp. High-grade pediatric gliomas differ from those of adult gliomas, consisting of mutations in H3F3A, ATRX, and DAXX, but not in IDH genes. In contrast, well-circumscribed low-grade neuroepithelial tumors in children, such as pilocytic astrocytoma, pleomorphic xanthoastrocytoma, and ganglioglioma, often have mutations or activating rearrangements in the BRAF, FGFR1, and MYB genes. Other CNS tumors, such as ependymomas, neuronal and glioneuronal tumors, embryonal tumors, meningothelial, and other mesenchymal tumors have important genetic alterations, many of which are diagnostic, prognostic, and predictive markers and therapeutic targets. Therefore, the neuropathological evaluation of brain tumors is increasingly dependent on molecular genetic tests for proper classification, prediction of biological behavior and patient management. Identifying these gene abnormalities requires cost-effective and high-throughput testing, such as next-generation sequencing. Overall, this paper reviews the global guidelines and diagnostic algorithms for molecular genetic testing of brain tumors. PMID:28535583

Exploring the possibility of modeling a genetic counseling guideline using agile methodology.

PubMed

Choi, Jeeyae

2013-01-01

Increased demand of genetic counseling services heightened the necessity of a computerized genetic counseling decision support system. In order to develop an effective and efficient computerized system, modeling of genetic counseling guideline is an essential step. Throughout this pilot study, Agile methodology with United Modeling Language (UML) was utilized to model a guideline. 13 tasks and 14 associated elements were extracted. Successfully constructed conceptual class and activity diagrams revealed that Agile methodology with UML was a suitable tool to modeling a genetic counseling guideline.

Barriers and Facilitators to Adoption of Genomic Services for Colorectal Care within the Veterans Health Administration.

PubMed

Sperber, Nina R; Andrews, Sara M; Voils, Corrine I; Green, Gregory L; Provenzale, Dawn; Knight, Sara

2016-04-28

We examined facilitators and barriers to adoption of genomic services for colorectal care, one of the first genomic medicine applications, within the Veterans Health Administration to shed light on areas for practice change. We conducted semi-structured interviews with 58 clinicians to understand use of the following genomic services for colorectal care: family health history documentation, molecular and genetic testing, and genetic counseling. Data collection and analysis were informed by two conceptual frameworks, the Greenhalgh Diffusion of Innovation and Andersen Behavioral Model, to allow for concurrent examination of both access and innovation factors. Specialists were more likely than primary care clinicians to obtain family history to investigate hereditary colorectal cancer (CRC), but with limited detail; clinicians suggested templates to facilitate retrieval and documentation of family history according to guidelines. Clinicians identified advantage of molecular tumor analysis prior to genetic testing, but tumor testing was infrequently used due to perceived low disease burden. Support from genetic counselors was regarded as facilitative for considering hereditary basis of CRC diagnosis, but there was variability in awareness of and access to this expertise. Our data suggest the need for tools and policies to establish and disseminate well-defined processes for accessing services and adhering to guidelines.

Developing Alnus for use in intensive culture

Treesearch

Richard B. Hall; Gregory A. Miller; Terry L. Robison; Oghenekome U. Onokpise

1983-01-01

Provenance tests and one clonal test have been analyzed to provide guidelines for the continuing efforts on the genetic improvement of Alnus. Observations also are made on the need for experiments with other silvicultural alternatives that might be applied to the intensive culture of alders.

General considerations in testing and evaluating crop varieties for agroforestry systems

Treesearch

Lolita N. Ragus

1993-01-01

Introduction of new crops in agroforestry is often suggested as a way to improve productivity. This paper provides general guidelines in selecting companion plant combinations and general considerations in evaluating, testing, naming, maintaining genetic purity and distributing crop varieties to farmers.

Challenges in managing genetic cancer risk: a long-term qualitative study of unaffected women carrying BRCA1/BRCA2 mutations.

PubMed

Caiata-Zufferey, Maria; Pagani, Olivia; Cina, Viviane; Membrez, Véronique; Taborelli, Monica; Unger, Sheila; Murphy, Anne; Monnerat, Christian; Chappuis, Pierre O

2015-09-01

Women carrying BRCA1/BRCA2 germ-line mutations have an increased risk of developing breast/ovarian cancer. To minimize this risk, international guidelines recommend lifelong surveillance and preventive measures. This study explores the challenges that unaffected women genetically predisposed to breast/ovarian cancer face in managing their risk over time and the psychosocial processes behind these challenges. Between 2011 and 2013, biographical qualitative interviews were conducted in Switzerland with 32 unaffected French- and Italian-speaking women carrying BRCA1/BRCA2 mutations. Their mutation status had been known for at least 3 years (mean, 6 years). Data were analyzed through constant comparative analysis using software for qualitative analysis. From the time these women received their positive genetic test results, they were encouraged to follow medical guidelines. Meanwhile, their adherence to these guidelines was constantly questioned by their social and medical environments. As a result of these contradictory pressures, BRCA1/BRCA2 mutation carriers experienced a sense of disorientation about the most appropriate way of dealing with genetic risk. Given the contradictory attitudes of health-care professionals in caring for unaffected BRCA1/BRCA2 mutation carriers, there is an urgent need to educate physicians in dealing with genetically at-risk women and to promote a shared representation of this condition among them.Genet Med 17 9, 726-732.

Attitudes and Practices Among Internists Concerning Genetic Testing

PubMed Central

Chung, Wendy; Marder, Karen; Shanmugham, Anita; Chin, Lisa J.; Stark, Meredith; Leu, Cheng-Shiun; Appelbaum, Paul S.

2012-01-01

Many questions remain concerning whether, when, and how physicians order genetic tests, and what factors are involved in their decisions. We surveyed 220 internists from two academic medical centers about their utilization of genetic testing. Rates of genetic utilizations varied widely by disease. Respondents were most likely to have ordered tests for Factor V Leiden (16.8%), followed by Breast/Ovarian Cancer (15.0%). In the past 6 months, 65% had counseled patients on genetic issues, 44% had ordered genetic tests, 38.5% had referred patients to a genetic counselor or geneticist, and 27.5% had received ads from commercial labs for genetic testing. Only 4.5% had tried to hide or disguise genetic information, and <2% have had patients report genetic discrimination. Only 53.4% knew of a geneticist/genetic counselor to whom to refer patients. Most rated their knowledge as very/somewhat poor concerning genetics (73.7%) and guidelines for genetic testing (87.1%). Most felt needs for more training on when to order tests (79%), and how to counsel patients (82%), interpret results (77.3%), and maintain privacy (80.6%). Physicians were more likely to have ordered a genetic test if patients inquired about genetic testing (p<.001), and if physicians had a geneticist/genetic counselor to whom to refer patients (p<.002), had referred patients to a geneticist/genetic counselor in the past 6 months, had more comfort counseling patients about testing (p<.019), counseled patients about genetics, larger practices (p<.032), fewer African-American patients (p<.027), and patients who had reported genetic discrimination (p<.044). In a multiple logistic regression, ordering a genetic test was associated with patients inquiring about testing, having referred patients to a geneticist/genetic counselor and knowing how to order tests., These data suggest that physicians recognize their knowledge deficits, and are interested in training. These findings have important implications for future medical practice, research, and education. PMID:22585186

Role of Genetic Testing for Inherited Prostate Cancer Risk: Philadelphia Prostate Cancer Consensus Conference 2017.

PubMed

Giri, Veda N; Knudsen, Karen E; Kelly, William K; Abida, Wassim; Andriole, Gerald L; Bangma, Chris H; Bekelman, Justin E; Benson, Mitchell C; Blanco, Amie; Burnett, Arthur; Catalona, William J; Cooney, Kathleen A; Cooperberg, Matthew; Crawford, David E; Den, Robert B; Dicker, Adam P; Eggener, Scott; Fleshner, Neil; Freedman, Matthew L; Hamdy, Freddie C; Hoffman-Censits, Jean; Hurwitz, Mark D; Hyatt, Colette; Isaacs, William B; Kane, Christopher J; Kantoff, Philip; Karnes, R Jeffrey; Karsh, Lawrence I; Klein, Eric A; Lin, Daniel W; Loughlin, Kevin R; Lu-Yao, Grace; Malkowicz, S Bruce; Mann, Mark J; Mark, James R; McCue, Peter A; Miner, Martin M; Morgan, Todd; Moul, Judd W; Myers, Ronald E; Nielsen, Sarah M; Obeid, Elias; Pavlovich, Christian P; Peiper, Stephen C; Penson, David F; Petrylak, Daniel; Pettaway, Curtis A; Pilarski, Robert; Pinto, Peter A; Poage, Wendy; Raj, Ganesh V; Rebbeck, Timothy R; Robson, Mark E; Rosenberg, Matt T; Sandler, Howard; Sartor, Oliver; Schaeffer, Edward; Schwartz, Gordon F; Shahin, Mark S; Shore, Neal D; Shuch, Brian; Soule, Howard R; Tomlins, Scott A; Trabulsi, Edouard J; Uzzo, Robert; Vander Griend, Donald J; Walsh, Patrick C; Weil, Carol J; Wender, Richard; Gomella, Leonard G

2018-02-01

Purpose Guidelines are limited for genetic testing for prostate cancer (PCA). The goal of this conference was to develop an expert consensus-driven working framework for comprehensive genetic evaluation of inherited PCA in the multigene testing era addressing genetic counseling, testing, and genetically informed management. Methods An expert consensus conference was convened including key stakeholders to address genetic counseling and testing, PCA screening, and management informed by evidence review. Results Consensus was strong that patients should engage in shared decision making for genetic testing. There was strong consensus to test HOXB13 for suspected hereditary PCA, BRCA1/2 for suspected hereditary breast and ovarian cancer, and DNA mismatch repair genes for suspected Lynch syndrome. There was strong consensus to factor BRCA2 mutations into PCA screening discussions. BRCA2 achieved moderate consensus for factoring into early-stage management discussion, with stronger consensus in high-risk/advanced and metastatic setting. Agreement was moderate to test all men with metastatic castration-resistant PCA, regardless of family history, with stronger agreement to test BRCA1/2 and moderate agreement to test ATM to inform prognosis and targeted therapy. Conclusion To our knowledge, this is the first comprehensive, multidisciplinary consensus statement to address a genetic evaluation framework for inherited PCA in the multigene testing era. Future research should focus on developing a working definition of familial PCA for clinical genetic testing, expanding understanding of genetic contribution to aggressive PCA, exploring clinical use of genetic testing for PCA management, genetic testing of African American males, and addressing the value framework of genetic evaluation and testing men at risk for PCA-a clinically heterogeneous disease.

The Changing Landscape of Genetic Testing for Inherited Breast Cancer Predisposition.

PubMed

Afghahi, Anosheh; Kurian, Allison W

2017-05-01

The advent of multiple-gene germline panel testing has led to significant advances in hereditary breast and ovarian cancer risk assessment. These include guideline-specific cancer risk management recommendations for patients and their families, such as screening with breast magnetic resonance imaging and risk-reducing surgeries, which have the potential to reduce substantially the morbidity and mortality associated with a hereditary cancer predisposition. However, controversy remains about the clinical validity and actionability of genetic testing in a broader patient population. We discuss events leading to the wider availability of commercialized multiple-gene germline panel testing, the recent data that support using this powerful tool to improve cancer risk assessment and reduction strategies, and remaining challenges to clinical optimization of this new genetic technology.

Revisiting sweat chloride test results based on recent guidelines for diagnosis of cystic fibrosis.

PubMed

Pagaduan, Jayson V; Ali, Mahesheema; Dowlin, Michael; Suo, Liye; Ward, Tabitha; Ruiz, Fadel; Devaraj, Sridevi

2018-03-01

Recent sweat chloride guidelines published by the Cystic Fibrosis Foundation changed the intermediate sweat chloride concentration range from 40-59 mmol/L to 30-59 mmol/L for age > 6 months. We wanted to know how this new guideline would impact detection of cystic fibrosis among patients who previously had sweat tests done at Texas Children's Hospital. We revisited sweat chloride test results (n = 3012) in the last 5 years at Texas Children's Hospital based on the new guidelines on diagnosis of cystic fibrosis from the Cystic Fibrosis Foundation. We identified 125 patients that would be reclassified in the intermediate sweat chloride value with the new guidelines that were classified as "unlikely to have CF" in the previous guidelines. 8 (32%) patients with CFTR gene testing were positive for CFTR gene mutation(s). 4 (50%) of these patients were identified to have 2 CFTR mutations. One had variant combination that was reported to cause CF but all were diagnosed with CFTR-related metabolic syndrome. Our findings concur with the new CF diagnosis guidelines that changing the intermediate cut-off to 30-59 mmol/L sweat chloride concentration in combination with CFTR genetic analysis enhances the probability of identifying individuals that have risk of developing CF or have CF and enables for earlier therapeutic intervention.

What is the role of genetic testing in movement disorders practice?

PubMed

Schneider, Susanne A; Klein, Christine

2011-08-01

Genetic testing holds many promises in movement disorders, but also pitfalls that require careful consideration for meaningful results. These include the primary indication for testing in the first place, concerns regarding the implications of symptomatic, presymptomatic, and susceptibility testing, the mutation frequency in the gene of interest, the general lack of neuroprotective treatment options for neurodegenerative movement disorders, the prognosis of the condition diagnosed, and patient confidentiality concerns. Furthermore, new technical achievements and the available technical expertise, feasibility of specific gene testing, and its coverage through a health insurance carrier should be considered. Guidelines for testing have been established by some disease societies to advise clinicians and in parallel legal regulations are being adjusted at a national and international level. We review these and other critical points and recent developments regarding genetic testing in the field of movement disorders.

Development of a tiered and binned genetic counseling model for informed consent in the era of multiplex testing for cancer susceptibility.

PubMed

Bradbury, Angela R; Patrick-Miller, Linda; Long, Jessica; Powers, Jacquelyn; Stopfer, Jill; Forman, Andrea; Rybak, Christina; Mattie, Kristin; Brandt, Amanda; Chambers, Rachelle; Chung, Wendy K; Churpek, Jane; Daly, Mary B; Digiovanni, Laura; Farengo-Clark, Dana; Fetzer, Dominique; Ganschow, Pamela; Grana, Generosa; Gulden, Cassandra; Hall, Michael; Kohler, Lynne; Maxwell, Kara; Merrill, Shana; Montgomery, Susan; Mueller, Rebecca; Nielsen, Sarah; Olopade, Olufunmilayo; Rainey, Kimberly; Seelaus, Christina; Nathanson, Katherine L; Domchek, Susan M

2015-06-01

Multiplex genetic testing, including both moderate- and high-penetrance genes for cancer susceptibility, is associated with greater uncertainty than traditional testing, presenting challenges to informed consent and genetic counseling. We sought to develop a new model for informed consent and genetic counseling for four ongoing studies. Drawing from professional guidelines, literature, conceptual frameworks, and clinical experience, a multidisciplinary group developed a tiered-binned genetic counseling approach proposed to facilitate informed consent and improve outcomes of cancer susceptibility multiplex testing. In this model, tier 1 "indispensable" information is presented to all patients. More specific tier 2 information is provided to support variable informational needs among diverse patient populations. Clinically relevant information is "binned" into groups to minimize information overload, support informed decision making, and facilitate adaptive responses to testing. Seven essential elements of informed consent are provided to address the unique limitations, risks, and uncertainties of multiplex testing. A tiered-binned model for informed consent and genetic counseling has the potential to address the challenges of multiplex testing for cancer susceptibility and to support informed decision making and adaptive responses to testing. Future prospective studies including patient-reported outcomes are needed to inform how to best incorporate multiplex testing for cancer susceptibility into clinical practice.Genet Med 17 6, 485-492.

Alphabet soup: making sense of genetic testing in CMT.

PubMed

Lawson, Victoria; Gharibshahi, Shahram

2010-09-01

The diagnosis of inherited neuropathies can be challenging in several ways. First, a hereditary neuropathy must be suspected. Although some family histories are clear with multiple members affected, other families require directed inquiry. Second, even when a hereditary neuropathy is clear, it can be difficult to make a genetic characterization. The field of genotyping is expanding so rapidly, it is difficult to know what tests to order. The authors share their guidelines for the diagnosis of inherited neuropathies. © Thieme Medical Publishers.

ClinGen Pathogenicity Calculator: a configurable system for assessing pathogenicity of genetic variants.

PubMed

Patel, Ronak Y; Shah, Neethu; Jackson, Andrew R; Ghosh, Rajarshi; Pawliczek, Piotr; Paithankar, Sameer; Baker, Aaron; Riehle, Kevin; Chen, Hailin; Milosavljevic, Sofia; Bizon, Chris; Rynearson, Shawn; Nelson, Tristan; Jarvik, Gail P; Rehm, Heidi L; Harrison, Steven M; Azzariti, Danielle; Powell, Bradford; Babb, Larry; Plon, Sharon E; Milosavljevic, Aleksandar

2017-01-12

The success of the clinical use of sequencing based tests (from single gene to genomes) depends on the accuracy and consistency of variant interpretation. Aiming to improve the interpretation process through practice guidelines, the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) have published standards and guidelines for the interpretation of sequence variants. However, manual application of the guidelines is tedious and prone to human error. Web-based tools and software systems may not only address this problem but also document reasoning and supporting evidence, thus enabling transparency of evidence-based reasoning and resolution of discordant interpretations. In this report, we describe the design, implementation, and initial testing of the Clinical Genome Resource (ClinGen) Pathogenicity Calculator, a configurable system and web service for the assessment of pathogenicity of Mendelian germline sequence variants. The system allows users to enter the applicable ACMG/AMP-style evidence tags for a specific allele with links to supporting data for each tag and generate guideline-based pathogenicity assessment for the allele. Through automation and comprehensive documentation of evidence codes, the system facilitates more accurate application of the ACMG/AMP guidelines, improves standardization in variant classification, and facilitates collaborative resolution of discordances. The rules of reasoning are configurable with gene-specific or disease-specific guideline variations (e.g. cardiomyopathy-specific frequency thresholds and functional assays). The software is modular, equipped with robust application program interfaces (APIs), and available under a free open source license and as a cloud-hosted web service, thus facilitating both stand-alone use and integration with existing variant curation and interpretation systems. The Pathogenicity Calculator is accessible at http://calculator.clinicalgenome.org . By enabling evidence-based reasoning about the pathogenicity of genetic variants and by documenting supporting evidence, the Calculator contributes toward the creation of a knowledge commons and more accurate interpretation of sequence variants in research and clinical care.

Current practices of commercial cryobanks in screening prospective donors for genetic disease and reproductive risk.

PubMed

Conrad, E A; Fine, B; Hecht, B R; Pergament, E

1996-01-01

To determine how the screening practices of commercial semen banks vary from published guidelines, which factors influence cryobanks to exclude prospective semen donors for genetic reasons, and the current role of clinical geneticists/genetic counselors in evaluating prospective semen donors. The genetic screening of prospective donors by commercial semen banks was evaluated using written questionnaires completed by bank directors. Responses were analyzed to determine exclusion criteria, adherence to published guidelines, and contribution of genetic professionals. Semen banks were selected on the basis of membership in the American Association of Tissue Banks and commercial use of semen for artificial insemination by donor. Semen bank practices as reported by commercial semen bank directors. Of 37 eligible banks, 16 responded. All screen prospective donors by medical/family history and physical examination, 94% have upper age limits; 63% examine for minor physical defects; 56% routinely karyotype; 81% screen men of ethnic groups at risk for Tay Sachs disease, sickle cell disease and thalassemia; 19% screen all donors; 25% screen all donors for cystic fibrosis and 50% only screen if family history positive. Donor rejection was based on three criteria: mode of inheritance of familial disorder, severity of disease, and availability of carrier/confirmatory testing of donor genotype. Ten of 16 banks have no genetic professional on staff. Commercial semen banks primarily rely on family history as the major exclusion criterion in genetic screening of donors. Considerable differences exist among semen bank practices in accordance with guidelines published by national agencies. Genetic professionals have a minimal effect overall on evaluation of semen donors.

Effect of enhanced information, values clarification, and removal of financial barriers on use of prenatal genetic testing: a randomized clinical trial.

PubMed

Kuppermann, Miriam; Pena, Sherri; Bishop, Judith T; Nakagawa, Sanae; Gregorich, Steven E; Sit, Anita; Vargas, Juan; Caughey, Aaron B; Sykes, Susan; Pierce, Lasha; Norton, Mary E

2014-09-24

Prenatal genetic testing guidelines recommend providing patients with detailed information to allow informed, preference-based screening and diagnostic testing decisions. The effect of implementing these guidelines is not well understood. To analyze the effect of a decision-support guide and elimination of financial barriers to testing on use of prenatal genetic testing and decision making among pregnant women of varying literacy and numeracy levels. Randomized trial conducted from 2010-2013 at prenatal clinics at 3 county hospitals, 1 community clinic, 1 academic center, and 3 medical centers of an integrated health care delivery system in the San Francisco Bay area. Participants were English- or Spanish-speaking women who had not yet undergone screening or diagnostic testing and remained pregnant at 11 weeks' gestation (n = 710). A computerized, interactive decision-support guide and access to prenatal testing with no out-of-pocket expense (n = 357) or usual care as per current guidelines (n = 353). The primary outcome was invasive diagnostic test use, obtained via medical record review. Secondary outcomes included testing strategy undergone, and knowledge about testing, risk comprehension, and decisional conflict and regret at 24 to 36 weeks' gestation. Women randomized to the intervention group, compared with those randomized to the control group, were less likely to have invasive diagnostic testing (5.9% vs 12.3%; odds ratio [OR], 0.45 [95% CI, 0.25-0.80]) and more likely to forgo testing altogether (25.6% vs 20.4%; OR, 3.30 [95% CI, 1.43-7.64], reference group screening followed by invasive testing). Women randomized to the intervention group also had higher knowledge scores (9.4 vs 8.6 on a 15-point scale; mean group difference, 0.82 [95% CI, 0.34-1.31]) and were more likely to correctly estimate the amniocentesis-related miscarriage risk (73.8% vs 59.0%; OR, 1.95 [95% CI, 1.39-2.75]) and their estimated age-adjusted chance of carrying a fetus with trisomy 21 (58.7% vs 46.1%; OR, 1.66 [95% CI, 1.22-2.28]). Significant differences did not emerge in decisional conflict or regret. Full implementation of prenatal testing guidelines using a computerized, interactive decision-support guide in the absence of financial barriers to testing resulted in less test use and more informed choices. If validated in additional populations, this approach may result in more informed and preference-based prenatal testing decision making and fewer women undergoing testing. clinicaltrials.gov Identifier: NCT00505596.

Genetics and the investigation of developmental delay/intellectual disability.

PubMed

Srour, Myriam; Shevell, Michael

2014-04-01

Global developmental delay and intellectual disabilities are common reasons for diagnostic assessment by paediatricians. There are a multiplicity of possible causes many of which have genetic, management and treatment implications for the child and family. Genetic causes are estimated to be responsible for approximately a quarter to one-half of identified cases. The multiplicity of individually rare genetic causes challenges the practitioner with respect to the selection of diagnostic tests and accurate diagnosis. To assist the practitioner practice guidelines have been formulated and these are reviewed and summarised in this particular article.

Pediatric Predispositional Genetic Risk Communication: Potential Utility for Prevention and Control of Melanoma Risk as an Exemplar.

PubMed

Wu, Yelena P; Mays, Darren; Kohlmann, Wendy; Tercyak, Kenneth P

2017-10-01

Predispositional genetic testing among minor children is intensely debated due to the potential benefits and harms of providing this type of genetic information to children and their families. Existing guidelines on pediatric genetic testing state that predispositional testing could be appropriate for minors if preventive services exist that mitigate children's risk for or severity of the health condition in question. We use the example of hereditary melanoma to illustrate the rationale for and potential application of genetic risk communication for an adult-onset cancer to a pediatric population where childhood behaviors may reduce risk of disease later in life. We draw from the adult melanoma genetic risk communication and pediatric health behavior change literatures to suggest ways in which genetic test reporting and complementary education could be delivered to children who carry a hereditary risk for melanoma and their families in order to foster children's engagement in melanoma preventive behaviors. Genetic discoveries will continue to yield new opportunities to provide predispositional genetic risk information to unaffected individuals, including children, and could be delivered within programs that provide personalized and translational approaches to cancer prevention.

Representing nursing guideline with unified modeling language to facilitate development of a computer system: a case study.

PubMed

Choi, Jeeyae; Choi, Jeungok E

2014-01-01

To provide best recommendations at the point of care, guidelines have been implemented in computer systems. As a prerequisite, guidelines are translated into a computer-interpretable guideline format. Since there are no specific tools to translate nursing guidelines, only a few nursing guidelines are translated and implemented in computer systems. Unified modeling language (UML) is a software writing language and is known to well and accurately represent end-users' perspective, due to the expressive characteristics of the UML. In order to facilitate the development of computer systems for nurses' use, the UML was used to translate a paper-based nursing guideline, and its ease of use and the usefulness were tested through a case study of a genetic counseling guideline. The UML was found to be a useful tool to nurse informaticians and a sufficient tool to model a guideline in a computer program.

Time to incorporate germline multigene panel testing into breast and ovarian cancer patient care.

PubMed

Graffeo, Rossella; Livraghi, Luca; Pagani, Olivia; Goldhirsch, Aron; Partridge, Ann H; Garber, Judy E

2016-12-01

Genetic evaluation is increasingly becoming an integral part of the management of women with newly diagnosed breast and ovarian cancer (OC), and of individuals at high risk for these diseases. Genetic counseling and testing have been incorporated into oncological care to help and complete management and treatment strategies. Risk assessment and early detection strategies in individuals with BRCA1/2 mutations and with Lynch syndrome have been quite extensively studied, whereas much less is known about the management of mutation carriers with less common high-penetrance cancer susceptibility genes (PTEN, TP53, STK11, CDH1), and particularly those who carry mutations in moderate-penetrance genes (e.g., PALB2, CHEK2, ATM, NF1, RAD51C, RAD51D, BRIP1). The latter patient groups represent important ongoing research opportunities to enable informed counseling about appropriate clinical management. We summarize the current guidelines for the management of high and moderate-penetrance mutations for breast and OC susceptibility. Continuous updating of guidelines for proper clinical management of these individuals is ongoing because of rapid advances in technology and knowledge in this field. Thus, we exhort the use of multigene panels for the assessment of cancer risk beyond the classic predisposition syndromes as a new standard of care in cancer genetics. We further support an increase of genetic counselors in Europe and use of their expertise to support genetic testing in specialist multidisciplinary teams.

Genetics of pulmonary hypertension in the clinic.

PubMed

Girerd, Barbara; Lau, Edmund; Montani, David; Humbert, Marc

2017-09-01

Heritable pulmonary arterial hypertension (PAH) is an autosomal dominant disease with incomplete penetrance because of mutations in bone morphogenetic protein receptor-II (BMPR2), activin A receptor type II-like kinase 1, endoglin, caveolin-1, potassium channel subfamily K, member 3, and T-box gene 4 genes. Heritable pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis (PVOD/PCH) is an autosomal recessive disease because of biallelic mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene. The 2015 european society of cardiology (ESC) and european respiratory society (ERS) pulmonary hypertension guidelines recommend genetic counselling and testing to adults and children with PAH or PVOD/PCH as well as in adult relatives at risk of carrying a predisposing mutation. In France, genetic counseling and testing are offered to all patients displaying sporadic or familial form of PAH or PVOD/PCH and to their relatives at high risk of carrying a predisposing mutation. Patients with a heritable form of PAH are younger at diagnosis with a worse hemodynamic and a dismal prognosis. Patients with a heritable form of PVOD/PCH are younger at diagnosis with a worse response to specific PAH therapies. A program to detect PAH in an early phase was offered to all asymptomatic BMPR2 mutation carriers, according to the 2015 ESC/ERS guidelines. Finally, preimplantation genetic diagnosis has been performed in families with a history of BMPR2 mutations. Genetic counseling and testing has to be implemented in pulmonary hypertension centers.

Good laboratory practices for biochemical genetic testing and newborn screening for inherited metabolic disorders.

PubMed

2012-04-06

Biochemical genetic testing and newborn screening are essential laboratory services for the screening, detection, diagnosis, and monitoring of inborn errors of metabolism or inherited metabolic disorders. Under the Clinical Laboratory Improvement Amendments of 1988 (CLIA) regulations, laboratory testing is categorized on the basis of the level of testing complexity as either waived (i.e., from routine regulatory oversight) or nonwaived testing (which includes tests of moderate and high complexity). Laboratories that perform biochemical genetic testing are required by CLIA regulations to meet the general quality systems requirements for nonwaived testing and the personnel requirements for high-complexity testing. Laboratories that perform public health newborn screening are subject to the same CLIA regulations and applicable state requirements. As the number of inherited metabolic diseases that are included in state-based newborn screening programs continues to increase, ensuring the quality of performance and delivery of testing services remains a continuous challenge not only for public health laboratories and other newborn screening facilities but also for biochemical genetic testing laboratories. To help ensure the quality of laboratory testing, CDC collaborated with the Centers for Medicare & Medicaid Services, the Food and Drug Administration, the Health Resources and Services Administration, and the National Institutes of Health to develop guidelines for laboratories to meet CLIA requirements and apply additional quality assurance measures for these areas of genetic testing. This report provides recommendations for good laboratory practices that were developed based on recommendations from the Clinical Laboratory Improvement Advisory Committee, with additional input from the Secretary's Advisory Committee on Genetics, Health, and Society; the Secretary's Advisory Committee on Heritable Disorders in Newborns and Children; and representatives of newborn screening laboratories. The recommended practices address the benefits of using a quality management system approach, factors to consider before introducing new tests, establishment and verification of test performance specifications, the total laboratory testing process (which consists of the preanalytic, analytic, and postanalytic phases), confidentiality of patient information and test results, and personnel qualifications and responsibilities for laboratory testing for inherited metabolic diseases. These recommendations are intended for laboratories that perform biochemical genetic testing to improve the quality of laboratory services and for newborn screening laboratories to ensure the quality of laboratory practices for inherited metabolic disorders. These recommendations also are intended as a resource for medical and public health professionals who evaluate laboratory practices, for users of laboratory services to facilitate their collaboration with newborn screening systems and use of biochemical genetic tests, and for standard-setting organizations and professional societies in developing future laboratory quality standards and practice recommendations. This report complements Good Laboratory Practices for Molecular Genetic Testing for Heritable Diseases and Conditions (CDC. Good laboratory practices for molecular genetic testing for heritable diseases and conditions. MMWR 2009;58 [No. RR-6]) to provide guidance for ensuring and improving the quality of genetic laboratory services and public health outcomes. Future recommendations for additional areas of genetic testing will be considered on the basis of continued monitoring and evaluation of laboratory practices, technology advancements, and the development of laboratory standards and guidelines.

Predictive Psychiatric Genetic Testing in Minors: An Exploration of the Non-Medical Benefits.

PubMed

Manzini, Arianna; Vears, Danya F

2018-03-01

Predictive genetic testing for susceptibility to psychiatric conditions is likely to become part of standard practice. Because the onset of most psychiatric diseases is in late adolescence or early adulthood, testing minors could lead to early identification that may prevent or delay the development of these disorders. However, due to their complex aetiology, psychiatric genetic testing does not provide the immediate medical benefits that current guidelines require for testing minors. While several authors have argued non-medical benefits may play a crucial role in favour of predictive testing for other conditions, little research has explored such a role in psychiatric disorders. This paper outlines the potential non-medical benefits and harms of psychiatric genetic testing in minors in order to consider whether the non-medical benefits could ever make such testing appropriate. Five non-medical themes arise in the literature: psychological impacts, autonomy/self-determination, implications of the biomedical approach, use of financial and intellectual resources, and discrimination. Non-medical benefits were prominent in all of them, suggesting that psychiatric genetic testing in minors may be appropriate in some circumstances. Further research needs to empirically assess these potential non-medical benefits, incorporate minors in the debate, and include normative reflection to evaluate the very purposes and motivations of psychiatric genetic testing in minors.

Current issues of personnel and laboratory practices in genetic testing

PubMed Central

Mark, Hon Fong Louie; Kelly, Thaddeus; Watson, Michael S; Hoeltge, Gerald; Miller, Wayne A; Beauregard, Laurent

1995-01-01

As genetic testing is an area with implications extending far beyond that of the primary patient, it is appropriately an area that is under increased scrutiny. To ensure that high quality is maintained in the delivery of genetic services, several agencies have developed standards and guidelines. The present article summarises important recommendations made by the American College of Medical Genetics (ACMG), the College of American Pathologists (CAP), the US Health Care Financing Administration (HCFA), and the US Food and Drug Administration (FDA) as they relate to genetic testing. Some of the standards are based on voluntary compliance, whereas others have the force of regulation. They all address issues of personnel credentials, laboratory operations, and the most critical quality assurance and control measures for diagnostic laboratories from the perspective of various agencies. In most instances, the standards promulgated by these agencies are offered as minimum criteria. The exact impact of these regulations on the practice of medical genetics has yet to be established. Images PMID:8558555

Ethical dilemmas in genetic testing: examples from the Cuban program for predictive diagnosis of hereditary ataxias.

PubMed

Mariño, Tania Cruz; Armiñán, Rubén Reynaldo; Cedeño, Humberto Jorge; Mesa, José Miguel Laffita; Zaldivar, Yanetza González; Rodríguez, Raúl Aguilera; Santos, Miguel Velázquez; Mederos, Luis Enrique Almaguer; Herrera, Milena Paneque; Pérez, Luis Velázquez

2011-06-01

Predictive testing protocols are intended to help patients affected with hereditary conditions understand their condition and make informed reproductive choices. However, predictive protocols may expose clinicians and patients to ethical dilemmas that interfere with genetic counseling and the decision making process. This paper describes ethical dilemmas in a series of five cases involving predictive testing for hereditary ataxias in Cuba. The examples herein present evidence of the deeply controversial situations faced by both individuals at risk and professionals in charge of these predictive studies, suggesting a need for expanded guidelines to address such complexities.

Singapore Cancer Network (SCAN) Guidelines for Referral for Genetic Evaluation of Common Hereditary Cancer Syndromes.

PubMed

2015-10-01

The SCAN cancer genetics workgroup aimed to develop Singapore Cancer Network (SCAN) clinical practice guidelines for referral for genetic evaluation of common hereditary cancer syndromes. The workgroup utilised a modified ADAPTE process to calibrate high quality international evidence-based clinical practice guidelines to our local setting. To formulate referral guidelines for the 3 most commonly encountered hereditary cancer syndromes to guide healthcare providers in Singapore who care for cancer patients and/or their family members, 7, 5, and 3 sets of international guidelines respectively for hereditary breast and ovarian cancer (HBOC) syndrome, Lynch syndrome (LS), and familial adenomatous polyposis (FAP) were evaluated. For each syndrome, the most applicable one was selected, with modifications made such that they would be appropriate to the local context. These adapted guidelines form the SCAN Guidelines 2015 for referral for genetic evaluation of common hereditary cancer syndromes.

Genetic Evaluation of Short Stature

PubMed Central

Rosenfeld, Ron G.

2014-01-01

Context: Genetics plays a major role in determining an individual's height. Although there are many monogenic disorders that lead to perturbations in growth and result in short stature, there is still no consensus as to the role that genetic diagnostics should play in the evaluation of a child with short stature. Evidence Acquisition: A search of PubMed was performed, focusing on the genetic diagnosis of short stature as well as on specific diagnostic subgroups included in this article. Consensus guidelines were reviewed. Evidence Synthesis: There are a multitude of rare genetic causes of severe short stature. There is no high-quality evidence to define the optimal approach to the genetic evaluation of short stature. We review genetic etiologies of a number of diagnostic subgroups and propose an algorithm for genetic testing based on these subgroups. Conclusion: Advances in genomic technologies are revolutionizing the diagnostic approach to short stature. Endocrinologists must become facile with the use of genetic testing in order to identify the various monogenic disorders that present with short stature. PMID:24915122

GENOTOXICITY RISK ASSESSMENT: A PROPOSED CLASSIFICATION STRATEGY

EPA Science Inventory

Recent advances in genetic toxicity (mutagenicity) testing methods and in approaches to performing risk assessment are prompting a renewed effort to harmonize genotoxicity risk assessment across the world. The US Environmental Protection Agency (EPA) first published Guidelines fo...

Utilization of genetic tests: analysis of gene-specific billing in Medicare claims data.

PubMed

Lynch, Julie A; Berse, Brygida; Dotson, W David; Khoury, Muin J; Coomer, Nicole; Kautter, John

2017-08-01

We examined the utilization of precision medicine tests among Medicare beneficiaries through analysis of gene-specific tier 1 and 2 billing codes developed by the American Medical Association in 2012. We conducted a retrospective cross-sectional study. The primary source of data was 2013 Medicare 100% fee-for-service claims. We identified claims billed for each laboratory test, the number of patients tested, expenditures, and the diagnostic codes indicated for testing. We analyzed variations in testing by patient demographics and region of the country. Pharmacogenetic tests were billed most frequently, accounting for 48% of the expenditures for new codes. The most common indications for testing were breast cancer, long-term use of medications, and disorders of lipid metabolism. There was underutilization of guideline-recommended tumor mutation tests (e.g., epidermal growth factor receptor) and substantial overutilization of a test discouraged by guidelines (methylenetetrahydrofolate reductase). Methodology-based tier 2 codes represented 15% of all claims billed with the new codes. The highest rate of testing per beneficiary was in Mississippi and the lowest rate was in Alaska. Gene-specific billing codes significantly improved our ability to conduct population-level research of precision medicine. Analysis of these data in conjunction with clinical records should be conducted to validate findings.Genet Med advance online publication 26 January 2017.

Does the diagnosis of breast or ovarian cancer trigger referral to genetic counseling?

PubMed

Powell, C Bethan; Littell, Ramey; Hoodfar, Elizabeth; Sinclair, Fiona; Pressman, Alice

2013-03-01

Kaiser Permanente Northern California is a large integrated health care delivery system in the United States that has guidelines for referring women with newly diagnosed BRCA1-and BRCA2-associated cancers for genetic counseling. This study assesses adherence to genetic counseling referral guidelines within this health system. Chart review was performed to identify patients with cancer who met the following pathology-based Kaiser Permanente Northern California guidelines for referral for genetic counseling: invasive breast cancer, younger than age 40; nonmucinous epithelial ovarian, fallopian tube, or peritoneal cancer, younger than age 60; women with synchronous or metachronous primary cancers of the breast and ovaries; and male breast cancer. We assessed compliance with referral guidelines. An electronic notice was sent to the managing physician of patients with newly diagnosed cancer to assess the feasibility of this intervention. A total of 340 patients were identified with breast cancer at younger than age 40 or with ovarian, peritoneal, or tubal cancer between January and June, 2008. Upon chart review, 105 of these patients met pathology-based criteria for referral to genetic counseling, of whom 47 (45%) were referred within the 2-year study period. Of the 67 subjects with breast cancer, 40 subjects (60%) were referred. In contrast, only 7 (21%) of 33 patients with ovarian cancer were referred (P < 0.001). A pilot study was performed to test the feasibility of notifying managing oncologists with an electronic letter alerting them of eligibility for genetic referral of patients with new diagnosis (n = 21). In the 3 to 6 months after this notification, 12 of these 21 patients were referred for counseling including 5 of 7 patients with a diagnosis of ovarian cancer. There is a missed opportunity for referring patients to genetic counseling, especially among patients with ovarian cancer. A pilot study suggests that alerting treating physicians is a feasible strategy to increase appropriate referral.

DOE Office of Scientific and Technical Information (OSTI.GOV)

McEwen, J.E.; McCarty, K.; Reilly, P.R.

Rapid advances in the ability to test persons presymptomatically for genetic diseases have generated increasing concern that genetic information will be abused by insurance companies. Reasoning that the insurance companies may have the strongest interest in using genetic data and that the medical directors of those companies with responsibility for rating applicants would be a good source of information on the use of such data, the authors conducted a large survey of medical directors of North American life insurance companies. They received responses from 27 medical directors. The results suggest that (1) few insurers perform genetic tests on applicants, butmore » most are interested in accessing genetic test information about applicants that already exists; (2) the degree of insurers' interest in using genetic test results may depend on the face amount of the policy applied for and on the specificity and sensitivity of the test; (3) many companies employ underwriting guidelines with respect to certain genetic conditions but may not always have specific actuarial data in house to support their rating decisions; (4) a considerable degree of subjectivity is involved in most insurers' rating decisions; and (5) some of the medical directors who responded to the survey are not fully informed about certain basic principles of medical genetics. 8 refs., 7 tabs.« less

Are All Ames Strains in the OECD Mutagenicity Test Guideline 471 Useful and Necessary? An Analysis of Large Mutagenicity Data Sets for the IWGT

EPA Science Inventory

The International Workshop on Genetic Toxicology (IWGT) meets every four years with an objective to reach consensus recommendations on difficult or conflicting approaches to genotoxicity testing based upon practical experience and newly available data and data analysis techniques...

Molecular Genetic Testing in Reward Deficiency Syndrome (RDS): Facts and Fiction.

PubMed

Blum, Kenneth; Badgaiyan, Rajendra D; Agan, Gozde; Fratantonio, James; Simpatico, Thomas; Febo, Marcelo; Haberstick, Brett C; Smolen, Andrew; Gold, Mark S

The Brain Reward Cascade (BRC) is an interaction of neurotransmitters and their respective genes to control the amount of dopamine released within the brain. Any variations within this pathway, whether genetic or environmental (epigenetic), may result in addictive behaviors or RDS, which was coined to define addictive behaviors and their genetic components. To carry out this review we searched a number of important databases including: Filtered: Cochrane Systematic reviews; DARE; Pubmed Central Clinical Quaries; National Guideline Clearinghouse and unfiltered resources: PsychINFO; ACP PIER; PsychSage; Pubmed/Medline. The major search terms included: dopamine agonist therapy for Addiction; dopamine agonist therapy for Reward dependence; dopamine antagonistic therapy for addiction; dopamine antagonistic therapy for reward dependence and neurogenetics of RDS. While there are many studies claiming a genetic association with RDS behavior, not all are scientifically accurate. Albeit our bias, this Clinical Pearl discusses the facts and fictions behind molecular genetic testing in RDS and the significance behind the development of the Genetic Addiction Risk Score (GARS PREDX ™), the first test to accurately predict one's genetic risk for RDS.

Inferring Genetic Ancestry: Opportunities, Challenges, and Implications

PubMed Central

Royal, Charmaine D.; Novembre, John; Fullerton, Stephanie M.; Goldstein, David B.; Long, Jeffrey C.; Bamshad, Michael J.; Clark, Andrew G.

2010-01-01

Increasing public interest in direct-to-consumer (DTC) genetic ancestry testing has been accompanied by growing concern about issues ranging from the personal and societal implications of the testing to the scientific validity of ancestry inference. The very concept of “ancestry” is subject to misunderstanding in both the general and scientific communities. What do we mean by ancestry? How exactly is ancestry measured? How far back can such ancestry be defined and by which genetic tools? How do we validate inferences about ancestry in genetic research? What are the data that demonstrate our ability to do this correctly? What can we say and what can we not say from our research findings and the test results that we generate? This white paper from the American Society of Human Genetics (ASHG) Ancestry and Ancestry Testing Task Force builds upon the 2008 ASHG Ancestry Testing Summary Statement in providing a more in-depth analysis of key scientific and non-scientific aspects of genetic ancestry inference in academia and industry. It culminates with recommendations for advancing the current debate and facilitating the development of scientifically based, ethically sound, and socially attentive guidelines concerning the use of these continually evolving technologies. PMID:20466090

A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.

PubMed

Hampel, Heather; Bennett, Robin L; Buchanan, Adam; Pearlman, Rachel; Wiesner, Georgia L

2015-01-01

The practice guidelines of the American College of Medical Genetics and Genomics (ACMG) and the National Society of Genetic Counselors (NSGC) are developed by members of the ACMG and NSGC to assist medical geneticists, genetic counselors, and other health-care providers in making decisions about appropriate management of genetic concerns, including access to and/or delivery of services. Each practice guideline focuses on a clinical or practice-based issue and is the result of a review and analysis of current professional literature believed to be reliable. As such, information and recommendations within the ACMG and NSGC joint practice guidelines reflect the current scientific and clinical knowledge at the time of publication, are current only as of their publication date, and are subject to change without notice as advances emerge. In addition, variations in practice, which take into account the needs of the individual patient and the resources and limitations unique to the institution or type of practice, may warrant approaches, treatments, and/or procedures that differ from the recommendations outlined in this guideline. Therefore, these recommendations should not be construed as dictating an exclusive course of management, nor does the use of such recommendations guarantee a particular outcome. Genetic counseling practice guidelines are never intended to displace a health-care provider's best medical judgment based on the clinical circumstances of a particular patient or patient population. Practice guidelines are published by the ACMG or the NSGC for educational and informational purposes only, and neither the ACMG nor the NSGC "approve" or "endorse" any specific methods, practices, or sources of information.Cancer genetic consultation is an important aspect of the care of individuals at increased risk of a hereditary cancer syndrome. Yet several patient, clinician, and system-level barriers hinder identification of individuals appropriate for cancer genetics referral. Thus, the purpose of this practice guideline is to present a single set of comprehensive personal and family history criteria to facilitate identification and maximize appropriate referral of at-risk individuals for cancer genetic consultation. To develop this guideline, a literature search for hereditary cancer susceptibility syndromes was conducted using PubMed. In addition, GeneReviews and the National Comprehensive Cancer Network guidelines were reviewed when applicable. When conflicting guidelines were identified, the evidence was ranked as follows: position papers from national and professional organizations ranked highest, followed by consortium guidelines, and then peer-reviewed publications from single institutions. The criteria for cancer genetic consultation referral are provided in two formats: (i) tables that list the tumor type along with the criteria that, if met, would warrant a referral for a cancer genetic consultation and (ii) an alphabetical list of the syndromes, including a brief summary of each and the rationale for the referral criteria that were selected. Consider referral for a cancer genetic consultation if your patient or any of their first-degree relatives meet any of these referral criteria.

Diagnosis and Management of Gaucher Disease in India - Consensus Guidelines of the Gaucher Disease Task Force of the Society for Indian Academy of Medical Genetics and the Indian Academy of Pediatrics.

PubMed

Puri, Ratna Dua; Kapoor, Seema; Kishnani, Priya S; Dalal, Ashwin; Gupta, Neerja; Muranjan, Mamta; Phadke, Shubha R; Sachdeva, Anupam; Verma, Ishwar C; Mistry, Pramod K

2018-02-15

Gaucher disease (GD) is amongst the most frequently occurring lysosomal storage disorder in all ethnicities. The clinical manifestations and natural history of GD is highly heterogeneous with extreme geographic and ethnic variations. The literature on GD has paucity of information and optimal management guidelines for Indian patients. Gaucher Disease Task Force was formed under the auspices of the Society for Indian Academy of Medical Genetics. Invited experts from various specialties formulated guidelines for the management of patients with GD. A writing committee was formed and the draft guidelines were circulated by email to all members for comments and inputs. The guidelines were finalized in December 2016 at the annual meeting of the Indian Academy of Medical Genetics. These guidelines are intended to serve as a standard framework for treating physicians and the health care systems for optimal management of Gaucher disease in India and to define unique needs of this patient population. Manifestations of GD are protean and a high index of suspicion is essential for timely diagnosis. Patients frequently experience diagnostic delays during which severe irreversible complications occur. Leucocyte acid b-glucosidase activity is mandatory for establishing the diagnosis of Gaucher disease; molecular testing can help identify patients at risk of neuronopathic disease. Enzyme replacement therapy for type 1 and type 3 Gaucher disease is the standard of care. Best outcomes are achieved by early initiation of therapy before onset of irreversible complications. However, in setting of progressive neurological symptoms such as seizures and or/ neuroregression, ERT is not recommended, as it cannot cross the blood brain barrier. The recommendations herein are for diagnosis, for initiation of therapy, therapeutic goals, monitoring and follow up of patients. We highlight that prevention of recurrence of the disease through genetic counseling and prenatal diagnosis is essential in India, due to uniformly severe phenotypes encountered in our population.

Predictive gene testing for Huntington disease and other neurodegenerative disorders.

PubMed

Wedderburn, S; Panegyres, P K; Andrew, S; Goldblatt, J; Liebeck, T; McGrath, F; Wiltshire, M; Pestell, C; Lee, J; Beilby, J

2013-12-01

Controversies exist around predictive testing (PT) programmes in neurodegenerative disorders. This study sets out to answer the following questions relating to Huntington disease (HD) and other neurodegenerative disorders: differences between these patients in their PT journeys, why and when individuals withdraw from PT, and decision-making processes regarding reproductive genetic testing. A case series analysis of patients having PT from the multidisciplinary Western Australian centre for PT over the past 20 years was performed using internationally recognised guidelines for predictive gene testing in neurodegenerative disorders. Of 740 at-risk patients, 518 applied for PT: 466 at risk of HD, 52 at risk of other neurodegenerative disorders - spinocerebellar ataxias, hereditary prion disease and familial Alzheimer disease. Thirteen percent withdrew from PT - 80.32% of withdrawals occurred during counselling stages. Major withdrawal reasons related to timing in the patients' lives or unknown as the patient did not disclose the reason. Thirty-eight HD individuals had reproductive genetic testing: 34 initiated prenatal testing (of which eight withdrew from the process) and four initiated pre-implantation genetic diagnosis. There was no recorded or other evidence of major psychological reactions or suicides during PT. People withdrew from PT in relation to life stages and reasons that are unknown. Our findings emphasise the importance of: (i) adherence to internationally recommended guidelines for PT; (ii) the role of the multidisciplinary team in risk minimisation; and (iii) patient selection. © 2013 The Authors; Internal Medicine Journal © 2013 Royal Australasian College of Physicians.

The McGill Interactive Pediatric OncoGenetic Guidelines: An approach to identifying pediatric oncology patients most likely to benefit from a genetic evaluation.

PubMed

Goudie, Catherine; Coltin, Hallie; Witkowski, Leora; Mourad, Stephanie; Malkin, David; Foulkes, William D

2017-08-01

Identifying cancer predisposition syndromes in children with tumors is crucial, yet few clinical guidelines exist to identify children at high risk of having germline mutations. The McGill Interactive Pediatric OncoGenetic Guidelines project aims to create a validated pediatric guideline in the form of a smartphone/tablet application using algorithms to process clinical data and help determine whether to refer a child for genetic assessment. This paper discusses the initial stages of the project, focusing on its overall structure, the methodology underpinning the algorithms, and the upcoming algorithm validation process. © 2017 Wiley Periodicals, Inc.

Direct-to-consumer genetic testing for predicting sports performance and talent identification: Consensus statement

PubMed Central

Webborn, Nick; Williams, Alun; McNamee, Mike; Bouchard, Claude; Pitsiladis, Yannis; Ahmetov, Ildus; Ashley, Euan; Byrne, Nuala; Camporesi, Silvia; Collins, Malcolm; Dijkstra, Paul; Eynon, Nir; Fuku, Noriyuki; Garton, Fleur C; Hoppe, Nils; Holm, Søren; Kaye, Jane; Klissouras, Vassilis; Lucia, Alejandro; Maase, Kamiel; Moran, Colin; North, Kathryn N; Pigozzi, Fabio; Wang, Guan

2015-01-01

The general consensus among sport and exercise genetics researchers is that genetic tests have no role to play in talent identification or the individualised prescription of training to maximise performance. Despite the lack of evidence, recent years have witnessed the rise of an emerging market of direct-to-consumer marketing (DTC) tests that claim to be able to identify children's athletic talents. Targeted consumers include mainly coaches and parents. There is concern among the scientific community that the current level of knowledge is being misrepresented for commercial purposes. There remains a lack of universally accepted guidelines and legislation for DTC testing in relation to all forms of genetic testing and not just for talent identification. There is concern over the lack of clarity of information over which specific genes or variants are being tested and the almost universal lack of appropriate genetic counselling for the interpretation of the genetic data to consumers. Furthermore independent studies have identified issues relating to quality control by DTC laboratories with different results being reported from samples from the same individual. Consequently, in the current state of knowledge, no child or young athlete should be exposed to DTC genetic testing to define or alter training or for talent identification aimed at selecting gifted children or adolescents. Large scale collaborative projects, may help to develop a stronger scientific foundation on these issues in the future. PMID:26582191

Looking at genes in the workplace.

PubMed

Holden, C

1982-07-23

The Office of Technology Assessment recently testified at a congressional hearing that many corporations are considering genetic screening of employees. Biochemical genetic screening of "susceptible" workers is aimed at identifying individuals unsuitable for specific jobs, and cytogenic monitoring involves the testing of groups of workers for chromosome aberrations that might occur as a result of exposure to chemicals. The apparent surge of interest in such testing requires that several legal, ethical, and policy issues be addressed, including the potential for discrimination, the misuse of screening as an alternative to cleaning up the workplace, the predictive capability of the tests, and the necessity for the development of guidelines for screening programs.

Changes in screening behaviors and attitudes toward screening from pre-test genetic counseling to post-disclosure in Lynch syndrome families

PubMed Central

Burton-Chase, Allison M.; Hovick, Shelly R.; Peterson, Susan K.; Marani, Salma K.; Vernon, Sally W.; Amos, Christopher I.; Frazier, Marsha L.; Lynch, Patrick M.; Gritz, Ellen R.

2013-01-01

Purpose This study examined colonoscopy adherence and attitudes towards colorectal cancer (CRC) screening in individuals who underwent Lynch syndrome genetic counseling and testing. Methods We evaluated changes in colonoscopy adherence and CRC screening attitudes in 78 cancer-unaffected relatives of Lynch syndrome mutation carriers before pre-test genetic counseling (baseline) and at 6 and 12 months post-disclosure of test results (52 mutation-negative, 26 mutation-positive). Results While both groups were similar at baseline, at 12 months post-disclosure, a greater number of mutation-positive individuals had had a colonoscopy compared with mutation-negative individuals. From baseline to 12 months post-disclosure, the mutation-positive group demonstrated an increase in mean scores on measures of colonoscopy commitment, self-efficacy, and perceived benefits of CRC screening, and a decrease in mean scores for perceived barriers to CRC screening. Mean scores on colonoscopy commitment decreased from baseline to 6 months in the mutation-negative group. Conclusion Adherence to risk-appropriate guidelines for CRC surveillance improved after genetic counseling and testing for Lynch syndrome. Mutation-positive individuals reported increasingly positive attitudes toward CRC screening after receiving genetic test results, potentially reinforcing longer term colonoscopy adherence. PMID:23414081

Aligning policy to promote cascade genetic screening for prevention and early diagnosis of heritable diseases.

PubMed

George, Rani; Kovak, Karen; Cox, Summer L

2015-06-01

Cascade genetic screening is a methodology for identifying and testing close blood relatives of individuals at increased risk for heritable conditions and follows a sequential process, minimizing testing costs and the number of family members who need to be tested. It offers considerable potential for cost savings and increased awareness of heritable conditions within families. CDC-classified Tier 1 genomic applications for hereditary breast and ovarian cancer syndrome (HBOC), Lynch Syndrome (LS), and familial hypercholesterolemia (FH) are recommended for clinical use and support the use of cascade genetic screening. Most individuals are unaware of their increased risk for heritable conditions such as HBOC, LS, and FH. Consistent implementation of cascade genetic screening could significantly increase awareness and prevention of heritable conditions. Limitations to effective implementation of cascade genetic screening include: insufficient genetic risk assessment and knowledge by a majority of healthcare providers without genetics credentials; a shortage of genetic specialists, especially in rural areas; a low rate of reimbursement for comprehensive genetic counseling services; and an individual focus on prevention by clinical guidelines and insurance coverage. The family-centric approach of cascade genetic screening improves prevention and early diagnosis of heritable diseases on a population health level. Cascade genetic screening could be better supported and augmented through changes in health policy.

Impact of Gene Patents and Licensing Practices on Access to Genetic Testing for Alzheimer’s Disease

PubMed Central

Skeehan, Katie; Heaney, Christopher; Cook-Deegan, Robert

2010-01-01

Genetic testing for Alzheimer’s disease (AD) includes genotyping for apolipoprotein E, for late-onset AD, and three rare autosomal dominant, early-onset forms of AD associated with different genes (APP, PSEN1 and PSEN2). According to researchers, patents have not impeded research in the field, nor were patents an important consideration in the quest for the genetic risk factors. Athena Diagnostics holds exclusive licenses from Duke University for three “method” patents covering APOE genetic testing. Athena offers tests for APOE and genes associated with early onset, autosomal dominant AD. One of those presenilin genes is patented and exclusively licensed to Athena; the other presenilin gene was patented but the patent was allowed to lapse; and one (APP) is patented only as a research tool and patent claims do not cover diagnostic use. Direct-to-consumer testing is available for some AD-related genes, apparently without a license. Athena Diagnostics consolidated its position in the market for AD genetic testing by collecting exclusive rights to patents arising from university research. Duke University also used its licenses to Athena to enforce adherence to clinical guidelines, including elimination of the service from Smart Genetics, which was offering direct-to-consumer risk assessment based on APOE genotyping. PMID:20393312

Genetic Testing for Hereditary Breast Cancer: The Decision to Decline.

PubMed

White, V Brook; Walsh, Kendall K; Foss, Kimberly Showers; Amacker-North, Lisa; Lenarcic, Stacy; McNeely, Lindsay; White, Richard L

2018-01-01

Genetic testing is important for comprehensive cancer care. Commercial analysis of the BRCA1/2 genes has been available since 1996, and testing for hereditary breast and ovarian cancer syndrome is well established. The National Comprehensive Cancer Network (NCCN) guidelines identify individuals for whom BRCA1/2 analysis is appropriate and define management recommendations for mutation carriers. Despite recommendations, not all who meet NCCN criteria undergo genetic testing. We assess the frequency that individuals meeting NCCN criteria decline BRCA1/2 analysis, as well as factors that affect the decision-making process. A retrospective chart review was performed from September 2013 through August 2014 of individuals who received genetic counseling at the Levine Cancer Institute. A total of 1082 individuals identified through the retrospective chart review met NCCN criteria for BRCA1/2 analysis. Of these, 267 (24.7%) did not pursue genetic testing. Of the Nontested cohort, 59 (22.1%) were disinterested in testing and 108 (40.4%) were advised to gather additional genetic or medical information about their relatives before testing. The remaining 100 (37.5%) individuals were insured and desired to undergo genetic testing but were prohibited by the expense. Eighty five of these 100 patients were responsible for the total cost of the test, whereas the remaining 15 faced a prohibitive copay expense. Financial concerns are a major deterrent to the pursuit of BRCA1/2 analysis among those who meet NCNN criteria, especially in patients diagnosed with breast or ovarian cancer. These findings highlight the need to address financial concerns for genetic testing in this high-risk population.

Genetic counseling services and development of training programs in Malaysia.

PubMed

Lee, Juliana Mei-Har; Thong, Meow-Keong

2013-12-01

Genetic counseling service is urgently required in developing countries. In Malaysia, the first medical genetic service was introduced in 1994 at one of the main teaching hospitals in Kuala Lumpur. Two decades later, the medical genetic services have improved with the availability of genetic counseling, genetic testing and diagnosis, for both paediatric conditions and adult-onset inherited conditions, at four main centers of medical genetic services in Malaysia. Prenatal diagnosis services and assisted reproductive technologies are available at tertiary centres and private medical facilities. Positive developments include governmental recognition of Clinical Genetics as a subspecialty, increased funding for genetics services, development of medical ethics guidelines, and establishment of support groups. However, the country lacked qualified genetic counselors. Proposals were presented to policy-makers to develop genetic counseling courses. Challenges encountered included limited resources and public awareness, ethical dilemmas such as religious and social issues and inadequate genetic health professionals especially genetic counselors.

40 CFR 798.5460 - Rodent heritable translocation assays.

Code of Federal Regulations, 2010 CFR

2010-07-01

... treatment and control groups. (4) Control groups—(i) Concurrent controls. No concurrent positive or negative... control groups. Historical or concurrent controls shall be specified, as well as the randomization... SUBSTANCES CONTROL ACT (CONTINUED) HEALTH EFFECTS TESTING GUIDELINES Genetic Toxicity § 798.5460 Rodent...

40 CFR 798.5460 - Rodent heritable translocation assays.

Code of Federal Regulations, 2013 CFR

2013-07-01

... treatment and control groups. (4) Control groups—(i) Concurrent controls. No concurrent positive or negative... control groups. Historical or concurrent controls shall be specified, as well as the randomization... SUBSTANCES CONTROL ACT (CONTINUED) HEALTH EFFECTS TESTING GUIDELINES Genetic Toxicity § 798.5460 Rodent...

40 CFR 798.5460 - Rodent heritable translocation assays.

Code of Federal Regulations, 2012 CFR

2012-07-01

... treatment and control groups. (4) Control groups—(i) Concurrent controls. No concurrent positive or negative... control groups. Historical or concurrent controls shall be specified, as well as the randomization... SUBSTANCES CONTROL ACT (CONTINUED) HEALTH EFFECTS TESTING GUIDELINES Genetic Toxicity § 798.5460 Rodent...

40 CFR 798.5460 - Rodent heritable translocation assays.

Code of Federal Regulations, 2011 CFR

2011-07-01

... treatment and control groups. (4) Control groups—(i) Concurrent controls. No concurrent positive or negative... control groups. Historical or concurrent controls shall be specified, as well as the randomization... SUBSTANCES CONTROL ACT (CONTINUED) HEALTH EFFECTS TESTING GUIDELINES Genetic Toxicity § 798.5460 Rodent...

40 CFR 798.5460 - Rodent heritable translocation assays.

Code of Federal Regulations, 2014 CFR

2014-07-01

... treatment and control groups. (4) Control groups—(i) Concurrent controls. No concurrent positive or negative... control groups. Historical or concurrent controls shall be specified, as well as the randomization... SUBSTANCES CONTROL ACT (CONTINUED) HEALTH EFFECTS TESTING GUIDELINES Genetic Toxicity § 798.5460 Rodent...

Physicians’ Perspectives on the Uncertainties and Implications of Chromosomal Microarray Testing of Children and Families

PubMed Central

Reiff, Marian; Ross, Kathryn; Mulchandani, Surabhi; Propert, Kathleen Joy; Pyeritz, Reed E.; Spinner, Nancy B.; Bernhardt, Barbara A.

2012-01-01

Chromosomal microarray analysis (CMA) has improved the diagnostic rate of genomic disorders in pediatric populations, but can produce uncertain and unexpected findings. This paper explores clinicians’ perspectives and identifies challenges in effectively interpreting results and communicating with families about CMA. Responses to an online survey were obtained from 40 clinicians who had ordered CMA. Content included practice characteristics and perceptions, and queries about a hypothetical case involving uncertain and incidental findings. Data were analyzed using non-parametric statistical tests. Clinicians’ comfort levels differed significantly for explaining uncertain, abnormal, and normal CMA results, with lowest levels for uncertain results. Despite clinical guidelines recommending informed consent, many clinicians did not consider it pertinent to discuss the potential for CMA to reveal information concerning biological parentage or predisposition to late-onset disease, in a hypothetical case. Many non-genetics professionals ordering CMA did not feel equipped to interpret the results for patients, and articulated needs for education and access to genetics professionals. This exploratory study highlights key challenges in the practice of genomic medicine, and identifies needs for education, disseminated practice guidelines, and access to genetics professionals, especially when dealing with uncertain or unexpected findings. PMID:22989118

Too Many Referrals of Low-risk Women for BRCA1/2 Genetic Services by Family Physicians

PubMed Central

White, Della Brown; Bonham, Vence L.; Jenkins, Jean; Stevens, Nancy; McBride, Colleen M.

2009-01-01

Increasing availability and public awareness of BRCA1/2 genetic testing will increase women’s self-referrals to genetic services. The objective of this study was to examine whether patient characteristics influence family physicians’ (FPs’) referral decisions when a patient requests BRCA1/2 genetic testing. FPs (n = 284) completed a web-based survey in 2006 to assess their attitudes and practices related to using genetics in their clinical practice. Using a 2×2×2 factorial design we tested the effects of a hypothetical patient’s race, level of worry and insurance status on FPs’ decisions to refer her for BRCA1/2 testing. The patient was not appropriate for referral based on USPSTF guidelines. No patient characteristics were associated with FPs’ referral decisions. Although referral was not indicated, only 8% did not refer to genetic services, 92% referred for genetic services, and 50% referred to genetic counseling. FPs regarded it unlikely that the patient carried a mutation. However, 65% of FPs believed if they refused to refer for genetic services it would harm their relationship with the patient. Despite scarce and costly genetic services FPs were likely to inappropriately refer a low-risk patient who requested BRCA1/2 testing. The implications of this inappropriate referral on women’s screening behavior, genetic services, and health care costs are unknown. Clinicians and patients could benefit from education about appropriate use of genetic services so that both are more comfortable with a decision against referral. PMID:18990739

Gaps in Incorporating Germline Genetic Testing Into Treatment Decision-Making for Early-Stage Breast Cancer.

PubMed

Kurian, Allison W; Li, Yun; Hamilton, Ann S; Ward, Kevin C; Hawley, Sarah T; Morrow, Monica; McLeod, M Chandler; Jagsi, Reshma; Katz, Steven J

2017-07-10

Purpose Genetic testing for breast cancer risk is evolving rapidly, with growing use of multiple-gene panels that can yield uncertain results. However, little is known about the context of such testing or its impact on treatment. Methods A population-based sample of patients with breast cancer diagnosed in 2014 to 2015 and identified by two SEER registries (Georgia and Los Angeles) were surveyed about genetic testing experiences (N = 3,672; response rate, 68%). Responses were merged with SEER data. A patient subgroup at higher pretest risk of pathogenic mutation carriage was defined according to genetic testing guidelines. Patients' attending surgeons were surveyed about genetic testing and results management. We examined patterns and correlates of genetic counseling and testing and the impact of results on bilateral mastectomy (BLM) use. Results Six hundred sixty-six patients reported genetic testing. Although two thirds of patients were tested before surgical treatment, patients without private insurance more often experienced delays. Approximately half of patients (57% at higher pretest risk, 42% at average risk) discussed results with a genetic counselor. Patients with pathogenic mutations in BRCA1/2 or another gene had the highest rates of BLM (higher risk, 80%; average risk, 85%); however, BLM was also common among patients with genetic variants of uncertain significance (VUS; higher risk, 43%; average risk, 51%). Surgeons' confidence in discussing testing increased with volume of patients with breast cancer, but many surgeons (higher volume, 24%; lower volume, 50%) managed patients with BRCA1/2 VUS the same as patients with BRCA1/2 pathogenic mutations. Conclusion Many patients with breast cancer are tested without ever seeing a genetic counselor. Half of average-risk patients with VUS undergo BLM, suggesting a limited understanding of results that some surgeons share. These findings emphasize the need to address challenges in personalized communication about genetic testing.

Pharmacogenetic Predictors of Treatment-Related Toxicity Among Children With Acute Lymphoblastic Leukemia.

PubMed

Maxwell, Rochelle R; Cole, Peter D

2017-06-01

The aim of this review is to summarize the most recent and most robust pharmacogenetic predictors of treatment-related toxicity (TRT) in childhood acute lymphoblastic leukemia (ALL). Multiple studies have examined the toxicities of the primary chemotherapeutic agents used to treat childhood ALL in relation to host genetic factors. However, few results have been replicated independently, largely due to cohort differences in ancestry, chemotherapy treatment protocols, and definitions of toxicities. To date, there is only one widely accepted clinical guideline for dose modification based on gene status: thiopurine dosing based on TPMT genotype. Based on recent data, it is likely that this guideline will be modified to incorporate other gene variants, such as NUDT15. We highlight genetic variants that have been consistently associated with TRT across treatment groups, as well as those that best illustrate the underlying pathophysiology of TRT. In the coming decade, we expect that survivorship care will routinely specify screening recommendations based on genetics. Furthermore, clinical trials testing protective interventions may modify inclusion criteria based on genetically determined risk of specific TRTs.

[Hot topics of circulating tumor DNA testing in breast cancer].

PubMed

Liu, Y H; Zhou, B; Xu, L; Xin, L

2017-02-01

The progress of gene detection technologies represented by next generation sequencing (NGS) and digital PCR laid a foundation for studies of circulating tumor DNA (ctDNA) in breast cancer. In 2014, the NGS workgroup organized by the College of American Pathologists (CAP) published the College of American Pathologists ' Laboratory Standards for Next - Generation Sequencing Clinical Tests, which provides a blueprint for the standardization of gene testing. In 2015, the Guidelines for Diagnostic Next - generation Sequencing published by the European Society of Human Genetics claimed that NGS is unacceptable in clinical practice before studies guided by guidelines are approved. Although existing studies show the benefits of ctDNA testing in disease monitoring and prognosis analyzing, we have a ways to go to normalize the procedure and build strict detection criteria.

Predictive genetic testing for adult-onset disorders in minors: a critical analysis of the arguments for and against the 2013 ACMG guidelines.

PubMed

Anderson, J A; Hayeems, R Z; Shuman, C; Szego, M J; Monfared, N; Bowdin, S; Zlotnik Shaul, R; Meyn, M S

2015-04-01

The publication of the ACMG recommendations has reignited the debate over predictive testing for adult-onset disorders in minors. Response has been polarized. With this in mind, we review and critically analyze this debate. First, we identify long-standing inconsistencies between consensus guidelines and clinical practice regarding risk assessment for adult-onset genetic disorders in children using family history and molecular analysis. Second, we discuss the disparate assumptions regarding the nature of whole genome and exome sequencing underlying arguments of both supporters and critics, and the role these assumptions play in the arguments for and against reporting. Third, we suggest that implicit differences regarding the definition of best interests of the child underlie disparate conclusions as to the best interests of children in this context. We conclude by calling for clarity and consensus concerning the central foci of this debate. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Lifestyle Risk Factors Among People Who Have Had Cancer Genetic Testing.

PubMed

Quillin, John M

2016-10-01

Hereditary cancer genetic counseling often focuses on medically intensive risk-reduction strategies, like imaging and risk-reducing surgeries. Lifestyle factors also influence cancer risk, but health behavior counseling is not common in genetic counseling. Information about typical lifestyle risk factors among patients seeking hereditary cancer risk is sparse. The current study describes cancer risk-relevant lifestyle factors for people who have had cancer genetic testing. Data came from the Health Information National Trends Survey (HINTS 4) collected in 2013. Analytic variables represented American Cancer Society nutrition and physical activity guidelines. Lifestyle factors were assessed for people who had undergone testing for BRCA1, BRCA2, or Lynch Syndrome genes. Among 3016 HINTS respondents, 135 had cancer genetic testing. Of these, 58 % were overweight or obese. Eighteen percent reported no moderate-intensity physical activity. Average sedentary screen-time was 3.4 h (SE = 0.472) daily. Sixty-three percent drank non-diet soda, and 23 % of these people drank soda every day. Between 18 and 36 % consumed less than 2 ½ cups fruits/vegetables daily. Twenty-four percent were current smokers. Lifestyle risk factors were not different between people who had genetic testing and those who had not. In conclusion, most people who had genetic testing for cancer susceptibility have at least one modifiable risk factor. Genetic counselors have opportunities to impact a counselee's cancer risk not only through risk-tailored medical procedures, but also through lifestyle modification recommendations. Results of the current study may foster a broader discussion of genetic counselors' roles in healthy lifestyle education.

40 CFR 798.5265 - The salmonella typhimurium reverse mutation assay.

Code of Federal Regulations, 2011 CFR

2011-07-01

..., exogenous glucose 6-phosphate dehydrogenase, NADH and excess of glucose-6-phosphate. (5) Control groups—(i... (CONTINUED) TOXIC SUBSTANCES CONTROL ACT (CONTINUED) HEALTH EFFECTS TESTING GUIDELINES Genetic Toxicity § 798... number of spontaneous revertants in an untreated and/or vehicle control culture. (2) Description. Several...

40 CFR 798.5265 - The salmonella typhimurium reverse mutation assay.

Code of Federal Regulations, 2012 CFR

2012-07-01

..., exogenous glucose 6-phosphate dehydrogenase, NADH and excess of glucose-6-phosphate. (5) Control groups—(i... (CONTINUED) TOXIC SUBSTANCES CONTROL ACT (CONTINUED) HEALTH EFFECTS TESTING GUIDELINES Genetic Toxicity § 798... number of spontaneous revertants in an untreated and/or vehicle control culture. (2) Description. Several...

40 CFR 798.5265 - The salmonella typhimurium reverse mutation assay.

Code of Federal Regulations, 2014 CFR

2014-07-01

..., exogenous glucose 6-phosphate dehydrogenase, NADH and excess of glucose-6-phosphate. (5) Control groups—(i... (CONTINUED) TOXIC SUBSTANCES CONTROL ACT (CONTINUED) HEALTH EFFECTS TESTING GUIDELINES Genetic Toxicity § 798... number of spontaneous revertants in an untreated and/or vehicle control culture. (2) Description. Several...

40 CFR 798.5265 - The salmonella typhimurium reverse mutation assay.

Code of Federal Regulations, 2013 CFR

2013-07-01

..., exogenous glucose 6-phosphate dehydrogenase, NADH and excess of glucose-6-phosphate. (5) Control groups—(i... (CONTINUED) TOXIC SUBSTANCES CONTROL ACT (CONTINUED) HEALTH EFFECTS TESTING GUIDELINES Genetic Toxicity § 798... number of spontaneous revertants in an untreated and/or vehicle control culture. (2) Description. Several...

40 CFR 798.5265 - The salmonella typhimurium reverse mutation assay.

Code of Federal Regulations, 2010 CFR

2010-07-01

..., exogenous glucose 6-phosphate dehydrogenase, NADH and excess of glucose-6-phosphate. (5) Control groups—(i... (CONTINUED) TOXIC SUBSTANCES CONTROL ACT (CONTINUED) HEALTH EFFECTS TESTING GUIDELINES Genetic Toxicity § 798... number of spontaneous revertants in an untreated and/or vehicle control culture. (2) Description. Several...

Changes in screening behaviors and attitudes toward screening from pre-test genetic counseling to post-disclosure in Lynch syndrome families.

PubMed

Burton-Chase, A M; Hovick, S R; Peterson, S K; Marani, S K; Vernon, S W; Amos, C I; Frazier, M L; Lynch, P M; Gritz, E R

2013-03-01

The purpose of this study was to examine colonoscopy adherence and attitudes toward colorectal cancer (CRC) screening in individuals who underwent Lynch syndrome genetic counseling and testing. We evaluated changes in colonoscopy adherence and CRC screening attitudes in 78 cancer-unaffected relatives of Lynch syndrome mutation carriers before pre-test genetic counseling (baseline) and at 6 and 12 months post-disclosure of test results (52 mutation negative and 26 mutation positive). While both groups were similar at baseline, at 12 months post-disclosure, a greater number of mutation-positive individuals had had a colonoscopy compared with mutation-negative individuals. From baseline to 12 months post-disclosure, the mutation-positive group demonstrated an increase in mean scores on measures of colonoscopy commitment, self-efficacy, and perceived benefits of CRC screening, and a decrease in mean scores for perceived barriers to CRC screening. Mean scores on colonoscopy commitment decreased from baseline to 6 months in the mutation-negative group. To conclude, adherence to risk-appropriate guidelines for CRC surveillance improved after genetic counseling and testing for Lynch syndrome. Mutation-positive individuals reported increasingly positive attitudes toward CRC screening after receiving genetic test results, potentially reinforcing longer term colonoscopy adherence. © 2013 John Wiley & Sons A/S.

Precision Cardiovascular Medicine: State of Genetic Testing.

PubMed

Giudicessi, John R; Kullo, Iftikhar J; Ackerman, Michael J

2017-04-01

In the 15 years following the release of the first complete human genome sequences, our understanding of rare and common genetic variation as determinants of cardiovascular disease susceptibility, prognosis, and therapeutic response has grown exponentially. As such, the use of genomics to enhance the care of patients with cardiovascular diseases has garnered increased attention from clinicians, researchers, and regulatory agencies eager to realize the promise of precision genomic medicine. However, owing to a large burden of "complex" common diseases, emphasis on evidence-based practice, and a degree of unfamiliarity/discomfort with the language of genomic medicine, the development and implementation of genomics-guided approaches designed to further individualize the clinical management of a variety of cardiovascular disorders remains a challenge. In this review, we detail a practical approach to genetic testing initiation and interpretation as well as review the current state of cardiovascular genetic and pharmacogenomic testing in the context of relevant society and regulatory agency recommendations/guidelines. Copyright © 2017 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.

Consensus for genes to be included on cancer panel tests offered by UK genetics services: guidelines of the UK Cancer Genetics Group.

PubMed

Taylor, Amy; Brady, Angela F; Frayling, Ian M; Hanson, Helen; Tischkowitz, Marc; Turnbull, Clare; Side, Lucy

2018-04-16

Genetic testing for hereditary cancer predisposition has evolved rapidly in recent years with the discovery of new genes, but there is much debate over the clinical utility of testing genes for which there are currently limited data regarding the degree of associated cancer risk. To address the discrepancies that have arisen in the provision of these tests across the UK, the UK Cancer Genetics Group facilitated a 1-day workshop with representation from the majority of National Health Service (NHS) clinical genetics services. Using a preworkshop survey followed by focused discussion of genes without prior majority agreement for inclusion, we achieved consensus for panels of cancer genes with sufficient evidence for clinical utility, to be adopted by all NHS genetics services. To support consistency in the delivery of these tests and advice given to families across the country, we also developed management proposals for individuals who are found to have pathogenic mutations in these genes. However, we fully acknowledge that the decision regarding what test is most appropriate for an individual family rests with the clinician, and will depend on factors including specific phenotypic features and the family structure. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Genetic consultation embedded in a gynecologic oncology clinic improves compliance with guideline-based care.

PubMed

Senter, Leigha; O'Malley, David M; Backes, Floor J; Copeland, Larry J; Fowler, Jeffery M; Salani, Ritu; Cohn, David E

2017-10-01

Analyze the impact of embedding genetic counseling services in gynecologic oncology on clinician referral and patient uptake of cancer genetics services. Data were reviewed for a total of 737 newly diagnosed epithelial ovarian cancer patients seen in gynecologic oncology at a large academic medical center including 401 from 11/2011-7/2014 (a time when cancer genetics services were provided as an off-site consultation). These data were compared to data from 8/2014-9/2016 (n=336), when the model changed to the genetics embedded model (GEM), incorporating a cancer genetic counselor on-site in the gynecologic oncology clinic. A statistically significant difference in proportion of patients referred pre- and post-GEM was observed (21% vs. 44%, p<0.0001). Pre-GEM, only 38% of referred patients were actually scheduled for genetics consultation and post-GEM 82% were scheduled (p<0.00001). The difference in the time from referral to scheduling in genetics was also statistically significant (3.92months pre-GEM vs. 0.79months post-GEM, p<0.00001) as was the time from referral to completion of genetics consultation (2.52months pre-GEM vs. 1.67months post-GEM, p<0.01). Twenty-five percent of patients referred post GEM were seen by the genetic counselor on the same day as the referral. Providing cancer genetics services on-site in gynecologic oncology and modifying the process by which patients are referred and scheduled significantly increases referral to cancer genetics and timely completion of genetics consultation, improving compliance with guideline-based care. Practice changes are critical given the impact of genetic test results on treatment and familial cancer risks. Copyright © 2017 Elsevier Inc. All rights reserved.

Genetic testing in steroid-resistant nephrotic syndrome: why, who, when and how?

PubMed

Preston, Rebecca; Stuart, Helen M; Lennon, Rachel

2017-11-27

Steroid-resistant nephrotic syndrome (SRNS) is a common cause of chronic kidney disease in childhood and has a significant risk of rapid progression to end-stage renal disease. The identification of over 50 monogenic causes of SRNS has revealed dysfunction in podocyte-associated proteins in the pathogenesis of proteinuria, highlighting their essential role in glomerular function. Recent technological advances in high-throughput sequencing have enabled indication-driven genetic panel testing for patients with SRNS. The availability of genetic testing, combined with the significant phenotypic variability of monogenic SRNS, poses unique challenges for clinicians when directing genetic testing. This highlights the need for clear clinical guidelines that provide a systematic approach for mutational screening in SRNS. The likelihood of identifying a causative mutation is inversely related to age at disease onset and is increased with a positive family history or the presence of extra-renal manifestations. An unequivocal molecular diagnosis could allow for a personalised treatment approach with weaning of immunosuppressive therapy, avoidance of renal biopsy and provision of accurate, well-informed genetic counselling. Identification of novel causative mutations will continue to unravel the pathogenic mechanisms of glomerular disease and provide new insights into podocyte biology and glomerular function.

Diagnostic guidelines for newborns who screen positive in newborn screening.

PubMed

Kronn, David; Mofidi, Shideh; Braverman, Nancy; Harris, Katharine

2010-12-01

Recent expansion of the newborn screening panels has presented an interesting challenge to specialty care centers, especially the clinical genetics community. Some of the conditions in the core and secondary newborn screening panels have extremely variable clinical presentations; others are so rare that only a handful of newborns have been diagnosed with them to date (Region 4 Collaborative MS/MS project-http://region4genetics.org/msms_data_project/data_project_home.aspx). Definition of some disorders is problematic-does continued abnormality of the screening analyte constitute diagnosis or is further testing necessary? A work group of the New York Mid-Atlantic Consortium for Genetic and Newborn Screening Services (region 2), one of seven regional collaboratives funded by the Federal Health Resources and Services Administration and administered by the Maternal and Child Health Bureau (U22MC03956), has developed guidelines for the confirmation of diagnosis of the conditions in the newborn screening panels for use by the specialty care centers. The diagnostic guidelines are a work in progress and are being reviewed and revised regularly as our understanding of the newborn screened disorders improves. The aim is to make it a relevant guide for specialty care physicians and other healthcare professionals in the diagnostic workup of these patients.

Ethical and Legal Issues Regarding Selective Abortion of Fetuses with Down Syndrome.

ERIC Educational Resources Information Center

Glover, Noreen M.; Glover, Samuel J.

1996-01-01

Selective abortion of fetuses with Down syndrome is discussed in terms of abortion perspectives, genetic testing, legislation, and ethical principles. The ethical principles of autonomy, beneficence, nonmaleficence, fidelity, and justice are offered as guidelines for the examination of legal standards imposed by legislation. (Author/PB)

40 CFR 798.5300 - Detection of gene mutations in somatic cells in culture.

Code of Federal Regulations, 2011 CFR

2011-07-01

.... (5) Control groups. Positive and negative (untreated and/or vehicle) controls shall be included in.... Data shall be presented in tabular form. Individual colony counts for the treated and control groups... (CONTINUED) TOXIC SUBSTANCES CONTROL ACT (CONTINUED) HEALTH EFFECTS TESTING GUIDELINES Genetic Toxicity § 798...

40 CFR 798.5300 - Detection of gene mutations in somatic cells in culture.

Code of Federal Regulations, 2010 CFR

2010-07-01

.... (5) Control groups. Positive and negative (untreated and/or vehicle) controls shall be included in.... Data shall be presented in tabular form. Individual colony counts for the treated and control groups... (CONTINUED) TOXIC SUBSTANCES CONTROL ACT (CONTINUED) HEALTH EFFECTS TESTING GUIDELINES Genetic Toxicity § 798...

40 CFR 798.5300 - Detection of gene mutations in somatic cells in culture.

Code of Federal Regulations, 2012 CFR

2012-07-01

.... (5) Control groups. Positive and negative (untreated and/or vehicle) controls shall be included in.... Data shall be presented in tabular form. Individual colony counts for the treated and control groups... (CONTINUED) TOXIC SUBSTANCES CONTROL ACT (CONTINUED) HEALTH EFFECTS TESTING GUIDELINES Genetic Toxicity § 798...

40 CFR 798.5300 - Detection of gene mutations in somatic cells in culture.

Code of Federal Regulations, 2013 CFR

2013-07-01

.... (5) Control groups. Positive and negative (untreated and/or vehicle) controls shall be included in.... Data shall be presented in tabular form. Individual colony counts for the treated and control groups... (CONTINUED) TOXIC SUBSTANCES CONTROL ACT (CONTINUED) HEALTH EFFECTS TESTING GUIDELINES Genetic Toxicity § 798...

40 CFR 798.5300 - Detection of gene mutations in somatic cells in culture.

Code of Federal Regulations, 2014 CFR

2014-07-01

.... (5) Control groups. Positive and negative (untreated and/or vehicle) controls shall be included in.... Data shall be presented in tabular form. Individual colony counts for the treated and control groups... (CONTINUED) TOXIC SUBSTANCES CONTROL ACT (CONTINUED) HEALTH EFFECTS TESTING GUIDELINES Genetic Toxicity § 798...

American Epilepsy Society

MedlinePlus

... Epilepsy Society CLINICAL RESOURCES FAQs GUIDELINES IOM EPILEPSY MEDICAL MARIJUANA SUDEP SURGERY DEVICES GENETICS TREATMENTS Drug Alerts and ... RESOURCES Navigation CLINICAL RESOURCES FAQs GUIDELINES IOM EPILEPSY MEDICAL MARIJUANA SUDEP SURGERY DEVICES GENETICS TREATMENTS Drug Alerts and ...

Performance and Practice Guideline for the Use of Neoadjuvant Systemic Therapy in the Management of Breast Cancer.

PubMed

Holmes, Dennis; Colfry, A; Czerniecki, Brian; Dickson-Witmer, Diana; Francisco Espinel, C; Feldman, Elizabeth; Gallagher, Kristalyn; Greenup, Rachel; Herrmann, Virginia; Kuerer, Henry; Malik, Manmeet; Manahan, Eric; O'Neill, Jennifer; Patel, Mita; Sebastian, Molly; Wheeler, Amanda; Kass, Rena

2015-10-01

The American Society of Breast Surgeons (ASBrS) sought to provide an evidence-based guideline on the use of neoadjuvant systemic therapy (NST) in the management of clinical stage II and III invasive breast cancer. A comprehensive nonsystematic review was performed of selected peer-reviewed literature published since 2000. The Education Committee of the ASBrS convened to develop guideline recommendations. A performance and practice guideline was prepared to outline the baseline assessment and perioperative management of patients with clinical stage II-III breast cancer under consideration for NST. Preoperative or NST is emerging as an important initial strategy for the management of invasive breast cancer. From the surgeon's perspective, the primary goal of NST is to increase the resectability of locally advanced breast cancer, increase the feasibility of breast-conserving surgery and sentinel node biopsy, and decrease surgical morbidity. To ensure optimal patient selection and efficient patient care, the guideline recommends: (1) baseline breast and axillary imaging; (2) minimally invasive biopsies of breast and axillary lesions; (3) determination of tumor biomarkers; (4) systemic staging; (5) care coordination, including referrals to medical oncology, radiation oncology, plastic surgery, social work, and genetic counseling, if indicated; (6) initiation of NST; (7) post-NST breast and axillary imaging; and (8) decision for surgery based on extent of disease at presentation, patient choice, clinical response to NST, and genetic testing results, if performed.

Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing

PubMed Central

Susswein, Lisa R.; Marshall, Megan L.; Nusbaum, Rachel; Vogel Postula, Kristen J.; Weissman, Scott M.; Yackowski, Lauren; Vaccari, Erica M.; Bissonnette, Jeffrey; Booker, Jessica K.; Cremona, M. Laura; Gibellini, Federica; Murphy, Patricia D.; Pineda-Alvarez, Daniel E.; Pollevick, Guido D.; Xu, Zhixiong; Richard, Gabi; Bale, Sherri; Klein, Rachel T.; Hruska, Kathleen S.; Chung, Wendy K.

2016-01-01

Purpose: Germ-line testing for panels of cancer genes using next-generation sequencing is becoming more common in clinical care. We report our experience as a clinical laboratory testing both well-established, high-risk cancer genes (e.g., BRCA1/2, MLH1, MSH2) as well as more recently identified cancer genes (e.g., PALB2, BRIP1), many of which have increased but less well-defined penetrance. Genet Med 18 8, 823–832. Methods: Clinical genetic testing was performed on over 10,000 consecutive cases referred for evaluation of germ-line cancer genes, and results were analyzed for frequency of pathogenic or likely pathogenic variants, and were stratified by testing panel, gene, and clinical history. Genet Med 18 8, 823–832. Results: Overall, a molecular diagnosis was made in 9.0% of patients tested, with the highest yield in the Lynch syndrome/colorectal cancer panel. In patients with breast, ovarian, or colon/stomach cancer, positive yields were 9.7, 13.4, and 14.8%, respectively. Approximately half of the pathogenic variants identified in patients with breast or ovarian cancer were in genes other than BRCA1/2. Genet Med 18 8, 823–832. Conclusion: The high frequency of positive results in a wide range of cancer genes, including those of high penetrance and with clinical care guidelines, underscores both the genetic heterogeneity of hereditary cancer and the usefulness of multigene panels over genetic tests of one or two genes. Genet Med 18 8, 823–832. PMID:26681312

Direct-to-consumer genetic testing for predicting sports performance and talent identification: Consensus statement.

PubMed

Webborn, Nick; Williams, Alun; McNamee, Mike; Bouchard, Claude; Pitsiladis, Yannis; Ahmetov, Ildus; Ashley, Euan; Byrne, Nuala; Camporesi, Silvia; Collins, Malcolm; Dijkstra, Paul; Eynon, Nir; Fuku, Noriyuki; Garton, Fleur C; Hoppe, Nils; Holm, Søren; Kaye, Jane; Klissouras, Vassilis; Lucia, Alejandro; Maase, Kamiel; Moran, Colin; North, Kathryn N; Pigozzi, Fabio; Wang, Guan

2015-12-01

The general consensus among sport and exercise genetics researchers is that genetic tests have no role to play in talent identification or the individualised prescription of training to maximise performance. Despite the lack of evidence, recent years have witnessed the rise of an emerging market of direct-to-consumer marketing (DTC) tests that claim to be able to identify children's athletic talents. Targeted consumers include mainly coaches and parents. There is concern among the scientific community that the current level of knowledge is being misrepresented for commercial purposes. There remains a lack of universally accepted guidelines and legislation for DTC testing in relation to all forms of genetic testing and not just for talent identification. There is concern over the lack of clarity of information over which specific genes or variants are being tested and the almost universal lack of appropriate genetic counselling for the interpretation of the genetic data to consumers. Furthermore independent studies have identified issues relating to quality control by DTC laboratories with different results being reported from samples from the same individual. Consequently, in the current state of knowledge, no child or young athlete should be exposed to DTC genetic testing to define or alter training or for talent identification aimed at selecting gifted children or adolescents. Large scale collaborative projects, may help to develop a stronger scientific foundation on these issues in the future. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Technical standards and guidelines: prenatal screening for Down syndrome that includes first-trimester biochemistry and/or ultrasound measurements.

PubMed

Palomaki, Glenn E; Lee, Jo Ellen S; Canick, Jacob A; McDowell, Geraldine A; Donnenfeld, Alan E

2009-09-01

This statement is intended to augment the current general ACMG Standards and Guidelines for Clinical Genetics Laboratories and to address guidelines specific to first-trimester screening for Down syndrome. The aim is to provide the laboratory the necessary information to ensure accurate and reliable Down syndrome screening results given a screening protocol (e.g., combined first trimester and integrated testing). Information about various test combinations and their expected performance are provided, but other issues such as availability of reagents, patient interest in early test results, access to open neural tube defect screening, and availability of chorionic villus sampling are all contextual factors in deciding which screening protocol(s) will be selected by individual health care providers. Individual laboratories are responsible for meeting the quality assurance standards described by the Clinical Laboratory Improvement Act, the College of American Pathologists, and other regulatory agencies, with respect to appropriate sample documentation, assay validation, general proficiency, and quality control measures. These guidelines address first-trimester screening that includes ultrasound measurement and interpretation of nuchal translucency thickness and protocols that combine markers from both the first and second trimesters. Laboratories can use their professional judgment to make modification or additions.

A decade of molecular genetic testing for MODY: a retrospective study of utilization in The Netherlands.

PubMed

Weinreich, Stephanie S; Bosma, Astrid; Henneman, Lidewij; Rigter, Tessel; Spruijt, Carla M J; Grimbergen, Anneliese J E M A; Breuning, Martijn H; de Koning, Eelco J P; Losekoot, Monique; Cornel, Martina C

2015-01-01

Genetic testing for maturity-onset diabetes of the young (MODY) may be relevant for treatment and prognosis in patients with usually early-onset, non-ketotic, insulin-sensitive diabetes and for monitoring strategies in non-diabetic mutation carriers. This study describes the first 10 years of genetic testing for MODY in The Netherlands in terms of volume and test positive rate, medical setting, purpose of the test and age of patients tested. Some analyses focus on the most prevalent subtype, HNF1A MODY. Data were retrospectively extracted from a laboratory database. In total, 502 individuals were identified with a pathogenic mutation in HNF4A, GCK or HNF1A between 2001 and 2010. Although mutation scanning for MODY was used at an increasing rate, cascade testing was only used for one relative, on average, per positive index patient. Testing for HNF1A MODY was mostly requested by internists and paediatricians, often from regional hospitals. Primary care physicians and clinical geneticists rarely requested genetic testing for HNF1A MODY. Clinical geneticists requested cascade testing relatively more often than other health professionals. A substantial proportion (currently 29%) of HNF1A MODY probands was at least 40 years old at the time of testing. In conclusion, the number of individuals genetically tested for MODY so far in The Netherlands is low compared with previously predicted numbers of patients. Doctors' valuation of the test and patients' and family members' response to (an offer of) genetic testing on the other hand need to be investigated. Efforts may be needed to develop and implement translational guidelines.

Molecular Biomarkers for the Evaluation of Colorectal Cancer: Guideline From the American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and American Society of Clinical Oncology.

PubMed

Sepulveda, Antonia R; Hamilton, Stanley R; Allegra, Carmen J; Grody, Wayne; Cushman-Vokoun, Allison M; Funkhouser, William K; Kopetz, Scott E; Lieu, Christopher; Lindor, Noralane M; Minsky, Bruce D; Monzon, Federico A; Sargent, Daniel J; Singh, Veena M; Willis, Joseph; Clark, Jennifer; Colasacco, Carol; Rumble, R Bryan; Temple-Smolkin, Robyn; Ventura, Christina B; Nowak, Jan A

2017-03-01

To develop evidence-based guideline recommendations through a systematic review of the literature to establish standard molecular biomarker testing of colorectal cancer (CRC) tissues to guide epidermal growth factor receptor (EGFR) therapies and conventional chemotherapy regimens. The American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and American Society of Clinical Oncology convened an expert panel to develop an evidence-based guideline to establish standard molecular biomarker testing and guide therapies for patients with CRC. A comprehensive literature search that included more than 4,000 articles was conducted. Twenty-one guideline statements were established. Evidence supports mutational testing for EGFR signaling pathway genes, since they provide clinically actionable information as negative predictors of benefit to anti-EGFR monoclonal antibody therapies for targeted therapy of CRC. Mutations in several of the biomarkers have clear prognostic value. Laboratory approaches to operationalize CRC molecular testing are presented. Key Words: Molecular diagnostics; Gastrointestinal; Histology; Genetics; Oncology. Copyright © 2017 American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, American Society for Clinical Oncology, and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Diagnosis of primary ciliary dyskinesia: summary of the ERS Task Force report

PubMed Central

Lucas, Jane S.

2017-01-01

Key points Primary ciliary dyskinesia (PCD) is a genetically and clinically heterogeneous disease characterised by abnormal motile ciliary function. There is no “gold standard” diagnostic test for PCD. The European Respiratory Society (ERS) Task Force Guidelines for diagnosing PCD recommend that patients should be referred for diagnostic testing if they have several of the following features: persistent wet cough; situs anomalies; congenital cardiac defects; persistent rhinitis; chronic middle ear disease with or without hearing loss; or a history, in term infants, of neonatal upper and lower respiratory symptoms or neonatal intensive care admission. The ERS Task Force recommends that patients should be investigated in a specialist PCD centre with access to a range of complementary tests: nasal nitric oxide, high-speed video microscopy analysis and transmission electron microscopy. Additional tests including immunofluorescence labelling of ciliary proteins and genetic testing may also help determine the diagnosis. Educational aims This article is intended for primary and secondary care physicians interested in primary ciliary dyskinesia (PCD), i.e. those who identify patients for testing, and those involved in diagnosing and managing PCD patients. It aims: to inform readers about the new European Respiratory Society Task Force Guidelines for diagnosing patients with PCDto enable primary and secondary care physicians to: identify patients who need diagnostic testing; understand the diagnostic tests that their patients will undergo, the results of the tests and their limitations; and ensure that appropriate care is subsequently delivered. PMID:28894478

Challenges in reproducibility of genetic association studies: lessons learned from the obesity field.

PubMed

Li, A; Meyre, D

2013-04-01

A robust replication of initial genetic association findings has proved to be difficult in human complex diseases and more specifically in the obesity field. An obvious cause of non-replication in genetic association studies is the initial report of a false positive result, which can be explained by a non-heritable phenotype, insufficient sample size, improper correction for multiple testing, population stratification, technical biases, insufficient quality control or inappropriate statistical analyses. Replication may, however, be challenging even when the original study describes a true positive association. The reasons include underpowered replication samples, gene × gene, gene × environment interactions, genetic and phenotypic heterogeneity and subjective interpretation of data. In this review, we address classic pitfalls in genetic association studies and provide guidelines for proper discovery and replication genetic association studies with a specific focus on obesity.

Development of hardwood seed zones for Tennessee using a geographic information system

USGS Publications Warehouse

Post, L.S.; Schlarbaum, S.E.; Van Manen, F.; Cecich, R.A.; Saxton, A.M.; Schneider, J.F.

2003-01-01

For species that have no or limited information on genetic variation and adaptability to nonnative sites, there is a need for seed collection guidelines based on biological, climatological, and/or geographical criteria. Twenty-eight hardwood species are currently grown for reforestation purposes at the East Tennessee State Nursery. The majority of these species have had no genetic testing to define guidelines for seed collection location and can be distributed to sites that have a very different environment than that of seed origin(s). Poor survival and/or growth may result if seedlings are not adapted to environmental conditions at the planting location. To address this problem, 30 yr of Tennessee county precipitation and minimum temperature data were analyzed and grouped using a centroid hierarchical cluster analysis. The weather data and elevational data were entered into a Geographic Information System (GIS) and separately layered over Bailey's Ecoregions to develop a seed zone system for Tennessee. The seed zones can be used as a practical guideline for collecting seeds to ensure that the resulting seedlings will be adapted to planting environments.

Classification and Reporting of Potentially Proarrhythmic Common Genetic Variation in Long QT Syndrome Genetic Testing.

PubMed

Giudicessi, John R; Roden, Dan M; Wilde, Arthur A M; Ackerman, Michael J

2018-02-06

The acquired and congenital forms of long QT syndrome represent 2 distinct but clinically and genetically intertwined disorders of cardiac repolarization characterized by the shared final common pathway of QT interval prolongation and risk of potentially life-threatening arrhythmias. Over the past 2 decades, our understanding of the spectrum of genetic variation that (1) perturbs the function of cardiac ion channel macromolecular complexes and intracellular calcium-handling proteins, (2) underlies acquired/congenital long QT syndrome susceptibility, and (3) serves as a determinant of QT interval duration in the general population has grown exponentially. In turn, these molecular insights led to the development and increased utilization of clinically impactful genetic testing for congenital long QT syndrome. However, the widespread adoption and potential misinterpretation of the 2015 American College of Medical Genetics and Genomics variant classification and reporting guidelines may have contributed unintentionally to the reduced reporting of common genetic variants, with compelling epidemiological and functional evidence to support a potentially proarrhythmic role in patients with congenital and acquired long QT syndrome. As a result, some genetic testing reports may fail to convey the full extent of a patient's genetic susceptibility for a potentially life-threatening arrhythmia to the ordering healthcare professional. In this white paper, we examine the current classification and reporting (or lack thereof) of potentially proarrhythmic common genetic variants and investigate potential mechanisms to facilitate the reporting of these genetic variants without increasing the risk of diagnostic miscues. © 2018 American Heart Association, Inc.

The effect of referral for genetic counseling on genetic testing and surgical prevention in women at high risk for ovarian cancer: Results from a randomized controlled trial.

PubMed

Drescher, Charles W; Beatty, J David; Resta, Robert; Andersen, M Robyn; Watabayashi, Kate; Thorpe, Jason; Hawley, Sarah; Purkey, Hannah; Chubak, Jessica; Hanson, Nancy; Buist, Diana S M; Urban, Nicole

2016-07-22

Guidelines recommend genetic counseling and testing for women who have a pedigree suggestive of an inherited susceptibility for ovarian cancer. The authors evaluated the effect of referral to genetic counseling on genetic testing and prophylactic oophorectomy in a randomized controlled trial. Data from an electronic mammography reporting system identified 12,919 women with a pedigree that included breast cancer, of whom 625 were identified who had a high risk for inherited susceptibility to ovarian cancer using a risk-assessment questionnaire. Of these, 458 women provided informed consent and were randomized 1:1 to intervention consisting of a genetic counseling referral (n = 228) or standard clinical care (n = 230). Participants were predominantly aged 45 to 65 years, and 30% and 20% reported a personal history of breast cancer or a family history of ovarian cancer, respectively. Eighty-five percent of women in the intervention group participated in a genetic counseling session. Genetic testing was reported by 74 (33%) and 20 (9%) women in the intervention and control arms (P < .005), respectively. Five women in the intervention arm and 2 in the control arm were identified as germline mutation carriers. Ten women in the intervention arm and 3 in the control arm underwent prophylactic bilateral salpingo-oophorectomy (P < .05). Routine referral of women at high risk for ovarian cancer to genetic counseling promotes genetic testing and prophylactic surgery. The findings from the current randomized controlled trial demonstrate the value of implementing strategies that target women at high risk for ovarian cancer to ensure they are offered access to recommended care. CA Cancer J Clin 2016. © 2016 American Cancer Society, Inc. © 2016 American Cancer Society.

Current perspectives on recommendations for BRCA genetic testing in ovarian cancer patients.

PubMed

Vergote, Ignace; Banerjee, Susana; Gerdes, Anne-Marie; van Asperen, Christi; Marth, Christian; Vaz, Fatima; Ray-Coquard, Isabelle; Stoppa-Lyonnet, Dominique; Gonzalez-Martin, Antonio; Sehouli, Jalid; Colombo, Nicoletta

2016-12-01

Traditionally, BRCA genetic testing has been undertaken to identify patients and family members at future risk of developing cancer and patients have been referred for testing based on family history. However, the now recognised risk of ovarian cancer (OC) patients, even those with no known family history, harbouring a mutation in BRCA1/2, together with the first poly adenosine diphosphate ribose polymerase inhibitor (PARPi; olaparib [Lynparza]) being licenced for the treatment of BRCA-mutated OC, has led to reconsideration of referral criteria for OC patients. Provided here is a review of the existing data and guidelines in the European Union, relating to recommendations, as well as considerations, for the referral of OC patients for BRCA genetic testing. Based on this review of newly updated guidance and up-to-date evidence, the following is recommended: all patients with invasive epithelial OC (excluding borderline or mucinous), including those with fallopian tube and peritoneal cancers, should be considered as candidates for referral for BRCA genetic testing, irrespective of age; genetic testing should ideally be offered at diagnosis, although patients can be referred at any stage; retrospective testing should be offered to patients in long-term follow-up because of the implications for family members and individual future breast cancer risk; and germline BRCA testing of a blood/saliva sample should initially be conducted and, if negative, tumour tissue should be tested (to identify non-germline [somatic] BRCA PARPi therapy candidates). Copyright © 2016 Elsevier Ltd. All rights reserved.

[Genetics and family medicine].

PubMed

Bugarín-González, R; Carracedo, Á

There have been spectacular advances in genetics in the last decades. Their implications in medicine have been so relevant that the family doctor cannot ignore them. However, interestingly, our specialty training program has hardly any contents related to this discipline. For this reason, several publications have warned of the need to correct this deficit and to determine the knowledge, skills and abilities in genetics that should be acquired by family physicians. It is considered that, in addition to some general concepts, we must have training related to genetic testing, genetic counselling, aspects related to hereditary cancers, and to be aware of the ethical and legal limits of genetic information. It is also necessary to establish guidelines for collaboration with the genetic services. Copyright © 2017 Sociedad Española de Médicos de Atención Primaria (SEMERGEN). Publicado por Elsevier España, S.L.U. All rights reserved.

Prenatal Diagnosis Procedures and Techniques to Obtain a Diagnostic Fetal Specimen or Tissue: Maternal and Fetal Risks and Benefits.

PubMed

Wilson, R Douglas; Gagnon, Alain; Audibert, François; Campagnolo, Carla; Carroll, June

2015-07-01

To provide maternity care providers and their patients with current evidence-based guidelines for maternal risk/benefit counselling for a prenatally identified at-risk pregnancy that requires ultrasound-guided prenatal diagnostic procedures and/or techniques for a genetic diagnosis and for subsequent pregnancy management decisions on questions such as level of obstetrical care provider, antenatal surveillance, location of care and delivery, and continuation or termination of pregnancy. This guideline is limited to maternal risk/benefit counselling and pregnancy management decisions for women who require, or are considering, an invasive ultrasound-guided procedure or technique for prenatal diagnosis. Pregnant women identified as having an increased risk of a fetal genetic abnormality secondary to the process of established prenatal screening protocols (maternal serum±imaging, high-risk cell-free DNA results, abnormal diagnostic fetal imaging, or a positive family history of an inherited condition). These women may require or request counselling about pregnancy risks and benefits of an invasive ultrasound-guided procedure to determine the etiology, diagnosis, and/or pathology for the possible fetal anomaly or anomalies. Published literature was retrieved through searches of Medline, PubMed, and the Cochrane Library in and prior to June 2014 using an appropriate controlled vocabulary (prenatal diagnosis, amniocentesis, chorionic villi sampling, cordocentesis) and key words (prenatal screening, prenatal genetic counselling, post-procedural pregnancy loss rate). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies written in English and published from January 1985 to June 2014. Searches were updated on a regular basis and incorporated in the guideline to June 2014. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical speciality societies. The quality of evidence in this document was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table 1). Health benefits, side effects, and risks: Patient informed consent, knowledge translation, genetic prenatal risk assessment, anxiety relief, anxiety creation, advocacy, understanding or limitation for fetal testing, pregnancy management choice, pregnancy complication or loss, timely and improved care for birth of a neonate with recognized morbidity. Recommendations 1. The health care provider should counsel the at-risk pregnant woman on the different levels of genetic fetal testing in order for her to have a clear understanding and expectation of the level of testing and type of results that are offered. (III-B) 2. As part of the informed consent process, the health care provider should review with the at-risk pregnant woman the risks and benefits of in utero genetic diagnostic techniques associated with fetal genetic testing options. (III-A) 3. During risk/benefit counselling, the health care provider should advise that the best estimate of the pregnancy loss rate related to: a.amniocentesis is 0.5% to 1.0% (range 0.17 to 1.53%) (I) b.chorionic villus sampling is 0.5% to 1.0% (I) and c.cordocentesis or percutaneous umbilical blood sampling is 1.3% for fetuses with no anomalies and 1.3% to 25% for fetuses with single or multiple anomalies or intrauterine growth restriction. (II-2A).

40 CFR 798.5500 - Differential growth inhibition of repair proficient and repair deficient bacteria: “Bacterial DNA...

Code of Federal Regulations, 2012 CFR

2012-07-01

..., tissues or techniques may also be appropriate. (6) Control groups—(i) Concurrent controls. Concurrent positive, negative, and vehicle controls should be included in each assay. (ii) Negative controls. The... CONTROL ACT (CONTINUED) HEALTH EFFECTS TESTING GUIDELINES Genetic Toxicity § 798.5500 Differential growth...

40 CFR 798.5500 - Differential growth inhibition of repair proficient and repair deficient bacteria: “Bacterial DNA...

Code of Federal Regulations, 2013 CFR

2013-07-01

..., tissues or techniques may also be appropriate. (6) Control groups—(i) Concurrent controls. Concurrent positive, negative, and vehicle controls should be included in each assay. (ii) Negative controls. The... CONTROL ACT (CONTINUED) HEALTH EFFECTS TESTING GUIDELINES Genetic Toxicity § 798.5500 Differential growth...

40 CFR 798.5500 - Differential growth inhibition of repair proficient and repair deficient bacteria: “Bacterial DNA...

Code of Federal Regulations, 2011 CFR

2011-07-01

..., tissues or techniques may also be appropriate. (6) Control groups—(i) Concurrent controls. Concurrent positive, negative, and vehicle controls should be included in each assay. (ii) Negative controls. The... CONTROL ACT (CONTINUED) HEALTH EFFECTS TESTING GUIDELINES Genetic Toxicity § 798.5500 Differential growth...

40 CFR 798.5500 - Differential growth inhibition of repair proficient and repair deficient bacteria: “Bacterial DNA...

Code of Federal Regulations, 2014 CFR

2014-07-01

..., tissues or techniques may also be appropriate. (6) Control groups—(i) Concurrent controls. Concurrent positive, negative, and vehicle controls should be included in each assay. (ii) Negative controls. The... CONTROL ACT (CONTINUED) HEALTH EFFECTS TESTING GUIDELINES Genetic Toxicity § 798.5500 Differential growth...

Predictive Medicine: Recombinant DNA Technology and Adult-Onset Genetic Disorders

PubMed Central

Hayden, Michael

1988-01-01

Genetic factors are of great importance in common adult-onset disorders such as atherosclerosis, cancer, and neuro-degenerative diseases. Advances in DNA technology now allow identification of persons at high-risk of developing some of these diseases. This advance is leading to predictive medicine. In some genetic disorders, such as those leading to atherosclerosis and cancer, identification of high-risk individuals allows intervention which alters the natural history of the disorder. In other diseases, for which there is no treatment, such as Huntington's disease, the application of this technology provides information that relieves uncertainty and may affect quality of life, but does not alter the course of the illness. General implementation of predictive testing programs awaits the results of pilot projects, which will demonstrate the needs, appropriate levels of support, and guidelines for delivery of such testing. PMID:21253100

Expert guidelines for the management of Alport syndrome and thin basement membrane nephropathy.

PubMed

Savige, Judy; Gregory, Martin; Gross, Oliver; Kashtan, Clifford; Ding, Jie; Flinter, Frances

2013-02-01

Few prospective, randomized controlled clinical trials address the diagnosis and management of patients with Alport syndrome or thin basement membrane nephropathy. Adult and pediatric nephrologists and geneticists from four continents whose clinical practice focuses on these conditions have developed the following guidelines. The 18 recommendations are based on Level D (Expert opinion without explicit critical appraisal, or based on physiology, bench research, or first principles-National Health Service category) or Level III (Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees-U.S. Preventive Services Task Force) evidence. The recommendations include the use of genetic testing as the gold standard for the diagnosis of Alport syndrome and the demonstration of its mode of inheritance; the need to identify and follow all affected members of a family with X-linked Alport syndrome, including most mothers of affected males; the treatment of males with X-linked Alport syndrome and individuals with autosomal recessive disease with renin-angiotensin system blockade, possibly even before the onset of proteinuria; discouraging the affected mothers of males with X-linked Alport syndrome from renal donation because of their own risk of kidney failure; and consideration of genetic testing to exclude X-linked Alport syndrome in some individuals with thin basement membrane nephropathy. The authors recognize that as evidence emerges, including data from patient registries, these guidelines will evolve further.

Pharmacoeconomic evaluations of pharmacogenetic and genomic screening programmes: a systematic review on content and adherence to guidelines.

PubMed

Vegter, Stefan; Boersma, Cornelis; Rozenbaum, Mark; Wilffert, Bob; Navis, Gerjan; Postma, Maarten J

2008-01-01

The fields of pharmacogenetics and pharmacogenomics have become important practical tools to progress goals in medical and pharmaceutical research and development. As more screening tests are being developed, with some already used in clinical practice, consideration of cost-effectiveness implications is important. A systematic review was performed on the content of and adherence to pharmacoeconomic guidelines of recent pharmacoeconomic analyses performed in the field of pharmacogenetics and pharmacogenomics. Economic analyses of screening strategies for genetic variations, which were evidence-based and assumed to be associated with drug efficacy or safety, were included in the review. The 20 papers included cover a variety of healthcare issues, including screening tests on several cytochrome P450 (CYP) enzyme genes, thiopurine S-methyltransferase (TMPT) and angiotensin-converting enzyme (ACE) insertion deletion (ACE I/D) polymorphisms. Most economic analyses reported that genetic screening was cost effective and often even clearly dominated existing non-screening strategies. However, we found a lack of standardization regarding aspects such as the perspective of the analysis, factors included in the sensitivity analysis and the applied discount rates. In particular, an important limitation of several studies related to the failure to provide a sufficient evidence-based rationale for an association between genotype and phenotype. Future economic analyses should be conducted utilizing correct methods, with adherence to guidelines and including extensive sensitivity analyses. Most importantly, genetic screening strategies should be based on good evidence-based rationales. For these goals, we provide a list of recommendations for good pharmacoeconomic practice deemed useful in the fields of pharmacogenetics and pharmacogenomics, regardless of country and origin of the economic analysis.

The micropolitics of responsibility vis-à-vis autonomy: parental accounts of childhood genetic testing and (non)disclosure.

PubMed

Arribas-Ayllon, Michael; Sarangi, Srikant; Clarke, Angus

2008-03-01

Genetic testing and (non)disclosure of genetic information present ethical and moral dilemmas for the management of parental responsibility vis-à-vis the child's autonomy. Ethical guidelines aimed at professionals currently seek to defer childhood testing where there is no clear medical or psychosocial benefit. This version of autonomy is derived from a bioethical paradigm which brackets the individual rights and capacities of the child. In this paper we focus on situated parental accounts of responsibility/autonomy to understand the complex forms of relational work -i.e. the micropolitics of balancing rights and responsibilities - involving a range of inherited genetic disorders. Interviews (n= 20) were conducted with parents whose genetic condition may have had consequences for their children. Using rhetorical discourse analysis, we show how parents draw upon a number of rhetorical/discoursal devices to produce accounts where genetic responsibility is actually or potentially transmitted to the child. We identify three kinds of accounting practice: (1) aligned responsibility; (2) deferred responsibility; and (3) misaligned responsibility. Each of these practices demonstrates how parents position themselves responsibly by foregrounding figures and events onto which the child's autonomy is selectively mapped. Rather than simple representations, we regard these accounts as complex moral performances that seek alignment with broader bioethical discourses.

Utility of Post-Mortem Genetic Testing in Cases of Sudden Arrhythmic Death Syndrome.

PubMed

Lahrouchi, Najim; Raju, Hariharan; Lodder, Elisabeth M; Papatheodorou, Efstathios; Ware, James S; Papadakis, Michael; Tadros, Rafik; Cole, Della; Skinner, Jonathan R; Crawford, Jackie; Love, Donald R; Pua, Chee J; Soh, Bee Y; Bhalshankar, Jaydutt D; Govind, Risha; Tfelt-Hansen, Jacob; Winkel, Bo G; van der Werf, Christian; Wijeyeratne, Yanushi D; Mellor, Greg; Till, Jan; Cohen, Marta C; Tome-Esteban, Maria; Sharma, Sanjay; Wilde, Arthur A M; Cook, Stuart A; Bezzina, Connie R; Sheppard, Mary N; Behr, Elijah R

2017-05-02

Sudden arrhythmic death syndrome (SADS) describes a sudden death with negative autopsy and toxicological analysis. Cardiac genetic disease is a likely etiology. This study investigated the clinical utility and combined yield of post-mortem genetic testing (molecular autopsy) in cases of SADS and comprehensive clinical evaluation of surviving relatives. We evaluated 302 expertly validated SADS cases with suitable DNA (median age: 24 years; 65% males) who underwent next-generation sequencing using an extended panel of 77 primary electrical disorder and cardiomyopathy genes. Pathogenic and likely pathogenic variants were classified using American College of Medical Genetics (ACMG) consensus guidelines. The yield of combined molecular autopsy and clinical evaluation in 82 surviving families was evaluated. A gene-level rare variant association analysis was conducted in SADS cases versus controls. A clinically actionable pathogenic or likely pathogenic variant was identified in 40 of 302 cases (13%). The main etiologies established were catecholaminergic polymorphic ventricular tachycardia and long QT syndrome (17 [6%] and 11 [4%], respectively). Gene-based rare variants association analysis showed enrichment of rare predicted deleterious variants in RYR2 (p = 5 × 10 -5 ). Combining molecular autopsy with clinical evaluation in surviving families increased diagnostic yield from 26% to 39%. Molecular autopsy for electrical disorder and cardiomyopathy genes, using ACMG guidelines for variant classification, identified a modest but realistic yield in SADS. Our data highlighted the predominant role of catecholaminergic polymorphic ventricular tachycardia and long QT syndrome, especially the RYR2 gene, as well as the minimal yield from other genes. Furthermore, we showed the enhanced utility of combined clinical and genetic evaluation. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Stakeholder Buy-In and Physician Education Improve Adherence to Guidelines for Down Syndrome.

PubMed

Santoro, Stephanie L; Martin, Lisa J; Pleatman, Stephen I; Hopkin, Robert J

2016-04-01

To assess adherence to the 2011 American Academy of Pediatrics (AAP) health supervision guidelines for Down syndrome, to determine whether pediatrician education improves adherence, and to evaluate stakeholder attitudes toward these guidelines. Twenty-two pediatric care sites participated in chart review of adherence to the components of the AAP guidelines for Down syndrome in this longitudinal cohort study. We analyzed universal recommendations which apply to all children with Down syndrome. Thirteen pediatric practices caring for 82 patients with Down syndrome received educational information. Frequency calculations with Bonferroni adjustment of the P value threshold (P = .05/9 = .0056) were performed. Adherence rates were compared between cohorts and within the individual before and after intervention using 2 × 2 contingency tables and goodness-of-fit tests. Pediatricians and parents of children with Down syndrome completed an anonymous survey regarding their attitudes toward the guidelines. Statistically significant increases in adherence were seen in 5 of the 8 universal recommendations following pediatrician education (P ≤ .002), including cardiology and genetics visits, rates of echocardiography, annual audiology testing, and sleep studies by age 4 years. Both physicians and parents reported generally positive views of the guidelines, yet baseline adherence rates were suboptimal. Pediatrician education preferences include directly integrating the guidelines into an electronic medical record system. Stakeholder attitudes reflect a willingness to follow the AAP guidelines for Down syndrome. Providing rapid access to simple, clear reminders of recommended assessments successfully improved adherence to the AAP guidelines for Down syndrome. Copyright © 2016 Elsevier Inc. All rights reserved.

Contemporary genetic testing in inherited cardiac disease: tools, ethical issues, and clinical applications.

PubMed

Girolami, Francesca; Frisso, Giulia; Benelli, Matteo; Crotti, Lia; Iascone, Maria; Mango, Ruggiero; Mazzaccara, Cristina; Pilichou, Kalliope; Arbustini, Eloisa; Tomberli, Benedetta; Limongelli, Giuseppe; Basso, Cristina; Olivotto, Iacopo

2018-01-01

: Inherited cardiac diseases comprise a wide and heterogeneous spectrum of diseases of the heart, including the cardiomyopathies and the arrhythmic diseases in structurally normal hearts, that is, channelopathies. With a combined estimated prevalence of 3% in the general population, these conditions represent a relevant epidemiological entity worldwide, and are a major cause of cardiac morbidity and mortality in the young. The extraordinary progress achieved in molecular genetics over the last three decades has unveiled the complex molecular basis of many familial cardiac conditions, paving the way for routine use of gene testing in clinical practice. In current practice, genetic testing can be used in a clinically affected patient to confirm diagnosis, or to formulate a differential diagnosis among overlapping phenotypes or between hereditary and acquired (nongenetic) forms of disease. Although genotype-phenotype correlations are generally unpredictable, a precise molecular diagnosis can help predict prognosis in specific patient subsets and may guide management. In clinically unaffected relatives, genetic cascade testing is recommended, after the initial identification of a pathogenic variation, with the aim of identifying asymptomatic relatives who might be at risk of disease-related complications, including unexpected sudden cardiac death. Future implications include the identification of novel therapeutic targets and development of tailored treatments including gene therapy. This document reflects the multidisciplinary, 'real-world' experience required when implementing genetic testing in cardiomyopathies and arrhythmic syndromes, along the recommendations of various guidelines.

Contemporary genetic testing in inherited cardiac disease: tools, ethical issues, and clinical applications

PubMed Central

Girolami, Francesca; Frisso, Giulia; Benelli, Matteo; Crotti, Lia; Iascone, Maria; Mango, Ruggiero; Mazzaccara, Cristina; Pilichou, Kalliope; Arbustini, Eloisa; Tomberli, Benedetta; Limongelli, Giuseppe; Basso, Cristina; Olivotto, Iacopo

2018-01-01

Inherited cardiac diseases comprise a wide and heterogeneous spectrum of diseases of the heart, including the cardiomyopathies and the arrhythmic diseases in structurally normal hearts, that is, channelopathies. With a combined estimated prevalence of 3% in the general population, these conditions represent a relevant epidemiological entity worldwide, and are a major cause of cardiac morbidity and mortality in the young. The extraordinary progress achieved in molecular genetics over the last three decades has unveiled the complex molecular basis of many familial cardiac conditions, paving the way for routine use of gene testing in clinical practice. In current practice, genetic testing can be used in a clinically affected patient to confirm diagnosis, or to formulate a differential diagnosis among overlapping phenotypes or between hereditary and acquired (nongenetic) forms of disease. Although genotype–phenotype correlations are generally unpredictable, a precise molecular diagnosis can help predict prognosis in specific patient subsets and may guide management. In clinically unaffected relatives, genetic cascade testing is recommended, after the initial identification of a pathogenic variation, with the aim of identifying asymptomatic relatives who might be at risk of disease-related complications, including unexpected sudden cardiac death. Future implications include the identification of novel therapeutic targets and development of tailored treatments including gene therapy. This document reflects the multidisciplinary, ‘real-world’ experience required when implementing genetic testing in cardiomyopathies and arrhythmic syndromes, along the recommendations of various guidelines. PMID:29176389

Verification of consumers' experiences and perceptions of genetic discrimination and its impact on utilization of genetic testing.

PubMed

Barlow-Stewart, Kristine; Taylor, Sandra D; Treloar, Susan A; Stranger, Mark; Otlowski, Margaret

2009-03-01

To undertake a systematic process of verification of consumer accounts of alleged genetic discrimination. Verification of incidents reported in life insurance and other contexts that met the criteria of genetic discrimination, and the impact of fear of such treatment, was determined, with consent, through interview, document analysis and where appropriate, direct contact with the third party involved. The process comprised obtaining evidence that the alleged incident was accurately reported and determining whether the decision or action seemed to be justifiable and/or ethical. Reported incidents of genetic discrimination were verified in life insurance access, underwriting and coercion (9), applications for worker's compensation (1) and early release from prison (1) and in two cases of fear of discrimination impacting on access to genetic testing. Relevant conditions were inherited cancer susceptibility (8), Huntington disease (3), hereditary hemochromatosis (1), and polycystic kidney disease (1). In two cases, the reversal of an adverse underwriting decision to standard rate after intervention with insurers by genetics health professionals was verified. The mismatch between consumer and third party accounts in three life insurance incidents involved miscommunication or lack of information provision by financial advisers. These first cases of verified genetic discrimination make it essential for policies and guidelines to be developed and implemented to ensure appropriate use of genetic test results in insurance underwriting, to promote education and training in the financial industry, and to provide support for consumers and health professionals undertaking challenges of adverse decisions.

Practical aspects of mutagenicity testing strategy: an industrial perspective.

PubMed

Gollapudi, B B; Krishna, G

2000-11-20

Genetic toxicology studies play a central role in the development and marketing of new chemicals for pharmaceutical, agricultural, industrial, and consumer use. During the discovery phase of product development, rapid screening tests that require minimal amounts of test materials are used to assist in the design and prioritization of new molecules. At this stage, a modified Salmonella reverse mutation assay and an in vitro micronucleus test with mammalian cell culture are frequently used for screening. Regulatory genetic toxicology studies are conducted with a short list of compounds using protocols that conform to various international guidelines. A set of four assays usually constitutes the minimum test battery that satisfies global requirements. This set includes a bacterial reverse mutation assay, an in vitro cytogenetic test with mammalian cell culture, an in vitro gene mutation assay in mammalian cell cultures, and an in vivo rodent bone marrow micronucleus test. Supplementary studies are conducted in certain instances either as a follow-up to the findings from this initial testing battery and/or to satisfy a regulatory requirement. Currently available genetic toxicology assays have helped the scientific and industrial community over the past several decades in evaluating the mutagenic potential of chemical agents. The emerging field of toxicogenomics has the potential to redefine our ability to study the response of cells to genetic damage and hence our ability to study threshold phenomenon.

Publishing web-based guidelines using interactive decision models.

PubMed

Sanders, G D; Nease, R F; Owens, D K

2001-05-01

Commonly used methods for guideline development and dissemination do not enable developers to tailor guidelines systematically to specific patient populations and update guidelines easily. We developed a web-based system, ALCHEMIST, that uses decision models and automatically creates evidence-based guidelines that can be disseminated, tailored and updated over the web. Our objective was to demonstrate the use of this system with clinical scenarios that provide challenges for guideline development. We used the ALCHEMIST system to develop guidelines for three clinical scenarios: (1) Chlamydia screening for adolescent women, (2) antiarrhythmic therapy for the prevention of sudden cardiac death; and (3) genetic testing for the BRCA breast-cancer mutation. ALCHEMIST uses information extracted directly from the decision model, combined with the additional information from the author of the decision model, to generate global guidelines. ALCHEMIST generated electronic web-based guidelines for each of the three scenarios. Using ALCHEMIST, we demonstrate that tailoring a guideline for a population at high-risk for Chlamydia changes the recommended policy for control of Chlamydia from contact tracing of reported cases to a population-based screening programme. We used ALCHEMIST to incorporate new evidence about the effectiveness of implantable cardioverter defibrillators (ICD) and demonstrate that the cost-effectiveness of use of ICDs improves from $74 400 per quality-adjusted life year (QALY) gained to $34 500 per QALY gained. Finally, we demonstrate how a clinician could use ALCHEMIST to incorporate a woman's utilities for relevant health states and thereby develop patient-specific recommendations for BRCA testing; the patient-specific recommendation improved quality-adjusted life expectancy by 37 days. The ALCHEMIST system enables guideline developers to publish both a guideline and an interactive decision model on the web. This web-based tool enables guideline developers to tailor guidelines systematically, to update guidelines easily, and to make the underlying evidence and analysis transparent for users.

Current use of pharmacogenetic testing: a national survey of thiopurine methyltransferase testing prior to azathioprine prescription.

PubMed

Fargher, E A; Tricker, K; Newman, W; Elliott, R; Roberts, S A; Shaffer, J L; Bruce, I; Payne, K

2007-04-01

Azathioprine is an immunosuppressant prescribed for the treatment of inflammatory conditions and after organ transplantation. Risk of neutropaenia has limited the effective use of azathioprine (AZA) and driven requirements for careful monitoring and blood tests. Thiopurine methyltransferase (TPMT) is a genetically moderated key enzyme involved in the metabolism of AZA that can be used to stratify individuals into different levels of risk of developing neutropaenia. Two techniques can be used to measure TPMT status: enzyme-level testing (phenotype testing) and DNA based testing (genotype testing). To identify the current uptake of TPMT enzyme-level testing, TPMT genotype testing, and, the role of guidelines; to inform the prescribing and monitoring of AZA. A survey was mailed to a consultant dermatologist, gastroenterologist, and rheumatologist at every NHS Hospital Trust in England. The survey comprised mainly closed questions exploring: use of AZA and monitoring; use of TPMT enzyme-level testing and genotype testing; and, the role of guidelines to guide prescribing practice. A 70% (n=287) response rate was obtained. The majority of respondents reported prescribing AZA (99%, n=283). Prescribing and monitoring patterns differed between individual respondents and between the three disciplines. TPMT enzyme-level testing was reportedly used by 67% (n=189) of respondents, but this differed by discipline (dermatologists 94%, gastroenterologists 60%, rheumatologists 47%). In 91% of cases enzyme-level testing was carried out prior to prescribing AZA. Genotype testing is not typically available to NHS clinicians but 15 clinicians (six dermatologists, six gastroenterologists, three rheumatologists) reported using it. Most consultants (82%) reported using guidelines to inform their AZA prescribing and monitoring (dermatologists 81%, gastroenterologists 75%, rheumatologists 94%). Two-thirds of the consultants surveyed in England are using TPMT enzyme-level testing, prior to AZA treatment. Uptake differs between specialities. High uptake of TPMT enzyme-level testing by dermatologists, compared with gastroenterologists and rheumatologists, may reflect national guidelines advocating its use prior to AZA. Uptake of enzyme-level testing may alter in other specialties as other guidelines are developed.

European Society of Endocrinology Clinical Practice Guideline for long-term follow-up of patients operated on for a phaeochromocytoma or a paraganglioma.

PubMed

Plouin, P F; Amar, L; Dekkers, O M; Fassnacht, M; Gimenez-Roqueplo, A P; Lenders, J W M; Lussey-Lepoutre, C; Steichen, O

2016-05-01

Phaeochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumours. Standard treatment is surgical resection. Following complete resection of the primary tumour, patients with PPGL are at risk of developing new tumoural events. The present guideline aims to propose standardised clinical care of long-term follow-up in patients operated on for a PPGL. The guideline has been developed by The European Society of Endocrinology and based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) principles. We performed a systematic review of the literature and analysed the European Network for the Study of Adrenal Tumours (ENS@T) database. The risk of new events persisted in the long term and was higher for patients with genetic or syndromic diseases. Follow-up in the published cohorts and in the ENS@T database was neither standardised nor exhaustive, resulting in a risk of follow-up bias and in low statistical power beyond 10 years after complete surgery. To inform patients and care providers in this context of low-quality evidence, the Guideline Working Group therefore prepared recommendations on the basis of expert consensus. Key recommendations are the following: we recommend that all patients with PPGL be considered for genetic testing; we recommend assaying plasma or urinary metanephrines every year to screen for local or metastatic recurrences or new tumours; and we suggest follow-up for at least 10 years in all patients operated on for a PPGL. High-risk patients (young patients and those with a genetic disease, a large tumour and/or a paraganglioma) should be offered lifelong annual follow-up. © 2016 European Society of Endocrinology.

Peroxisome biogenesis disorders in the Zellweger spectrum: An overview of current diagnosis, clinical manifestations, and treatment guidelines.

PubMed

Braverman, Nancy E; Raymond, Gerald V; Rizzo, William B; Moser, Ann B; Wilkinson, Mark E; Stone, Edwin M; Steinberg, Steven J; Wangler, Michael F; Rush, Eric T; Hacia, Joseph G; Bose, Mousumi

2016-03-01

Peroxisome biogenesis disorders in the Zellweger spectrum (PBD-ZSD) are a heterogeneous group of genetic disorders caused by mutations in PEX genes responsible for normal peroxisome assembly and functions. As a result of impaired peroxisomal activities, individuals with PBD-ZSD can manifest a complex spectrum of clinical phenotypes that typically result in shortened life spans. The extreme variability in disease manifestation ranging from onset of profound neurologic symptoms in newborns to progressive degenerative disease in adults presents practical challenges in disease diagnosis and medical management. Recent advances in biochemical methods for newborn screening and genetic testing have provided unprecedented opportunities for identifying patients at the earliest possible time and defining the molecular bases for their diseases. Here, we provide an overview of current clinical approaches for the diagnosis of PBD-ZSD and provide broad guidelines for the treatment of disease in its wide variety of forms. Although we anticipate future progress in the development of more effective targeted interventions, the current guidelines are meant to provide a starting point for the management of these complex conditions in the context of personalized health care. Copyright © 2015 Elsevier Inc. All rights reserved.

Laboratory practice guidelines for detecting and reporting JAK2 and MPL mutations in myeloproliferative neoplasms: a report of the Association for Molecular Pathology.

PubMed

Gong, Jerald Z; Cook, James R; Greiner, Timothy C; Hedvat, Cyrus; Hill, Charles E; Lim, Megan S; Longtine, Janina A; Sabath, Daniel; Wang, Y Lynn

2013-11-01

Recurrent mutations in JAK2 and MPL genes are genetic hallmarks of BCR-ABL1-negative myeloproliferative neoplasms. Detection of JAK2 and MPL mutations has been incorporated into routine diagnostic algorithms for these diseases. This Special Article summarizes results from a nationwide laboratory survey of JAK2 and MPL mutation analysis. Based on the current practice pattern and the literature, this Special Article provides recommendations and guidelines for laboratory practice for detection of mutations in the JAK2 and MPL genes, including clinical manifestations for prompting the mutation analysis, current and recommended methodologies for testing the mutations, and standardization for reporting the test results. This Special Article also points to future directions for genomic testing in BCR-ABL1-negative myeloproliferative neoplasms. Copyright © 2013 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.

EMQN best practice guidelines for the molecular genetic testing and reporting of fragile X syndrome and other fragile X-associated disorders

PubMed Central

Biancalana, Valérie; Glaeser, Dieter; McQuaid, Shirley; Steinbach, Peter

2015-01-01

Different mutations occurring in the unstable CGG repeat in 5' untranslated region of FMR1 gene are responsible for three fragile X-associated disorders. An expansion of over ∼200 CGG repeats when associated with abnormal methylation and inactivation of the promoter is the mutation termed ‘full mutation' and is responsible for fragile X syndrome (FXS), a neurodevelopmental disorder described as the most common cause of inherited intellectual impairment. The term ‘abnormal methylation' is used here to distinguish the DNA methylation induced by the expanded repeat from the ‘normal methylation' occurring on the inactive X chromosomes in females with normal, premutation, and full mutation alleles. All male and roughly half of the female full mutation carriers have FXS. Another anomaly termed ‘premutation' is characterized by the presence of 55 to ∼200 CGGs without abnormal methylation, and is the cause of two other diseases with incomplete penetrance. One is fragile X-associated primary ovarian insufficiency (FXPOI), which is characterized by a large spectrum of ovarian dysfunction phenotypes and possible early menopause as the end stage. The other is fragile X-associated tremor/ataxia syndrome (FXTAS), which is a late onset neurodegenerative disorder affecting males and females. Because of the particular pattern and transmission of the CGG repeat, appropriate molecular testing and reporting is very important for the optimal genetic counselling in the three fragile X-associated disorders. Here, we describe best practice guidelines for genetic analysis and reporting in FXS, FXPOI, and FXTAS, including carrier and prenatal testing. PMID:25227148

Disentangling the heterogeneity of autism spectrum disorder through genetic findings

PubMed Central

Jeste, Shafali S.; Geschwind, Daniel H.

2014-01-01

Autism spectrum disorder (ASD) represents a heterogeneous group of disorders, which presents a substantial challenge to diagnosis and treatment. Over the past decade, considerable progress has been made in the identification of genetic risk factors for ASD that define specific mechanisms and pathways underlying the associated behavioural deficits. In this Review, we discuss how some of the latest advances in the genetics of ASD have facilitated parsing of the phenotypic heterogeneity of this disorder. We argue that only through such advances will we begin to define endophenotypes that can benefit from targeted, hypothesis-driven treatments. We review the latest technologies used to identify and characterize the genetics underlying ASD and then consider three themes—single-gene disorders, the gender bias in ASD, and the genetics of neurological comorbidities—that highlight ways in which we can use genetics to define the many phenotypes within the autism spectrum. We also present current clinical guidelines for genetic testing in ASD and their implications for prognosis and treatment. PMID:24468882

Genetic aspects of artificial insemination with donor semen: the French CECOS Federation guidelines.

PubMed

Jalbert, P; Leonard, C; Selva, J; David, G

1989-06-01

The genetic problems raised by assisted reproduction using donor gametes (AID) are numerous and often complex. They concern the legitimacy and the appropriate forms of genetic screening for both gamete donors and recipients; the identification of genetic indications justifying the use of this method of reproduction; and ascertainment of the state of health of the conceptus at birth. The experience and guidelines of the French CECOS Federation, which comprises 20 AID treatment centers, are described. The discussion emphasizes the need for an international exchange of view on this subject.

Implementation of inpatient models of pharmacogenetics programs

PubMed Central

Cavallari, Larisa H.; Lee, Craig R.; Duarte, Julio D.; Nutescu, Edith A.; Weitzel, Kristin W.; Stouffer, George A.; Johnson, Julie A.

2017-01-01

Purpose The operational elements essential for establishing an inpatient pharmacogenetic service are reviewed, and the role of the pharmacist in the provision of genotype-guided drug therapy in pharmacogenetics programs at three institutions is highlighted. Summary Pharmacists are well positioned to assume important roles in facilitating the clinical use of genetic information to optimize drug therapy given their expertise in clinical pharmacology and therapeutics. Pharmacists have assumed important roles in implementing inpatient pharmacogenetics programs. This includes programs designed to incorporate genetic test results to optimize antiplatelet drug selection after percutaneous coronary intervention and personalize warfarin dosing. Pharmacist involvement occurs on many levels, including championing and leading pharmacogenetics implementation efforts, establishing clinical processes to support genotype-guided therapy, assisting the clinical staff with interpreting genetic test results and applying them to prescribing decisions, and educating other healthcare providers and patients on genomic medicine. The three inpatient pharmacogenetics programs described use reactive versus preemptive genotyping, the most feasible approach under the current third-party payment structure. All three sites also follow Clinical Pharmacogenetics Implementation Consortium guidelines for drug therapy recommendations based on genetic test results. Conclusion With the clinical emergence of pharmacogenetics into the inpatient setting, it is important that pharmacists caring for hospitalized patients are well prepared to serve as experts in interpreting and applying genetic test results to guide drug therapy decisions. Since genetic test results may not be available until after patient discharge, pharmacists practicing in the ambulatory care setting should also be prepared to assist with genotype-guided drug therapy as part of transitions in care. PMID:27864202

Implementation of inpatient models of pharmacogenetics programs.

PubMed

Cavallari, Larisa H; Lee, Craig R; Duarte, Julio D; Nutescu, Edith A; Weitzel, Kristin W; Stouffer, George A; Johnson, Julie A

2016-12-01

The operational elements essential for establishing an inpatient pharmacogenetic service are reviewed, and the role of the pharmacist in the provision of genotype-guided drug therapy in pharmacogenetics programs at three institutions is highlighted. Pharmacists are well positioned to assume important roles in facilitating the clinical use of genetic information to optimize drug therapy given their expertise in clinical pharmacology and therapeutics. Pharmacists have assumed important roles in implementing inpatient pharmacogenetics programs. This includes programs designed to incorporate genetic test results to optimize antiplatelet drug selection after percutaneous coronary intervention and personalize warfarin dosing. Pharmacist involvement occurs on many levels, including championing and leading pharmacogenetics implementation efforts, establishing clinical processes to support genotype-guided therapy, assisting the clinical staff with interpreting genetic test results and applying them to prescribing decisions, and educating other healthcare providers and patients on genomic medicine. The three inpatient pharmacogenetics programs described use reactive versus preemptive genotyping, the most feasible approach under the current third-party payment structure. All three sites also follow Clinical Pharmacogenetics Implementation Consortium guidelines for drug therapy recommendations based on genetic test results. With the clinical emergence of pharmacogenetics into the inpatient setting, it is important that pharmacists caring for hospitalized patients are well prepared to serve as experts in interpreting and applying genetic test results to guide drug therapy decisions. Since genetic test results may not be available until after patient discharge, pharmacists practicing in the ambulatory care setting should also be prepared to assist with genotype-guided drug therapy as part of transitions in care. Copyright © 2016 by the American Society of Health-System Pharmacists, Inc. All rights reserved.

Genetic testing and genomic analysis: a debate on ethical, social and legal issues in the Arab world with a focus on Qatar.

PubMed

El Shanti, Hatem; Chouchane, Lotfi; Badii, Ramin; Gallouzi, Imed Eddine; Gasparini, Paolo

2015-11-14

In 2013 both Saudi Arabia and Qatar launched genome projects with the aim of providing information for better diagnosis, treatment and prevention of diseases and, ultimately to realize personalized medicine by sequencing hundred thousands samples. These population based genome activities raise a series of relevant ethical, legal and social issues general, related to the specific population structure as well as to the Islamic perspective on genomic analysis and genetic testing. To contribute to the debate, the Authors after reviewing the existing literature and taking advantage of their professional experience in the field and in the geographic area, discuss and provide their opinions. In particular, the Authors focus on the impact of consanguinity on population structure and disease frequency in the Arab world, on genetic testing and genomic analysis (i.e. technical aspects, impact, etc.) and on their regulations. A comparison between the Islamic perspective and the ethical, social and legal issues raised in other population contexts is also carried. In conclusion, this opinion article with an up-to-date contribution to the discussion on the relevance and impact of genomic analysis and genetic testing in the Arab world, might help in producing specific national guidelines on genetic testing and genomic analysis and help accelerate the implementation and roll out of genome projects in Muslim countries and more specifically in Qatar, and other countries of the Gulf.

Are people with chronic low back pain meeting the physical activity guidelines? A co-twin control study.

PubMed

Zadro, Joshua Robert; Shirley, Debra; Amorim, Anita; Pérez-Riquelme, Francisco; Ordoñana, Juan R; Ferreira, Paulo H

2017-06-01

Despite a large amount of research investigating physical activity (PA) levels in people with chronic low back pain (LBP), no study has investigated whether people with chronic LBP are meeting the World Health Organization (WHO) PA guidelines. Furthermore, with genetics and the early shared environment substantially influencing the presence of LBP and PA engagement, these factors could confound the association between LBP and PA and need to be controlled for. This study aimed to investigate the association between chronic LBP and meeting the PA guidelines, while controlling for the effects of genetics and early shared environment. This is a cross-sectional co-twin control study. A cross-sectional analysis was performed on 1,588 twins from the Murcia Twin Registry in Spain with available data on LBP and PA from the 2013 data collection wave. The exposure and outcome variables in our study were self-reported. Twins reporting a history of chronic LBP were asked follow-up questions to inform on the presence of recent LBP (within the past 4 weeks), previous LBP (no pain within the past 4 weeks), and persistent LBP (no pain-free month in the last 6 months). These were our exposure variables. Our outcome variable was meeting the WHO PA guidelines, which involved at least 75 minutes of vigorous-intensity PA, or at least 150 minutes of moderate-intensity PA per week. To investigate the association between chronic LBP and meeting the PA guidelines, we first performed a multivariate logistic regression on the total sample of twins. Co-variables entered the model if the univariate association between the co-variable, and both the exposure and the outcome reached a significance of p<.2. Second, to adjust for the influence of genetics and early shared environment, we performed a conditional multivariate logistic regression on complete twin pairs discordant for LBP. The Murcia Twin Registry is supported by Fundación Séneca, Regional Agency for Science and Technology, Murcia, Spain (08633/PHCS/08 and 15302/PHCS/10) and the Ministry of Science and Innovation, Spain (PSI11560-2009). Funding for this project has also been received from Fundación MAPFRE (2012). The authors declare that there are no conflicts of interest. There was a significant inverse association between recent LBP and meeting the PA guidelines (odds ratio [OR]=0.71, p=.034). When controlling for genetics and early shared environment, this association disappeared. There was no association between previous (OR=0.95, p=.779) or persistent LBP (OR=0.78, p=.192) and meeting the PA guidelines. Twins with recent LBP are less likely to meet the PA guidelines than those with no history of chronic LBP, highlighting the importance of incorporating PA promotion in the treatment of these individuals. Genetics and early shared environment appear to be confounding the association between LBP and PA, although this needs to be further tested in larger twin samples. Copyright © 2017 Elsevier Inc. All rights reserved.

Molecular Testing Guideline for Selection of Lung Cancer Patients for EGFR and ALK Tyrosine Kinase Inhibitors

PubMed Central

Lindeman, Neal I.; Cagle, Philip T.; Beasley, Mary Beth; Chitale, Dhananjay Arun; Dacic, Sanja; Giaccone, Giuseppe; Jenkins, Robert Brian; Kwiatkowski, David J.; Saldivar, Juan-Sebastian; Squire, Jeremy; Thunnissen, Erik; Ladanyi, Marc

2014-01-01

Objective To establish evidence-based recommendations for the molecular analysis of lung cancers that are required to guide EGFR- and ALK-directed therapies, addressing which patients and samples should be tested, and when and how testing should be performed. Participants Three cochairs without conflicts of interest were selected, one from each of the 3 sponsoring professional societies: College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. Writing and advisory panels were constituted from additional experts from these societies. Evidence Three unbiased literature searches of electronic databases were performed to capture articles published from January 2004 through February 2012, yielding 1533 articles whose abstracts were screened to identify 521 pertinent articles that were then reviewed in detail for their relevance to the recommendations. Evidence was formally graded for each recommendation. Consensus Process Initial recommendations were formulated by the cochairs and panel members at a public meeting. Each guideline section was assigned to at least 2 panelists. Drafts were circulated to the writing panel (version 1), advisory panel (version 2), and the public (version 3) before submission (version 4). Conclusions The 37 guideline items address 14 subjects, including 15 recommendations (evidence grade A/B). The major recommendations are to use testing for EGFR mutations and ALK fusions to guide patient selection for therapy with an epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) inhibitor, respectively, in all patients with advanced-stage adenocarcinoma, regardless of sex, race, smoking history, or other clinical risk factors, and to prioritize EGFR and ALK testing over other molecular predictive tests. As scientific discoveries and clinical practice outpace the completion of randomized clinical trials, evidence-based guidelines developed by expert practitioners are vital for communicating emerging clinical standards. Already, new treatments targeting genetic alterations in other, less common driver oncogenes are being evaluated in lung cancer, and testing for these may be addressed in future versions of these guidelines. PMID:23551194

Molecular Testing Guideline for Selection of Lung Cancer Patients for EGFR and ALK Tyrosine Kinase Inhibitors

PubMed Central

Lindeman, Neal I.; Cagle, Philip T.; Beasley, Mary Beth; Chitale, Dhananjay Arun; Dacic, Sanja; Giaccone, Giuseppe; Jenkins, Robert Brian; Kwiatkowski, David J.; Saldivar, Juan-Sebastian; Squire, Jeremy; Thunnissen, Erik; Ladanyi, Marc

2014-01-01

Objective To establish evidence-based recommendations for the molecular analysis of lung cancers that are that are required to guide EGFR- and ALK-directed therapies, addressing which patients and samples should be tested, and when and how testing should be performed. Participants Three cochairs without conflicts of interest were selected, one from each of the 3 sponsoring professional societies: College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. Writing and advisory panels were constituted from additional experts from these societies. Evidence Three unbiased literature searches of electronic databases were performed to capture articles published published from January 2004 through February 2012, yielding 1533 articles whose abstracts were screened to identify 521 pertinent articles that were then reviewed in detail for their relevance to the recommendations. Evidence was formally graded for each recommendation. Consensus Process Initial recommendations were formulated by the cochairs and panel members at a public meeting. Each guideline section was assigned to at least 2 panelists. Drafts were circulated to the writing panel (version 1), advisory panel (version 2), and the public (version 3) before submission (version 4). Conclusions The 37 guideline items address 14 subjects, including 15 recommendations (evidence grade A/B). The major recommendations are to use testing for EGFR mutations and ALK fusions to guide patient selection for therapy with an epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) inhibitor, respectively, in all patients with advanced-stage adenocarcinoma, regardless of sex, race, smoking history, or other clinical risk factors, and to prioritize EGFR and ALK testing over other molecular predictive tests. As scientific discoveries and clinical practice outpace the completion of randomized clinical trials, evidence-based guidelines developed by expert practitioners are vital for communicating emerging clinical standards. Already, new treatments targeting genetic alterations in other, less common driver oncogenes are being evaluated in lung cancer, and testing for these may be addressed in future versions of these guidelines. PMID:23552377

Genetic Influences on Learning Disabilties I: Clinical Genetics.

ERIC Educational Resources Information Center

Smith, Shelley D.; Pennington, Bruce F.

1983-01-01

A discussion of basic genetic principles is followed by a review of selected genetic syndromes involving learning disabilites (such as Noonan Syndrome, Neurofibromatosis, Pheuylketonuria, and cleft lip and palate). Guidelines for securing a genetic evaluation are given. (CL)

Best practices for fungal germplasm repositories and perspectives on their implementation.

PubMed

Wiest, Aric; Schnittker, Robert; Plamann, Mike; McCluskey, Kevin

2012-02-01

In over 50 years, the Fungal Genetics Stock Center has grown to become a world-recognized biological resource center. Along with this growth comes the development and implementation of myriad practices for the management and curation of a diverse collection of filamentous fungi, yeast, and molecular genetic tools for working with the fungi. These practices include techniques for the testing, manipulation, and preservation of individual fungal isolates as well as for processing of thousands of isolates in parallel. In addition to providing accurate record keeping, an electronic managements system allows the observation of trends in strain distribution and in sample characteristics. Because many ex situ fungal germplasm repositories around the world share similar objectives, best-practice guidelines have been developed by a number of organizations such as the Organization for Economic Cooperation and Development or the International Society for Biological and Environmental Repositories. These best-practice guidelines provide a framework for the successful operation of collections and promote the development and interactions of biological resource centers around the world.

Sequence variant classification and reporting: recommendations for improving the interpretation of cancer susceptibility genetic test results

PubMed Central

Plon, Sharon E.; Eccles, Diana M.; Easton, Douglas; Foulkes, William D.; Genuardi, Maurizio; Greenblatt, Marc S.; Hogervorst, Frans B.L.; Hoogerbrugge, Nicoline; Spurdle, Amanda B.; Tavtigian, Sean

2011-01-01

Genetic testing of cancer susceptibility genes is now widely applied in clinical practice to predict risk of developing cancer. In general, sequence-based testing of germline DNA is used to determine whether an individual carries a change that is clearly likely to disrupt normal gene function. Genetic testing may detect changes that are clearly pathogenic, clearly neutral or variants of unclear clinical significance. Such variants present a considerable challenge to the diagnostic laboratory and the receiving clinician in terms of interpretation and clear presentation of the implications of the result to the patient. There does not appear to be a consistent approach to interpreting and reporting the clinical significance of variants either among genes or among laboratories. The potential for confusion among clinicians and patients is considerable and misinterpretation may lead to inappropriate clinical consequences. In this article we review the current state of sequence-based genetic testing, describe other standardized reporting systems used in oncology and propose a standardized classification system for application to sequence based results for cancer predisposition genes. We suggest a system of five classes of variants based on the degree of likelihood of pathogenicity. Each class is associated with specific recommendations for clinical management of at-risk relatives that will depend on the syndrome. We propose that panels of experts on each cancer predisposition syndrome facilitate the classification scheme and designate appropriate surveillance and cancer management guidelines. The international adoption of a standardized reporting system should improve the clinical utility of sequence-based genetic tests to predict cancer risk. PMID:18951446

Genotoxicity assessment of nanomaterials: recommendations on best practices, assays and methods.

PubMed

Elespuru, Rosalie; Pfuhler, Stefan; Aardema, Marilyn; Chen, Tao; Doak, Shareen H; Doherty, Ann; Farabaugh, Christopher S; Kenny, Julia; Manjanatha, Mugimane; Mahadevan, Brinda; Moore, Martha M; Ouédraogo, Gladys; Stankowski, Leon F; Tanir, Jennifer Y

2018-04-26

Nanomaterials (NMs) present unique challenges in safety evaluation. An international working group, the Genetic Toxicology Technical Committee of the International Life Sciences Institute's Health and Environmental Sciences Institute, has addressed issues related to the genotoxicity assessment of NMs. A critical review of published data has been followed by recommendations on methods alterations and best practices for the standard genotoxicity assays: bacterial reverse mutation (Ames); in vitro mammalian assays for mutations, chromosomal aberrations, micronucleus induction, or DNA strand breaks (comet); and in vivo assays for genetic damage (micronucleus, comet and transgenic mutation assays). The analysis found a great diversity of tests and systems used for in vitro assays; many did not meet criteria for a valid test, and/or did not use validated cells and methods in the Organization for Economic Co-operation and Development Test Guidelines, and so these results could not be interpreted. In vivo assays were less common but better performed. It was not possible to develop conclusions on test system agreement, NM activity, or mechanism of action. However, the limited responses observed for most NMs were consistent with indirect genotoxic effects, rather than direct interaction of NMs with DNA. We propose a revised genotoxicity test battery for NMs that includes in vitro mammalian cell mutagenicity and clastogenicity assessments; in vivo assessments would be added only if warranted by information on specific organ exposure or sequestration of NMs. The bacterial assays are generally uninformative for NMs due to limited particle uptake and possible lack of mechanistic relevance, and are thus omitted in our recommended test battery for NM assessment. Recommendations include NM characterization in the test medium, verification of uptake into target cells, and limited assay-specific methods alterations to avoid interference with uptake or endpoint analysis. These recommendations are summarized in a Roadmap guideline for testing.

The (in)famous GWAS P-value threshold revisited and updated for low-frequency variants.

PubMed

Fadista, João; Manning, Alisa K; Florez, Jose C; Groop, Leif

2016-08-01

Genome-wide association studies (GWAS) have long relied on proposed statistical significance thresholds to be able to differentiate true positives from false positives. Although the genome-wide significance P-value threshold of 5 × 10(-8) has become a standard for common-variant GWAS, it has not been updated to cope with the lower allele frequency spectrum used in many recent array-based GWAS studies and sequencing studies. Using a whole-genome- and -exome-sequencing data set of 2875 individuals of European ancestry from the Genetics of Type 2 Diabetes (GoT2D) project and a whole-exome-sequencing data set of 13 000 individuals from five ancestries from the GoT2D and T2D-GENES (Type 2 Diabetes Genetic Exploration by Next-generation sequencing in multi-Ethnic Samples) projects, we describe guidelines for genome- and exome-wide association P-value thresholds needed to correct for multiple testing, explaining the impact of linkage disequilibrium thresholds for distinguishing independent variants, minor allele frequency and ancestry characteristics. We emphasize the advantage of studying recent genetic isolate populations when performing rare and low-frequency genetic association analyses, as the multiple testing burden is diminished due to higher genetic homogeneity.

An experimental test of alternative population augmentation scenarios.

PubMed

Kronenberger, John A; Gerberich, Jill C; Fitzpatrick, Sarah W; Broder, E Dale; Angeloni, Lisa M; Funk, W Chris

2018-01-19

Human land use is fragmenting habitats worldwide and inhibiting dispersal among previously connected populations of organisms, often leading to inbreeding depression and reduced evolutionary potential in the face of rapid environmental change. To combat this augmentation of isolated populations with immigrants is sometimes used to facilitate demographic and genetic rescue. Augmentation with immigrants that are genetically and adaptively similar to the target population effectively increases population fitness, but if immigrants are very genetically or adaptively divergent, augmentation can lead to outbreeding depression. Despite well-cited guidelines for the best practice selection of immigrant sources, often only highly divergent populations remain, and experimental tests of these riskier augmentation scenarios are essentially nonexistent. We conducted a mesocosm experiment with Trinidadian guppies (Poecilia reticulata) to test the multigenerational demographic and genetic effects of augmenting 2 target populations with 3 types of divergent immigrants. We found no evidence of demographic rescue, but we did observe genetic rescue in one population. Divergent immigrant treatments tended to maintain greater genetic diversity, abundance, and hybrid fitness than controls that received immigrants from the source used to seed the mesocosms. In the second population, divergent immigrants had a slightly negative effect in one treatment, and the benefits of augmentation were less apparent overall, likely because this population started with higher genetic diversity and a lower reproductive rate that limited genetic admixture. Our results add to a growing consensus that gene flow can increase population fitness even when immigrants are more highly divergent and may help reduce uncertainty about the use of augmentation in conservation. © 2018 Society for Conservation Biology.

Guiding the process of health technology disinvestment.

PubMed

Ibargoyen-Roteta, Nora; Gutiérrez-Ibarluzea, Iñaki; Asua, José

2010-12-01

To develop a guideline for health technology disinvestment. The Nominal Group Technique was used to determine relevant aspects of disinvestment decision-making. Ideas reaching consensus and previous Spanish guidelines on the acquisition of new health technologies (GANT) and new genetic tests (GEN) structures were used to develop the domains and contents of GuNFT (Guideline for Not Funding Health Technologies). The draft was peer reviewed by local and international experts and their suggestions were incorporated to the first GuNFT version. Thirty-five ideas reached consensus. The most relevant ones referred to the reasons for disinvesting in a technology and the key aspects that would facilitate disinvestment acceptance. Considering both consensus ideas and GANT and GEN guidelines, the first GuNFT draft was elaborated. After the review process, section numbers and contents were changed. The resulting GuNFT guideline was finally divided into six domains related to: (1) general preliminary recommendations, (2) completing the application form, (3) checking and prioritising applications, (4) assessment, (5) final decision and (6) action plan design. A software was also developed to facilitate GuNFT implementation. Disinvestment should be a guided process. Accordingly, we present the first guideline for that purpose. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Importance and pitfalls of molecular analysis to parasite epidemiology.

PubMed

Constantine, Clare C

2003-08-01

Molecular tools are increasingly being used to address questions about parasite epidemiology. Parasites represent a diverse group and they might not fit traditional population genetic models. Testing hypotheses depends equally on correct sampling, appropriate tool and/or marker choice, appropriate analysis and careful interpretation. All methods of analysis make assumptions which, if violated, make the results invalid. Some guidelines to avoid common pitfalls are offered here.

Developing standards for chromosomal microarray testing counselling in paediatrics.

PubMed

Godfrey, Emma; Clark, Phillipa

2014-06-01

Chromosomal microarray testing (CMA) generally aids paediatric genetic diagnosis. However, pre-CMA counselling is important as results can be ambiguous, generate uncertainty and raise ethical issues. We developed standards for counselling and giving families results; using these we evaluated practice for children seen by the Auckland Developmental Paediatric team in 2011. Pretest discussion was documented in 14 of 28 subjects and potential outcomes in 4of 28. 8 of 28 received information leaflets, 1 of 28 gave signed consent. 3 of 3 with abnormal results and 4 of 5 with variants of unknown significance (VOUS) were offered clinical genetics referral. 8 of 20 families with normal results were written to; two with abnormal results were informed face-to-face and one in writing; most VOUS were communicated by phone, voicemail or letter. CMA testing requires clear patient information sheets and in-depth pretest discussion for informed consent, timely feedback of results and genetics referral as appropriate. Authoritative guidelines and training are needed to strengthen CMA counselling. ©2014 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.

Lynch syndrome in the 21st century: clinical perspectives.

PubMed

Tiwari, A K; Roy, H K; Lynch, H T

2016-03-01

Lynch syndrome (LS) is the most common of all inherited cancer syndromes, associated with substantially elevated risks for colonic and extracolonic malignancies, earlier onset and high rates of multiple primary cancers. At the genetic level, it is caused by a defective mismatch repair (MMR) system due to presence of germline defects in at least one of the MMR genes- MLH1, MSH2, MSH6, PMS2 or EPCAM. An impaired MMR function during replication introduces infidelity in DNA sequence and leads to ubiquitous mutations at simple repetitive sequences (microsatellites), causing microsatellite instability (MSI). Although previously, clinicopathological criteria such as Amsterdam I/II and Revised Bethesda Guidelines were commonly used to identify suspected LS mutation carriers, there has been a recent push towards universally testing, especially in case of colorectal cancers (CRCs), through immunohistochemistry for expression of MMR proteins or through molecular tests (polymerase chain reaction, PCR) for MSI, in order to identify LS mutation carriers and subject them to genetic testing to ascertain the specific gene implicated. In this review, we have discussed the latest diagnostic strategies and the current screening and treatment guidelines for colonic and extracolonic cancers in clinically affected and at-risk individuals for LS. © The Author 2015. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Prevalence and healthcare actions of women in a large health system with a family history meeting the 2005 USPSTF recommendation for BRCA genetic counseling referral.

PubMed

Bellcross, Cecelia A; Leadbetter, Steven; Alford, Sharon Hensley; Peipins, Lucy A

2013-04-01

In 2005, the United States Preventive Services Task Force (USPSTF) released guidelines which outlined specific family history patterns associated with an increased risk for BRCA1/2 mutations, and recommended at-risk individuals be referred for genetic counseling and evaluation for BRCA testing. The purpose of this study was to assess the prevalence of individuals with a USPSTF increased-risk family history pattern, the frequency with which specific patterns were met, and resulting healthcare actions among women from the Henry Ford Health System. As part of a study evaluating ovarian cancer risk perception and screening, 2,524 randomly selected participants completed a detailed interview (response rate 76%) from an initial eligible cohort of 16,720 women. Approximately 6% of participants had a family history fulfilling one or more of the USPSTF patterns. Although 90% of these women had shared their family history with their provider, less than 20% had been referred for genetic counseling and only 8% had undergone genetic testing. Caucasian women with higher income and education levels were more likely to receive referrals. Among the 95 participants in the total study cohort who reported BRCA testing, 78% did not have a family history that met one of the USPSTF patterns. These results suggest a higher prevalence of women with an increased-risk family history than originally predicted by the USPSTF, and lack of provider recognition and referral for genetic services. Improvements in healthcare infrastructure and clinician education will be required to realize population level benefits from BRCA genetic counseling and testing.

Duchenne Muscular Dystrophy: a Survey of Perspectives on Carrier Testing and Communication Within the Family.

PubMed

Hayes, Brenna; Hassed, Susan; Chaloner, Jae Lindsay; Aston, Christopher E; Guy, Carrie

2016-06-01

Carrier testing is widely available for multiple genetic conditions, and several professional organizations have created practice guidelines regarding appropriate clinical application and the testing of minors. Previous research has focused on carrier screening, predictive testing, and testing for X-linked conditions. However, family perspectives on carrier testing for X-linked lethal diseases have yet to be described. In this study, we explored communication within the family about carrier testing and the perspectives of mothers of sons with an X-linked lethal disease, Duchenne muscular dystrophy (DMD). Twenty-five mothers of sons with DMD participated in an anonymous online survey. Survey questions included multiple choice, Likert scale, and open ended, short answer questions. Analysis of the multiple choice and Likert scale questions revealed that most mothers preferred a gradual style of communication with their daughters regarding risk status. In addition, most participants reported having consulted with a genetic counselor and found it helpful. Comparisons between groups, analyzed using Fisher's exact tests, found no differences in preferred style due to mother's carrier status or having a daughter. Thematic analysis was conducted on responses to open ended questions. Themes identified included the impact of family implications, age and maturity, and a desire for autonomy regarding the decision to discuss and undergo carrier testing with at-risk daughters, particularly timing of these discussions. Implications for genetic counseling practice are discussed.

A Next Generation Sequencing custom gene panel as first line diagnostic tool for atypical cases of syndromic obesity: Application in a case of Alström syndrome.

PubMed

Maltese, Paolo E; Iarossi, Giancarlo; Ziccardi, Lucia; Colombo, Leonardo; Buzzonetti, Luca; Crinò, Antonino; Tezzele, Silvia; Bertelli, Matteo

2018-02-01

Obesity phenotype can be manifested as an isolated trait or accompanied by multisystem disorders as part of a syndromic picture. In both situations, same molecular pathways may be involved to different degrees. This evidence is stronger in syndromic obesity, in which phenotypes of different syndromes may overlap. In these cases, genetic testing can unequivocally provide a final diagnosis. Here we describe a patient who met the diagnostic criteria for Alström syndrome only during adolescence. Genetic testing was requested at 25 years of age for a final confirmation of the diagnosis. The genetic diagnosis of Alström syndrome was obtained through a Next Generation Sequencing genetic test approach using a custom-designed gene panel of 47 genes associated with syndromic and non-syndromic obesity. Genetic analysis revealed a novel homozygous frameshift variant p.(Arg1550Lysfs*10) on exon 8 of the ALMS1 gene. This case shows the need for a revision of the diagnostic criteria guidelines, as a consequence of the recent advent of massive parallel sequencing technology. Indications for genetic testing reported in these currently accepted diagnostic criteria for Alström syndrome, were drafted when sequencing was expensive and time consuming. Nowadays, Next Generation Sequencing testing could be considered as first line diagnostic tool not only for Alström syndrome but, more generally, for all those atypical or not clearly distinguishable cases of syndromic obesity, thus avoiding delayed diagnosis and treatments. Early diagnosis permits a better follow-up and pre-symptomatic interventions. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Recommendations for genetic testing to reduce the incidence of anthracycline-induced cardiotoxicity.

PubMed

Aminkeng, Folefac; Ross, Colin J D; Rassekh, Shahrad R; Hwang, Soomi; Rieder, Michael J; Bhavsar, Amit P; Smith, Anne; Sanatani, Shubhayan; Gelmon, Karen A; Bernstein, Daniel; Hayden, Michael R; Amstutz, Ursula; Carleton, Bruce C

2016-09-01

Anthracycline-induced cardiotoxicity (ACT) occurs in 57% of treated patients and remains an important limitation of anthracycline-based chemotherapy. In various genetic association studies, potential genetic risk markers for ACT have been identified. Therefore, we developed evidence-based clinical practice recommendations for pharmacogenomic testing to further individualize therapy based on ACT risk. We followed a standard guideline development process, including a systematic literature search, evidence synthesis and critical appraisal, and the development of clinical practice recommendations with an international expert group. RARG rs2229774, SLC28A3 rs7853758 and UGT1A6 rs17863783 variants currently have the strongest and the most consistent evidence for association with ACT. Genetic variants in ABCC1, ABCC2, ABCC5, ABCB1, ABCB4, CBR3, RAC2, NCF4, CYBA, GSTP1, CAT, SULT2B1, POR, HAS3, SLC22A7, SCL22A17, HFE and NOS3 have also been associated with ACT, but require additional validation. We recommend pharmacogenomic testing for the RARG rs2229774 (S427L), SLC28A3 rs7853758 (L461L) and UGT1A6*4 rs17863783 (V209V) variants in childhood cancer patients with an indication for doxorubicin or daunorubicin therapy (Level B - moderate). Based on an overall risk stratification, taking into account genetic and clinical risk factors, we recommend a number of management options including increased frequency of echocardiogram monitoring, follow-up, as well as therapeutic options within the current standard of clinical practice. Existing evidence demonstrates that genetic factors have the potential to improve the discrimination between individuals at higher and lower risk of ACT. Genetic testing may therefore support both patient care decisions and evidence development for an improved prevention of ACT. © 2016 The British Pharmacological Society.

Quality assessment of genetic counseling process in the context of presymptomatic testing for late-onset disorders: a thematic analysis of three review articles.

PubMed

Paneque, Milena; Sequeiros, Jorge; Skirton, Heather

2012-01-01

Presymptomatic testing (PST) is available for a range of late-onset disorders. Health practitioners generally follow guidelines regarding appropriate number of counseling sessions, involvement of multidisciplinary teams, topics for pretest discussion, and follow-up sessions; however, more understanding is needed about what helps consultands effectively and the impact of amount and quality of genetic counseling on the psychosocial sequelae of PST for late-onset disorders. We conducted a thematic analysis of three review articles on quality of the genetic counseling process, aiming at (1) exploring current evidence; (2) identifying quality assessment indicators; and (3) making recommendations for genetic counseling practice in late-onset disorders. We undertook a systematic search of 6 relevant databases: 38 articles were identified and 3 fitted our inclusion criteria; after quality appraisal, all were included in the review. The number of sessions, time spent, consultation environment, follow-up, and multidisciplinarity were identified as variables for quality assessment. Research on counseling in the context of genetic testing in familial cancer tends to be related to outcomes and indicators for quality assessment, while research concerning other late-onset diseases is mainly focused on the psychological impact of the test results. The quality and content of the overall process in noncancer late-onset diseases is insufficiently articulated. Despite the fact that PST for Huntington disease and other degenerative conditions has been offered for more than 20 years, good methodological approaches to assess quality of genetic counseling in that context remain elusive. This restricts improvement of the protocols for genetic services and, in general, healthcare for the at-risk population.

Recommendations for genetic testing to reduce the incidence of anthracycline‐induced cardiotoxicity

PubMed Central

Aminkeng, Folefac; Ross, Colin J. D.; Rassekh, Shahrad R.; Hwang, Soomi; Rieder, Michael J.; Bhavsar, Amit P.; Smith, Anne; Sanatani, Shubhayan; Gelmon, Karen A.; Bernstein, Daniel; Hayden, Michael R.; Amstutz, Ursula

2016-01-01

Aims Anthracycline‐induced cardiotoxicity (ACT) occurs in 57% of treated patients and remains an important limitation of anthracycline‐based chemotherapy. In various genetic association studies, potential genetic risk markers for ACT have been identified. Therefore, we developed evidence‐based clinical practice recommendations for pharmacogenomic testing to further individualize therapy based on ACT risk. Methods We followed a standard guideline development process, including a systematic literature search, evidence synthesis and critical appraisal, and the development of clinical practice recommendations with an international expert group. Results RARG rs2229774, SLC28A3 rs7853758 and UGT1A6 rs17863783 variants currently have the strongest and the most consistent evidence for association with ACT. Genetic variants in ABCC1, ABCC2, ABCC5, ABCB1, ABCB4, CBR3, RAC2, NCF4, CYBA, GSTP1, CAT, SULT2B1, POR, HAS3, SLC22A7, SCL22A17, HFE and NOS3 have also been associated with ACT, but require additional validation. We recommend pharmacogenomic testing for the RARG rs2229774 (S427L), SLC28A3 rs7853758 (L461L) and UGT1A6*4 rs17863783 (V209V) variants in childhood cancer patients with an indication for doxorubicin or daunorubicin therapy (Level B – moderate). Based on an overall risk stratification, taking into account genetic and clinical risk factors, we recommend a number of management options including increased frequency of echocardiogram monitoring, follow‐up, as well as therapeutic options within the current standard of clinical practice. Conclusions Existing evidence demonstrates that genetic factors have the potential to improve the discrimination between individuals at higher and lower risk of ACT. Genetic testing may therefore support both patient care decisions and evidence development for an improved prevention of ACT. PMID:27197003

Germline BRCA mutation evaluation in a prospective triple-negative breast cancer registry: implications for hereditary breast and/or ovarian cancer syndrome testing

PubMed Central

Klemp, Jennifer R.; Kimler, Bruce F.; Mahnken, Jonathan D.; Geier, Larry J.; Khan, Qamar J.; Elia, Manana; Connor, Carol S.; McGinness, Marilee K.; Mammen, Joshua M. W.; Wagner, Jamie L.; Ward, Claire; Ranallo, Lori; Knight, Catherine J.; Stecklein, Shane R.; Jensen, Roy A.; Fabian, Carol J.; Godwin, Andrew K.

2014-01-01

NCCN guidelines recommend genetic testing for all triple-negative breast cancer (TNBC) patients aged ≤60 years. However, due to the lack of prospective information in unselected patients, these guidelines are not uniformly adopted by clinicians and insurance carriers. The aim of this study was to determine the prevalence of BRCA mutations and evaluate the utility of NCCN guidelines in unselected TNBC population. Stage I–IV TNBC patients were enrolled on a prospective registry at academic and community practices. All patients underwent BRCA1/2 testing. Significant family history (SFH) was defined >1 relative with breast cancer at age ≤50 or ≥1 relative with ovarian cancer. Mutation prevalence in the entire cohort and subgroups was calculated. 207 TNBC patients were enrolled between 2011 and 2013. Racial/ethnic distribution: Caucasian (80 %), African–American (14 %), Ashkenazi (1 %). Deleterious BRCA1/2 mutations were identified in 15.4 % (32/207) of patients (BRCA1:11.1 %, BRCA2:4.3 %). SFH reported by 36 % of patients. Mutation prevalence in patients with and without SFH was 31.6 and 6.1 %, respectively. When assessed by age at TNBC diagnosis, the mutation prevalences were 27.6 % (≤50 years), 11.4 % (51–60 years), and 4.9 % (≥61 years). Using SFH or age ≤50 as criteria, 25 and 34 % of mutations, respectively, were missed. Mutation prevalence in patients meeting NCCN guidelines was 18.3 % (32/175) and 0 % (0/32) in patients who did not meet guidelines (p = .0059). In this unselected academic and community population with negligible Ashkenazi representation, we observed an overall BRCA mutation prevalence rate of 15.4 %. BRCA testing based on NCCN guidelines identified all carriers supporting its routine application in clinical practice for TNBC. PMID:24807107

Lods, wrods, and mods: the interpretation of lod scores calculated under different models.

PubMed

Hodge, S E; Elston, R C

1994-01-01

In this paper we examine the relationships among classical lod scores, "wrod" scores (lod scores calculated under the wrong genetic model), and "mod" scores (lod scores maximized over genetic model parameters). We compare the behavior of these scores when the state of nature is linkage to their behavior when the state of nature is no linkage. We describe sufficient conditions for mod scores to be valid and discuss their use to determine the correct genetic model. We show that lod scores represent a likelihood-ratio test for independence. We explain the "ascertainment-assumption-free" aspect of using mod scores to determine mode of inheritance and we set this aspect into a well-established statistical framework. Finally, we summarize practical guidelines for the use of mod scores.

Practice guideline: joint CCMG-SOGC recommendations for the use of chromosomal microarray analysis for prenatal diagnosis and assessment of fetal loss in Canada

PubMed Central

Armour, Christine M; Dougan, Shelley Danielle; Brock, Jo-Ann; Chari, Radha; Chodirker, Bernie N; DeBie, Isabelle; Evans, Jane A; Gibson, William T; Kolomietz, Elena; Nelson, Tanya N; Tihy, Frédérique; Thomas, Mary Ann; Stavropoulos, Dimitri J

2018-01-01

Background The aim of this guideline is to provide updated recommendations for Canadian genetic counsellors, medical geneticists, maternal fetal medicine specialists, clinical laboratory geneticists and other practitioners regarding the use of chromosomal microarray analysis (CMA) for prenatal diagnosis. This guideline replaces the 2011 Society of Obstetricians and Gynaecologists of Canada (SOGC)-Canadian College of Medical Geneticists (CCMG) Joint Technical Update. Methods A multidisciplinary group consisting of medical geneticists, genetic counsellors, maternal fetal medicine specialists and clinical laboratory geneticists was assembled to review existing literature and guidelines for use of CMA in prenatal care and to make recommendations relevant to the Canadian context. The statement was circulated for comment to the CCMG membership-at-large for feedback and, following incorporation of feedback, was approved by the CCMG Board of Directors on 5 June 2017 and the SOGC Board of Directors on 19 June 2017. Results and conclusions Recommendations include but are not limited to: (1) CMA should be offered following a normal rapid aneuploidy screen when multiple fetal malformations are detected (II-1A) or for nuchal translucency (NT) ≥3.5 mm (II-2B) (recommendation 1); (2) a professional with expertise in prenatal chromosomal microarray analysis should provide genetic counselling to obtain informed consent, discuss the limitations of the methodology, obtain the parental decisions for return of incidental findings (II-2A) (recommendation 4) and provide post-test counselling for reporting of test results (III-A) (recommendation 9); (3) the resolution of chromosomal microarray analysis should be similar to postnatal microarray platforms to ensure small pathogenic variants are detected. To minimise the reporting of uncertain findings, it is recommended that variants of unknown significance (VOUS) smaller than 500 Kb deletion or 1 Mb duplication not be routinely reported in the prenatal context. Additionally, VOUS above these cut-offs should only be reported if there is significant supporting evidence that deletion or duplication of the region may be pathogenic (III-B) (recommendation 5); (4) secondary findings associated with a medically actionable disorder with childhood onset should be reported, whereas variants associated with adult-onset conditions should not be reported unless requested by the parents or disclosure can prevent serious harm to family members (III-A) (recommendation 8). The working group recognises that there is variability across Canada in delivery of prenatal testing, and these recommendations were developed to promote consistency and provide a minimum standard for all provinces and territories across the country (recommendation 9). PMID:29496978

Initial Results of Multigene Panel Testing for Hereditary Breast and Ovarian Cancer and Lynch Syndrome.

PubMed

Howarth, Dt R; Lum, Sharon S; Esquivel, Pamela; Garberoglio, Carlos A; Senthil, Maheswari; Solomon, Naveenraj L

2015-10-01

Multigene panel testing for hereditary cancer risk has recently become commercially available; however, the impact of its use on patient care is undefined. We sought to evaluate results from implementation of panel testing in a multidisciplinary cancer center. We performed a retrospective review of consecutive patients undergoing genetic testing after initiating use of multigene panel testing at Loma Linda University Medical Center. From February 13 to August 25, 2014, 92 patients were referred for genetic testing based on National Comprehensive Cancer Network guidelines. Testing was completed in 90 patients. Overall, nine (10%) pathogenic mutations were identified: five BRCA1/2, and four in non-BRCA loci. Single-site testing identified one BRCA1 and one BRCA2 mutation. The remaining mutations were identified by use of panel testing for hereditary breast and ovarian cancer. There were 40 variants of uncertain significance identified in 34 patients. The use of panel testing more than doubled the identification rate of clinically significant pathogenic mutations that would have been missed with BRCA testing alone. The large number of variants of uncertain significance identified will require long-term follow-up for potential reclassification. Multigene panel testing provides additional information that may improve patient outcomes.

DNA-testing for BRCA1/2 prior to genetic counselling in patients with breast cancer: design of an intervention study, DNA-direct.

PubMed

Sie, Aisha S; Spruijt, Liesbeth; van Zelst-Stams, Wendy A G; Mensenkamp, Arjen R; Ligtenberg, Marjolijn J; Brunner, Han G; Prins, Judith B; Hoogerbrugge, Nicoline

2012-05-08

Current practice for patients with breast cancer referred for genetic counseling, includes face-to-face consultations with a genetic counselor prior to and following DNA-testing. This is based on guidelines regarding Huntington's disease in anticipation of high psychosocial impact of DNA-testing for mutations in BRCA1/2 genes. The initial consultation covers generic information regarding hereditary breast cancer and the (im)possibilities of DNA-testing, prior to such testing. Patients with breast cancer may see this information as irrelevant or unnecessary because individual genetic advice depends on DNA-test results. Also, verbal information is not always remembered well by patients. A different format for this information prior to DNA-testing is possible: replacing initial face-to-face genetic counseling (DNA-intake procedure) by telephone, written and digital information sent to patients' homes (DNA-direct procedure). In this intervention study, 150 patients with breast cancer referred to the department of Clinical Genetics of the Radboud University Nijmegen Medical Centre are given the choice between two procedures, DNA-direct (intervention group) or DNA-intake (usual care, control group). During a triage telephone call, patients are excluded if they have problems with Dutch text, family communication, or of psychological or psychiatric nature. Primary outcome measures are satisfaction and psychological distress. Secondary outcome measures are determinants for the participant's choice of procedure, waiting and processing times, and family characteristics. Data are collected by self-report questionnaires at baseline and following completion of genetic counseling. A minority of participants will receive an invitation for a 30 min semi-structured telephone interview, e.g. confirmed carriers of a BRCA1/2 mutation, and those who report problems with the procedure. This study compares current practice of an intake consultation (DNA-intake) to a home informational package of telephone, written and digital information (DNA-direct) prior to DNA-testing in patients with breast cancer. The aim is to determine whether DNA-direct is an acceptable procedure for BRCA1/2 testing, in order to provide customized care to patients with breast cancer, cutting down on the period of uncertainty during this diagnostic process.

EMQN Best Practice Guidelines for molecular and haematology methods for carrier identification and prenatal diagnosis of the haemoglobinopathies.

PubMed

Traeger-Synodinos, Joanne; Harteveld, Cornelis L; Old, John M; Petrou, Mary; Galanello, Renzo; Giordano, Piero; Angastioniotis, Michael; De la Salle, Barbara; Henderson, Shirley; May, Alison

2015-04-01

Haemoglobinopathies constitute the commonest recessive monogenic disorders worldwide, and the treatment of affected individuals presents a substantial global disease burden. Carrier identification and prenatal diagnosis represent valuable procedures that identify couples at risk for having affected children, so that they can be offered options to have healthy offspring. Molecular diagnosis facilitates prenatal diagnosis and definitive diagnosis of carriers and patients (especially 'atypical' cases who often have complex genotype interactions). However, the haemoglobin disorders are unique among all genetic diseases in that identification of carriers is preferable by haematological (biochemical) tests rather than DNA analysis. These Best Practice guidelines offer an overview of recommended strategies and methods for carrier identification and prenatal diagnosis of haemoglobinopathies, and emphasize the importance of appropriately applying and interpreting haematological tests in supporting the optimum application and evaluation of globin gene DNA analysis.

EMQN Best Practice Guidelines for molecular and haematology methods for carrier identification and prenatal diagnosis of the haemoglobinopathies

PubMed Central

Traeger-Synodinos, Joanne; Harteveld, Cornelis L; Old, John M; Petrou, Mary; Galanello, Renzo; Giordano, Piero; Angastioniotis, Michael; De la Salle, Barbara; Henderson, Shirley; May, Alison

2015-01-01

Haemoglobinopathies constitute the commonest recessive monogenic disorders worldwide, and the treatment of affected individuals presents a substantial global disease burden. Carrier identification and prenatal diagnosis represent valuable procedures that identify couples at risk for having affected children, so that they can be offered options to have healthy offspring. Molecular diagnosis facilitates prenatal diagnosis and definitive diagnosis of carriers and patients (especially ‘atypical' cases who often have complex genotype interactions). However, the haemoglobin disorders are unique among all genetic diseases in that identification of carriers is preferable by haematological (biochemical) tests rather than DNA analysis. These Best Practice guidelines offer an overview of recommended strategies and methods for carrier identification and prenatal diagnosis of haemoglobinopathies, and emphasize the importance of appropriately applying and interpreting haematological tests in supporting the optimum application and evaluation of globin gene DNA analysis. PMID:25052315

History and future of genetically engineered food animal regulation: an open request.

PubMed

Wells, Kevin D

2016-06-01

Modern biotechnology resulted from of a series of incremental improvements in the understanding of DNA and the enzymes that nature evolved to manipulate it. As the potential impact of genetic engineering became apparent, scientists began the process of trying to identify the potential unintended consequences. Restrictions to recombinant DNA experimentation were at first self-imposed. Collaborative efforts between scientists and lawyers formalized an initial set of guidelines. These guidelines have been used to promulgate regulations around world. However, the initial guidelines were only intended as a starting point and were motivated by a specific set of concerns. As new data became available, the guidelines and regulations should have been adapted to the new knowledge. Instead, other social drivers drove the development of regulations. For most species and most applications, the framework that was established has slowly allowed some products to reach the market. However, genetically engineered livestock that are intended for food have been left in a regulatory state of limbo. To date, no genetically engineered food animal is available in the marketplace. A short history and a U.S.-based genetic engineer's perspective are presented. In addition, a request to regulatory agencies is presented for consideration as regulation continues to evolve. Regulators appear to have shown preference for the slow, random progression of evolution over the efficiency of intentional design.

Guidelines and recommendations for laboratory analysis in the diagnosis and management of diabetes mellitus.

PubMed

Sacks, David B; Arnold, Mark; Bakris, George L; Bruns, David E; Horvath, Andrea Rita; Kirkman, M Sue; Lernmark, Ake; Metzger, Boyd E; Nathan, David M

2011-06-01

Multiple laboratory tests are used to diagnose and manage patients with diabetes mellitus. The quality of the scientific evidence supporting the use of these tests varies substantially. An expert committee compiled evidence-based recommendations for the use of laboratory testing for patients with diabetes. A new system was developed to grade the overall quality of the evidence and the strength of the recommendations. Draft guidelines were posted on the Internet and presented at the 2007 Arnold O. Beckman Conference. The document was modified in response to oral and written comments, and a revised draft was posted in 2010 and again modified in response to written comments. The National Academy of Clinical Biochemistry and the Evidence-Based Laboratory Medicine Committee of the American Association for Clinical Chemistry jointly reviewed the guidelines, which were accepted after revisions by the Professional Practice Committee and subsequently approved by the Executive Committee of the American Diabetes Association. In addition to long-standing criteria based on measurement of plasma glucose, diabetes can be diagnosed by demonstrating increased blood hemoglobin A(1c) (HbA(1c)) concentrations. Monitoring of glycemic control is performed by self-monitoring of plasma or blood glucose with meters and by laboratory analysis of HbA(1c). The potential roles of noninvasive glucose monitoring, genetic testing, and measurement of autoantibodies, urine albumin, insulin, proinsulin, C-peptide, and other analytes are addressed. The guidelines provide specific recommendations that are based on published data or derived from expert consensus. Several analytes have minimal clinical value at present, and their measurement is not recommended.

Guidelines and recommendations for laboratory analysis in the diagnosis and management of diabetes mellitus.

PubMed

Sacks, David B; Arnold, Mark; Bakris, George L; Bruns, David E; Horvath, Andrea Rita; Kirkman, M Sue; Lernmark, Ake; Metzger, Boyd E; Nathan, David M

2011-06-01

Multiple laboratory tests are used to diagnose and manage patients with diabetes mellitus. The quality of the scientific evidence supporting the use of these tests varies substantially. An expert committee compiled evidence-based recommendations for the use of laboratory testing for patients with diabetes. A new system was developed to grade the overall quality of the evidence and the strength of the recommendations. Draft guidelines were posted on the Internet and presented at the 2007 Arnold O. Beckman Conference. The document was modified in response to oral and written comments, and a revised draft was posted in 2010 and again modified in response to written comments. The National Academy of Clinical Biochemistry and the Evidence Based Laboratory Medicine Committee of the AACC jointly reviewed the guidelines, which were accepted after revisions by the Professional Practice Committee and subsequently approved by the Executive Committee of the American Diabetes Association. In addition to long-standing criteria based on measurement of plasma glucose, diabetes can be diagnosed by demonstrating increased blood hemoglobin A(1c) (Hb A(1c)) concentrations. Monitoring of glycemic control is performed by self-monitoring of plasma or blood glucose with meters and by laboratory analysis of Hb A(1c). The potential roles of noninvasive glucose monitoring, genetic testing, and measurement of autoantibodies, urine albumin, insulin, proinsulin, C-peptide, and other analytes are addressed. The guidelines provide specific recommendations that are based on published data or derived from expert consensus. Several analytes have minimal clinical value at present, and their measurement is not recommended.

Strategies to work with HLA data in human populations for histocompatibility, clinical transplantation, epidemiology and population genetics: HLA-NET methodological recommendations.

PubMed

Sanchez-Mazas, A; Vidan-Jeras, B; Nunes, J M; Fischer, G; Little, A-M; Bekmane, U; Buhler, S; Buus, S; Claas, F H J; Dormoy, A; Dubois, V; Eglite, E; Eliaou, J F; Gonzalez-Galarza, F; Grubic, Z; Ivanova, M; Lie, B; Ligeiro, D; Lokki, M L; da Silva, B Martins; Martorell, J; Mendonça, D; Middleton, D; Voniatis, D Papioannou; Papasteriades, C; Poli, F; Riccio, M E; Vlachou, M Spyropoulou; Sulcebe, G; Tonks, S; Nevessignsky, M Toungouz; Vangenot, C; van Walraven, A-M; Tiercy, J-M

2012-12-01

HLA-NET (a European COST Action) aims at networking researchers working in bone marrow transplantation, epidemiology and population genetics to improve the molecular characterization of the HLA genetic diversity of human populations, with an expected strong impact on both public health and fundamental research. Such improvements involve finding consensual strategies to characterize human populations and samples and report HLA molecular typings and ambiguities; proposing user-friendly access to databases and computer tools and defining minimal requirements related to ethical aspects. The overall outcome is the provision of population genetic characterizations and comparisons in a standard way by all interested laboratories. This article reports the recommendations of four working groups (WG1-4) of the HLA-NET network at the mid-term of its activities. WG1 (Population definitions and sampling strategies for population genetics' analyses) recommends avoiding outdated racial classifications and population names (e.g. 'Caucasian') and using instead geographic and/or cultural (e.g. linguistic) criteria to describe human populations (e.g. 'pan-European'). A standard 'HLA-NET POPULATION DATA QUESTIONNAIRE' has been finalized and is available for the whole HLA community. WG2 (HLA typing standards for population genetics analyses) recommends retaining maximal information when reporting HLA typing results. Rather than using the National Marrow Donor Program coding system, all ambiguities should be provided by listing all allele pairs required to explain each genotype, according to the formats proposed in 'HLA-NET GUIDELINES FOR REPORTING HLA TYPINGS'. The group also suggests taking into account a preliminary list of alleles defined by polymorphisms outside the peptide-binding sites that may affect population genetic statistics because of significant frequencies. WG3 (Bioinformatic strategies for HLA population data storage and analysis) recommends the use of programs capable of dealing with ambiguous data, such as the 'gene[rate]' computer tools to estimate frequencies, test for Hardy-Weinberg equilibrium and selective neutrality on data containing any number and kind of ambiguities. WG4 (Ethical issues) proposes to adopt thorough general principles for any HLA population study to ensure that it conforms to (inter)national legislation or recommendations/guidelines. All HLA-NET guidelines and tools are available through its website http://hla-net.eu. © 2012 Blackwell Publishing Ltd.

EFNS guidelines for the diagnosis and management of Alzheimer's disease.

PubMed

Hort, J; O'Brien, J T; Gainotti, G; Pirttila, T; Popescu, B O; Rektorova, I; Sorbi, S; Scheltens, P

2010-10-01

In 2008 a task force was set up to develop a revision of the European Federation of the Neurological Societies (EFNS) guideline for the diagnosis and management of Alzheimer's disease (AD) and other disorders associated with dementia, published in early 2007. The aim of this revised international guideline was to present a peer-reviewed evidence-based statement for the guidance of practice for clinical neurologists, geriatricians, psychiatrists, and other specialist physicians responsible for the care of patients with AD. Mild cognitive impairment and non-Alzheimer dementias are not included in this guideline. The task force working group reviewed evidence from original research articles, meta-analysis, and systematic reviews, published before May 2009. The evidence was classified and consensus recommendations graded (A, B, or C) according to the EFNS guidance. Where there was a lack of evidence, but clear consensus, good practice points were provided. The recommendations for clinical diagnosis, blood tests, neuropsychology, neuroimaging, electroencephalography, cerebrospinal fluid (CSF) analysis, genetic testing, disclosure of diagnosis, treatment of AD, behavioural and psychological symptoms in dementia, legal issues, counselling and support for caregivers were all revised as compared with the previous EFNS guideline. A number of new recommendations and good practice points are made, namely in CSF, neuropsychology, neuroimaging and reviewing non-evidence based therapies. The assessment, interpretation, and treatment of symptoms, disability, needs, and caregiver stress during the course of AD require the contribution of many different professionals. These professionals should adhere to these guideline to improve the diagnosis and management of AD. © 2010 The Author(s). European Journal of Neurology © 2010 EFNS.

Guidelines for collecting and maintaining archives for genetic monitoring

USGS Publications Warehouse

Jackson, Jennifer A.; Laikre, Linda; Baker, C. Scott; Kendall, Katherine C.; ,

2012-01-01

Rapid advances in molecular genetic techniques and the statistical analysis of genetic data have revolutionized the way that populations of animals, plants and microorganisms can be monitored. Genetic monitoring is the practice of using molecular genetic markers to track changes in the abundance, diversity or distribution of populations, species or ecosystems over time, and to follow adaptive and non-adaptive genetic responses to changing external conditions. In recent years, genetic monitoring has become a valuable tool in conservation management of biological diversity and ecological analysis, helping to illuminate and define cryptic and poorly understood species and populations. Many of the detected biodiversity declines, changes in distribution and hybridization events have helped to drive changes in policy and management. Because a time series of samples is necessary to detect trends of change in genetic diversity and species composition, archiving is a critical component of genetic monitoring. Here we discuss the collection, development, maintenance, and use of archives for genetic monitoring. This includes an overview of the genetic markers that facilitate effective monitoring, describes how tissue and DNA can be stored, and provides guidelines for proper practice.

Guidelines for collecting and maintaining archives for genetic monitoring

Treesearch

Jennifer A. Jackson; Linda Laikre; C. Scott Baker; Katherine C. Kendall; F. W. Allendorf; M. K. Schwartz

2011-01-01

Rapid advances in molecular genetic techniques and the statistical analysis of genetic data have revolutionized the way that populations of animals, plants and microorganisms can be monitored. Genetic monitoring is the practice of using molecular genetic markers to track changes in the abundance, diversity or distribution of populations, species or ecosystems over time...

Should children and adolescents be tested for Huntington's disease? Attitudes of future lawyers and physicians in Switzerland.

PubMed

Elger, Bernice S; Harding, Timothy W

2006-06-01

The objective of the study was to identify future lawyers' and physicians' views on testing children for Huntington's disease (HD) against parents' wishes. After receiving general information about HD, patient autonomy and confidentiality, law students and advanced medical students were shown an interview with a mother suffering from HD who is opposed to informing and testing her two children (aged 10 and 16) for HD. Students then filled out questionnaires concerning their agreement with testing. No significant differences were found between medical and law students or between students from different courses concerning the adolescent son. Three quarters of students thought that he should be told about his mother's disease, and 91% thought the adolescent son should have the opportunity of genetic testing for HD himself. However, significant differences were found concerning the 10-year old son, with 44% of law students and 30% of medical students in favour of testing the child for HD. Students raised some important ethical issues in their elective comments. In conclusion, we found highly positive attitudes towards informing a 16-year old of his mother's HD and offering to test him. These attitudes were not in tune with guidelines. Students did not consider several practical and ethical issues of genetic testing of children and adolescents. Specific education should ensure that attitudes are based on sufficiently detailed knowledge about all aspects of genetic testing of children to discourage pressures on persons at risk of HD.

Parent-child genetic testing for familial hypercholesterolaemia in an Australian context.

PubMed

Pang, Jing; Martin, Andrew C; Bates, Timothy R; Hooper, Amanda J; Bell, Damon A; Burnett, John R; Norman, Richard; Watts, Gerald F

2018-04-06

The aim of this study was to evaluate the clinical outcome of parent-child testing for familial hypercholesterolaemia (FH) employing genetic testing and the likely additional cost of treating each child. Parent-child testing for gene variants causative of FH was carried out according to Australian guidelines. The number of new cases detected, the low-density lipoprotein (LDL)-cholesterol that best predicted a mutation and the proportional reduction in LDL-cholesterol following statin treatment was evaluated. Treatment costs were calculated as the cost per mmol/L reduction in LDL-cholesterol. A total of 126 adult patients, known to have a pathogenic mutation causative of FH, and their children were studied. From 244 children identified, 148 (60.7%) were genetically screened; 84 children were identified as mutative positive (M+) and 64 as mutative negative. Six of the M+ children were already on statin treatment; 40 were subsequently treated with low-dose statins, with LDL-cholesterol falling significantly by 38% (P < 0.001). The estimated cost per mmol/L reduction of LDL-cholesterol of a child receiving statins from ages 10 to 18 years is AU$1361, which can potentially be cost-effective. An LDL-cholesterol threshold of 3.5 mmol/L had a sensitivity of 92.8% and specificity of 96.6% for the detection of a mutation. Genetic testing of children of affected parents with FH is an effective means of detecting new cases of FH. Cascade testing can enable early statin therapy with significant reductions in LDL-cholesterol concentration. © 2018 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).

[Present status and tasks for genetic testing and risk-reducing surgery in patients with hereditary breast and ovarian cancer].

PubMed

Arai, Masami; Taki, Keiko; Iwase, Haruko; Takizawa, Ken; Nishimura, Seiichiro; Iwase, Takuji

2012-04-01

In Japan, awareness of hereditary breast and ovarian cancer (HBOC) has gradually increased among health care workers and the general population. We focus on two current topics: genetic testing and risk-reducing surgery for HBOC. Genetic testing for BRCA1 and BRCA2, the genes responsible for HBOC, is performed to diagnose HBOC. PCR-direct sequencing is a standard method used for BRCA1/2 mutation analysis. Recently, genetic rearrangement of BRCA1 was reported in a Japanese patient with HBOC. Therefore, MLPA tests are also being included in routine genetic testing for the disease. The result of "uncertain significance, " which indicates unclear pathogenic significance, is obtained in about 3% of all patients who undergo BRCA1/2 genetic tests. Furthermore, novel candidate genes for HBOC, such as RAD51C, PALB2, and BRIP1, were recently identified. Prophylactic surgical intervention for HBOC includes procedures such as risk-reducing bilateral salpingo-oophorectomy (RRSO) and risk-reducing mastectomy(RRM). In Japan, RRSO is performed in very few patients at present. Increasing evidence from overseas indicates that RRSO contributes to a decreased incidence of ovarian/breast cancers and lowers overall mortality. Therefore, a system for performing RRSO was established in our institute. RRSO was approved to be performed as a clinical examination by our Institutional Review Board. The clinical significance of ipsilateral complete mastectomy and RRM remains unclear. Based on the NCCN guidelines, conservative mastectomy with radiation therapy is relatively contraindicated in patients with HBOC. However, several studies have reported that conservative mastectomy with radiation the rapydoes not increase the incidence of recurrent or metachronous breast cancers in the ipsilateral breast of mutation-positive patients when compared to mutation-negative or control patients. However, more aggressive malignancies seem to be included in the mutation-positive group(especially BRCA1 -mutation-positive cases). RRM clearly reduced the incidence of breast cancers. RRM may also be allowed as a treatment option for HBOC in Japan.

Clinical exome sequencing reports: current informatics practice and future opportunities.

PubMed

Swaminathan, Rajeswari; Huang, Yungui; Astbury, Caroline; Fitzgerald-Butt, Sara; Miller, Katherine; Cole, Justin; Bartlett, Christopher; Lin, Simon

2017-11-01

The increased adoption of clinical whole exome sequencing (WES) has improved the diagnostic yield for patients with complex genetic conditions. However, the informatics practice for handling information contained in whole exome reports is still in its infancy, as evidenced by the lack of a common vocabulary within clinical sequencing reports generated across genetic laboratories. Genetic testing results are mostly transmitted using portable document format, which can make secondary analysis and data extraction challenging. This paper reviews a sample of clinical exome reports generated by Clinical Laboratory Improvement Amendments-certified genetic testing laboratories at tertiary-care facilities to assess and identify common data elements. Like structured radiology reports, which enable faster information retrieval and reuse, structuring genetic information within clinical WES reports would help facilitate integration of genetic information into electronic health records and enable retrospective research on the clinical utility of WES. We identify elements listed as mandatory according to practice guidelines but are currently missing from some of the clinical reports, which might help to organize the data when stored within structured databases. We also highlight elements, such as patient consent, that, although they do not appear within any of the current reports, may help in interpreting some of the information within the reports. Integrating genetic and clinical information would assist the adoption of personalized medicine for improved patient care and outcomes. © The Author 2017. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

The ins and outs of molecular pathology reporting.

PubMed

Tack, Véronique; Dufraing, Kelly; Deans, Zandra C; van Krieken, Han J; Dequeker, Elisabeth M C

2017-08-01

The raid evolution in molecular pathology resulting in an increasing complexity requires careful reporting. The need for standardisation is clearer than ever. While synoptic reporting was first used for reporting hereditary genetic diseases, it is becoming more frequent in pathology, especially molecular pathology reports too. The narrative approach is no longer feasible with the growing amount of essential data present on the report, although narrative components are still necessary for interpretation in molecular pathology. On the way towards standardisation of reports, guidelines can be a helpful tool. There are several guidelines that focus on reporting in the field of hereditary diseases, but it is not always feasible to extrapolate these to the reporting of somatic variants in molecular pathology. The rise of multi-gene testing causes challenges for the laboratories. In order to provide a continuous optimisation of the laboratory testing process, including reporting, external quality assessment is essential and has already proven to improve the quality of reports. In general, a clear and concise report for molecular pathology can be created by including elements deemed important by different guidelines, adapting the report to the process flows of the laboratory and integrating the report with the laboratory information management system and the patient record.

Mucopolysaccharidosis VI in cats - clarification regarding genetic testing.

PubMed

Lyons, Leslie A; Grahn, Robert A; Genova, Francesca; Beccaglia, Michela; Hopwood, John J; Longeri, Maria

2016-07-02

The release of new DNA-based diagnostic tools has increased tremendously in companion animals. Over 70 different DNA variants are now known for the cat, including DNA variants in disease-associated genes and genes causing aesthetically interesting traits. The impact genetic tests have on animal breeding and health management is significant because of the ability to control the breeding of domestic cats, especially breed cats. If used properly, genetic testing can prevent the production of diseased animals, causing the reduction of the frequency of the causal variant in the population, and, potentially, the eventual eradication of the disease. However, testing of some identified DNA variants may be unwarranted and cause undo strife within the cat breeding community and unnecessary reduction of gene pools and availability of breeding animals. Testing for mucopolysaccharidosis Type VI (MPS VI) in cats, specifically the genetic testing of the L476P (c.1427T>C) and the D520N (c.1558G>A) variants in arylsulfatase B (ARSB), has come under scrutiny. No health problems are associated with the D520N (c.1558G>A) variant, however, breeders that obtain positive results for this variant are speculating as to possible correlation with health concerns. Birman cats already have a markedly reduced gene pool and have a high frequency of the MPS VI D520N variant. Further reduction of the gene pool by eliminating cats that are heterozygous or homozygous for only the MPS VI D520N variant could lead to more inbreeding depression effects on the breed population. Herein is debated the genetic testing of the MPS VI D520N variant in cats. Surveys from different laboratories suggest the L476P (c.1427T>C) disease-associated variant should be monitored in the cat breed populations, particularly breeds with Siamese derivations and outcrosses. However, the D520N has no evidence of association with disease in cats and testing is not recommended in the absence of L476P genotyping. Selection against the D520N is not warranted in cat populations. More rigorous guidelines may be required to support the genetic testing of DNA variants in all animal species.

Pharmacogenetic testing through the direct-to-consumer genetic testing company 23andMe.

PubMed

Lu, Mengfei; Lewis, Cathryn M; Traylor, Matthew

2017-06-19

Rapid advances in scientific research have led to an increase in public awareness of genetic testing and pharmacogenetics. Direct-to-consumer (DTC) genetic testing companies, such as 23andMe, allow consumers to access their genetic information directly through an online service without the involvement of healthcare professionals. Here, we evaluate the clinical relevance of pharmacogenetic tests reported by 23andMe in their UK tests. The research papers listed under each 23andMe report were evaluated, extracting information on effect size, sample size and ethnicity. A wider literature search was performed to provide a fuller assessment of the pharmacogenetic test and variants were matched to FDA recommendations. Additional evidence from CPIC guidelines, PharmGKB, and Dutch Pharmacogenetics Working Group was reviewed to determine current clinical practice. The value of the tests across ethnic groups was determined, including information on linkage disequilibrium between the tested SNP and causal pharmacogenetic variant, where relevant. 23andMe offers 12 pharmacogenetic tests to their UK customers, some of which are in standard clinical practice, and others which are less widely applied. The clinical validity and clinical utility varies extensively between tests. The variants tested are likely to have different degrees of sensitivity due to different risk allele frequencies and linkage disequilibrium patterns across populations. The clinical relevance depends on the ethnicity of the individual and variability of pharmacogenetic markers. Further research is required to determine causal variants and provide more complete assessment of drug response and side effects. 23andMe reports provide some useful pharmacogenetics information, mirroring clinical tests that are in standard use. Other tests are unspecific, providing limited guidance and may not be useful for patients without professional interpretation. Nevertheless, DTC companies like 23andMe act as a powerful intermediate step to integrate pharmacogenetic testing into clinical practice.

Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline.

PubMed

Lenders, Jacques W M; Duh, Quan-Yang; Eisenhofer, Graeme; Gimenez-Roqueplo, Anne-Paule; Grebe, Stefan K G; Murad, Mohammad Hassan; Naruse, Mitsuhide; Pacak, Karel; Young, William F

2014-06-01

The aim was to formulate clinical practice guidelines for pheochromocytoma and paraganglioma (PPGL). The Task Force included a chair selected by the Endocrine Society Clinical Guidelines Subcommittee (CGS), seven experts in the field, and a methodologist. The authors received no corporate funding or remuneration. This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe both the strength of recommendations and the quality of evidence. The Task Force reviewed primary evidence and commissioned two additional systematic reviews. One group meeting, several conference calls, and e-mail communications enabled consensus. Committees and members of the Endocrine Society, European Society of Endocrinology, and Americal Association for Clinical Chemistry reviewed drafts of the guidelines. The Task Force recommends that initial biochemical testing for PPGLs should include measurements of plasma free or urinary fractionated metanephrines. Consideration should be given to preanalytical factors leading to false-positive or false-negative results. All positive results require follow-up. Computed tomography is suggested for initial imaging, but magnetic resonance is a better option in patients with metastatic disease or when radiation exposure must be limited. (123)I-metaiodobenzylguanidine scintigraphy is a useful imaging modality for metastatic PPGLs. We recommend consideration of genetic testing in all patients, with testing by accredited laboratories. Patients with paraganglioma should be tested for SDHx mutations, and those with metastatic disease for SDHB mutations. All patients with functional PPGLs should undergo preoperative blockade to prevent perioperative complications. Preparation should include a high-sodium diet and fluid intake to prevent postoperative hypotension. We recommend minimally invasive adrenalectomy for most pheochromocytomas with open resection for most paragangliomas. Partial adrenalectomy is an option for selected patients. Lifelong follow-up is suggested to detect recurrent or metastatic disease. We suggest personalized management with evaluation and treatment by multidisciplinary teams with appropriate expertise to ensure favorable outcomes.

Guidelines and Recommendations for Laboratory Analysis in the Diagnosis and Management of Diabetes Mellitus

PubMed Central

Arnold, Mark; Bakris, George L.; Bruns, David E.; Horvath, Andrea Rita; Kirkman, M. Sue; Lernmark, Ake; Metzger, Boyd E.; Nathan, David M.

2011-01-01

BACKGROUND Multiple laboratory tests are used to diagnose and manage patients with diabetes mellitus. The quality of the scientific evidence supporting the use of these tests varies substantially. APPROACH An expert committee compiled evidence-based recommendations for the use of laboratory testing for patients with diabetes. A new system was developed to grade the overall quality of the evidence and the strength of the recommendations. Draft guidelines were posted on the Internet and presented at the 2007 Arnold O. Beckman Conference. The document was modified in response to oral and written comments, and a revised draft was posted in 2010 and again modified in response to written comments. The National Academy of Clinical Biochemistry and the Evidence-Based Laboratory Medicine Committee of the American Association for Clinical Chemistry jointly reviewed the guidelines, which were accepted after revisions by the Professional Practice Committee and subsequently approved by the Executive Committee of the American Diabetes Association. CONTENT In addition to long-standing criteria based on measurement of plasma glucose, diabetes can be diagnosed by demonstrating increased blood hemoglobin A1c (HbA1c) concentrations. Monitoring of glycemic control is performed by self-monitoring of plasma or blood glucose with meters and by laboratory analysis of HbA1c. The potential roles of noninvasive glucose monitoring, genetic testing, and measurement of autoantibodies, urine albumin, insulin, proinsulin, C-peptide, and other analytes are addressed. SUMMARY The guidelines provide specific recommendations that are based on published data or derived from expert consensus. Several analytes have minimal clinical value at present, and their measurement is not recommended. PMID:21617108

Strategies to work with HLA data in human populations for histocompatibility, clinical transplantation, epidemiology and population genetics: HLA-NET methodological recommendations

PubMed Central

Sanchez-Mazas, A; Vidan-Jeras, B; Nunes, J M; Fischer, G; Little, A-M; Bekmane, U; Buhler, S; Buus, S; Claas, F H J; Dormoy, A; Dubois, V; Eglite, E; Eliaou, J F; Gonzalez-Galarza, F; Grubic, Z; Ivanova, M; Lie, B; Ligeiro, D; Lokki, M L; da Silva, B Martins; Martorell, J; Mendonça, D; Middleton, D; Voniatis, D Papioannou; Papasteriades, C; Poli, F; Riccio, M E; Vlachou, M Spyropoulou; Sulcebe, G; Tonks, S; Nevessignsky, M Toungouz; Vangenot, C; van Walraven, A-M; Tiercy, J-M

2012-01-01

HLA-NET (a European COST Action) aims at networking researchers working in bone marrow transplantation, epidemiology and population genetics to improve the molecular characterization of the HLA genetic diversity of human populations, with an expected strong impact on both public health and fundamental research. Such improvements involve finding consensual strategies to characterize human populations and samples and report HLA molecular typings and ambiguities; proposing user-friendly access to databases and computer tools and defining minimal requirements related to ethical aspects. The overall outcome is the provision of population genetic characterizations and comparisons in a standard way by all interested laboratories. This article reports the recommendations of four working groups (WG1-4) of the HLA-NET network at the mid-term of its activities. WG1 (Population definitions and sampling strategies for population genetics’ analyses) recommends avoiding outdated racial classifications and population names (e.g. ‘Caucasian’) and using instead geographic and/or cultural (e.g. linguistic) criteria to describe human populations (e.g. ‘pan-European’). A standard ‘HLA-NET POPULATION DATA QUESTIONNAIRE’ has been finalized and is available for the whole HLA community. WG2 (HLA typing standards for population genetics analyses) recommends retaining maximal information when reporting HLA typing results. Rather than using the National Marrow Donor Program coding system, all ambiguities should be provided by listing all allele pairs required to explain each genotype, according to the formats proposed in ‘HLA-NET GUIDELINES FOR REPORTING HLA TYPINGS’. The group also suggests taking into account a preliminary list of alleles defined by polymorphisms outside the peptide-binding sites that may affect population genetic statistics because of significant frequencies. WG3 (Bioinformatic strategies for HLA population data storage and analysis) recommends the use of programs capable of dealing with ambiguous data, such as the ‘gene[rate]’ computer tools to estimate frequencies, test for Hardy–Weinberg equilibrium and selective neutrality on data containing any number and kind of ambiguities. WG4 (Ethical issues) proposes to adopt thorough general principles for any HLA population study to ensure that it conforms to (inter)national legislation or recommendations/guidelines. All HLA-NET guidelines and tools are available through its website http://hla-net.eu. PMID:22533604

Germline mutation prevalence in individuals with pancreatic cancer and a history of previous malignancy.

PubMed

Dudley, Beth; Karloski, Eve; Monzon, Federico A; Singhi, Aatur D; Lincoln, Stephen E; Bahary, Nathan; Brand, Randall E

2018-04-15

Approximately 10% of pancreatic adenocarcinoma (PC) cases are attributed to hereditary causes. Individuals with PC and a personal history of another cancer associated with hereditary breast and ovarian cancer (HBOC) or Lynch syndrome (LS) may be more likely to carry germline mutations. Participants with PC and a history of cancer were selected from a pancreatic disease registry. Of 1296 individuals with PC, 149 had a relevant history of cancer. If banked DNA was available, a multigene panel was performed for individuals who had not 1) previously had a mutation identified through clinical testing or 2) undergone clinical multigene panel testing with no mutations detected. Twenty-two of 124 individuals with PC and another HBOC- or LS-related cancer who underwent genetic testing had a mutation identified in a PC susceptibility gene (18%). If prostate cancer is excluded, the mutation prevalence increased to 23% (21/93). Mutation carriers were more likely to have more than 1 previous cancer diagnosis (P = .001), to have had clinical genetic testing (P = .001), and to meet National Comprehensive Cancer Network (NCCN) genetic testing criteria (P < .001). Approximately 23% of mutation carriers did not meet NCCN HBOC or LS testing guidelines based on their personal cancer history and reported cancer history in first-degree relatives. At least 18% of individuals with PC and a personal history of other HBOC- or LS-related cancers carry mutations in a PC susceptibility gene based on our data, suggesting that criteria for genetic testing in individuals with PC should include consideration of previous cancer history. Cancer 2018;124:1691-700. © 2018 American Cancer Society. © 2018 American Cancer Society.

Prevalence and etiology of epilepsy in a Norwegian county-A population based study.

PubMed

Syvertsen, Marte; Nakken, Karl Otto; Edland, Astrid; Hansen, Gunnar; Hellum, Morten Kristoffer; Koht, Jeanette

2015-05-01

Epilepsy represents a substantial personal and social burden worldwide. When addressing the multifaceted issues of epilepsy care, updated epidemiologic studies using recent guidelines are essential. The aim of this study was to find the prevalence and causes of epilepsy in a representative Norwegian county, implementing the new guidelines and terminology suggested by the International League Against Epilepsy (ILAE). Included in the study were all patients from Buskerud County in Norway with a diagnosis of epilepsy at Drammen Hospital and the National Center for Epilepsy at Oslo University Hospital. The study period was 1999-2014. Patients with active epilepsy were identified through a systematic review of medical records, containing information about case history, electroencephalography (EEG), cerebral magnetic resonance imaging (MRI), genetic tests, blood samples, treatment, and other investigations. Epilepsies were classified according to the revised terminology suggested by the ILAE in 2010. In a population of 272,228 inhabitants, 1,771 persons had active epilepsy. Point prevalence on January 1, 2014 was 0.65%. Of the subjects registered with a diagnostic code of epilepsy, 20% did not fulfill the ILAE criteria of the diagnosis. Epilepsy etiology was structural-metabolic in 43%, genetic/presumed genetic in 20%, and unknown in 32%. Due to lack of information, etiology could not be determined in 4%. Epilepsy is a common disorder, affecting 0.65% of the subjects in this cohort. Every fifth subject registered with a diagnosis of epilepsy was misdiagnosed. In those with a reliable epilepsy diagnosis, every third patient had an unknown etiology. Future advances in genetic research will probably lead to an increased identification of genetic and hopefully treatable causes of epilepsy. Wiley Periodicals, Inc. © 2015 International League Against Epilepsy.

Exceptions to the rule: case studies in the prediction of pathogenicity for genetic variants in hereditary cancer genes.

PubMed

Rosenthal, E T; Bowles, K R; Pruss, D; van Kan, A; Vail, P J; McElroy, H; Wenstrup, R J

2015-12-01

Based on current consensus guidelines and standard practice, many genetic variants detected in clinical testing are classified as disease causing based on their predicted impact on the normal expression or function of the gene in the absence of additional data. However, our laboratory has identified a subset of such variants in hereditary cancer genes for which compelling contradictory evidence emerged after the initial evaluation following the first observation of the variant. Three representative examples of variants in BRCA1, BRCA2 and MSH2 that are predicted to disrupt splicing, prematurely truncate the protein, or remove the start codon were evaluated for pathogenicity by analyzing clinical data with multiple classification algorithms. Available clinical data for all three variants contradicts the expected pathogenic classification. These variants illustrate potential pitfalls associated with standard approaches to variant classification as well as the challenges associated with monitoring data, updating classifications, and reporting potentially contradictory interpretations to the clinicians responsible for translating test outcomes to appropriate clinical action. It is important to address these challenges now as the model for clinical testing moves toward the use of large multi-gene panels and whole exome/genome analysis, which will dramatically increase the number of genetic variants identified. © 2015 The Authors. Clinical Genetics published by John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Application of active learning modalities to achieve medical genetics competencies and their learning outcome assessments

PubMed Central

Hagiwara, Nobuko

2017-01-01

The steadily falling costs of genome sequencing, coupled with the growing number of genetic tests with proven clinical validity, have made the use of genetic testing more common in clinical practice. This development has necessitated nongeneticist physicians, especially primary care physicians, to become more responsible for assessing genetic risks for their patients. Providing undergraduate medical students a solid foundation in genomic medicine, therefore, has become all the more important to ensure the readiness of future physicians in applying genomic medicine to their patient care. In order to further enhance the effectiveness of instructing practical skills in medical genetics, the emphasis of active learning modules in genetics curriculum at medical schools has increased in recent years. This is because of the general acceptance of a better efficacy of active learner-centered pedagogy over passive lecturer-centered pedagogy. However, an objective standard to evaluate students’ skill levels in genomic medicine achieved by active learning is currently missing. Recently, entrustable professional activities (EPAs) in genomic medicine have been proposed as a framework for developing physician competencies in genomic medicine. EPAs in genomic medicine provide a convenient guideline for not only developing genomic medicine curriculum but also assessing students’ competency levels in practicing genomic medicine. In this review, the efficacy of different types of active learning modules reported for medical genetics curricula is discussed using EPAs in genomic medicine as a common evaluation standard for modules’ learning outcomes. The utility of the EPAs in genomic medicine for designing active learning modules in undergraduate medical genetics curricula is also discussed. PMID:29276425

Application of active learning modalities to achieve medical genetics competencies and their learning outcome assessments.

PubMed

Hagiwara, Nobuko

2017-01-01

The steadily falling costs of genome sequencing, coupled with the growing number of genetic tests with proven clinical validity, have made the use of genetic testing more common in clinical practice. This development has necessitated nongeneticist physicians, especially primary care physicians, to become more responsible for assessing genetic risks for their patients. Providing undergraduate medical students a solid foundation in genomic medicine, therefore, has become all the more important to ensure the readiness of future physicians in applying genomic medicine to their patient care. In order to further enhance the effectiveness of instructing practical skills in medical genetics, the emphasis of active learning modules in genetics curriculum at medical schools has increased in recent years. This is because of the general acceptance of a better efficacy of active learner-centered pedagogy over passive lecturer-centered pedagogy. However, an objective standard to evaluate students' skill levels in genomic medicine achieved by active learning is currently missing. Recently, entrustable professional activities (EPAs) in genomic medicine have been proposed as a framework for developing physician competencies in genomic medicine. EPAs in genomic medicine provide a convenient guideline for not only developing genomic medicine curriculum but also assessing students' competency levels in practicing genomic medicine. In this review, the efficacy of different types of active learning modules reported for medical genetics curricula is discussed using EPAs in genomic medicine as a common evaluation standard for modules' learning outcomes. The utility of the EPAs in genomic medicine for designing active learning modules in undergraduate medical genetics curricula is also discussed.

A comprehensive laboratory-based program for classification of variants of uncertain significance in hereditary cancer genes.

PubMed

Eggington, J M; Bowles, K R; Moyes, K; Manley, S; Esterling, L; Sizemore, S; Rosenthal, E; Theisen, A; Saam, J; Arnell, C; Pruss, D; Bennett, J; Burbidge, L A; Roa, B; Wenstrup, R J

2014-09-01

Genetic testing has the potential to guide the prevention and treatment of disease in a variety of settings, and recent technical advances have greatly increased our ability to acquire large amounts of genetic data. The interpretation of this data remains challenging, as the clinical significance of genetic variation detected in the laboratory is not always clear. Although regulatory agencies and professional societies provide some guidance regarding the classification, reporting, and long-term follow-up of variants, few protocols for the implementation of these guidelines have been described. Because the primary aim of clinical testing is to provide results to inform medical management, a variant classification program that offers timely, accurate, confident and cost-effective interpretation of variants should be an integral component of the laboratory process. Here we describe the components of our laboratory's current variant classification program (VCP), based on 20 years of experience and over one million samples tested, using the BRCA1/2 genes as a model. Our VCP has lowered the percentage of tests in which one or more BRCA1/2 variants of uncertain significance (VUSs) are detected to 2.1% in the absence of a pathogenic mutation, demonstrating how the coordinated application of resources toward classification and reclassification significantly impacts the clinical utility of testing. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Genetic data and the listing of species under the U.S. Endangered Species Act.

PubMed

Fallon, Sylvia M

2007-10-01

Genetic information is becoming an influential factor in determining whether species, subspecies, and distinct population segments qualify for protection under the U.S. Endangered Species Act. Nevertheless, there are currently no standards or guidelines that define how genetic information should be used by the federal agencies that administer the act. I examined listing decisions made over a 10-year period (February 1996-February 2006) that relied on genetic information. There was wide variation in the genetic data used to inform listing decisions in terms of which genomes (mitochondrial vs. nuclear) were sampled and the number of markers (or genetic techniques) and loci evaluated. In general, whether the federal agencies identified genetic distinctions between putative taxonomic units or populations depended on the type and amount of genetic data. Studies that relied on multiple genetic markers were more likely to detect distinctions, and those organisms were more likely to receive protection than studies that relied on a single genetic marker. Although the results may, in part, reflect the corresponding availability of genetic techniques over the given time frame, the variable use of genetic information for listing decisions has the potential to misguide conservation actions. Future management policy would benefit from guidelines for the critical evaluation of genetic information to list or delist organisms under the Endangered Species Act.

Practice guideline: joint CCMG-SOGC recommendations for the use of chromosomal microarray analysis for prenatal diagnosis and assessment of fetal loss in Canada.

PubMed

Armour, Christine M; Dougan, Shelley Danielle; Brock, Jo-Ann; Chari, Radha; Chodirker, Bernie N; DeBie, Isabelle; Evans, Jane A; Gibson, William T; Kolomietz, Elena; Nelson, Tanya N; Tihy, Frédérique; Thomas, Mary Ann; Stavropoulos, Dimitri J

2018-04-01

The aim of this guideline is to provide updated recommendations for Canadian genetic counsellors, medical geneticists, maternal fetal medicine specialists, clinical laboratory geneticists and other practitioners regarding the use of chromosomal microarray analysis (CMA) for prenatal diagnosis. This guideline replaces the 2011 Society of Obstetricians and Gynaecologists of Canada (SOGC)-Canadian College of Medical Geneticists (CCMG) Joint Technical Update. A multidisciplinary group consisting of medical geneticists, genetic counsellors, maternal fetal medicine specialists and clinical laboratory geneticists was assembled to review existing literature and guidelines for use of CMA in prenatal care and to make recommendations relevant to the Canadian context. The statement was circulated for comment to the CCMG membership-at-large for feedback and, following incorporation of feedback, was approved by the CCMG Board of Directors on 5 June 2017 and the SOGC Board of Directors on 19 June 2017. Recommendations include but are not limited to: (1) CMA should be offered following a normal rapid aneuploidy screen when multiple fetal malformations are detected (II-1A) or for nuchal translucency (NT) ≥3.5 mm (II-2B) (recommendation 1); (2) a professional with expertise in prenatal chromosomal microarray analysis should provide genetic counselling to obtain informed consent, discuss the limitations of the methodology, obtain the parental decisions for return of incidental findings (II-2A) (recommendation 4) and provide post-test counselling for reporting of test results (III-A) (recommendation 9); (3) the resolution of chromosomal microarray analysis should be similar to postnatal microarray platforms to ensure small pathogenic variants are detected. To minimise the reporting of uncertain findings, it is recommended that variants of unknown significance (VOUS) smaller than 500 Kb deletion or 1 Mb duplication not be routinely reported in the prenatal context. Additionally, VOUS above these cut-offs should only be reported if there is significant supporting evidence that deletion or duplication of the region may be pathogenic (III-B) (recommendation 5); (4) secondary findings associated with a medically actionable disorder with childhood onset should be reported, whereas variants associated with adult-onset conditions should not be reported unless requested by the parents or disclosure can prevent serious harm to family members (III-A) (recommendation 8).The working group recognises that there is variability across Canada in delivery of prenatal testing, and these recommendations were developed to promote consistency and provide a minimum standard for all provinces and territories across the country (recommendation 9). © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Guidelines on severity assessment and classification of genetically altered mouse and rat lines.

PubMed

Zintzsch, Anne; Noe, Elena; Reißmann, Monika; Ullmann, Kristina; Krämer, Stephanie; Jerchow, Boris; Kluge, Reinhart; Gösele, Claudia; Nickles, Hannah; Puppe, Astrid; Rülicke, Thomas

2017-12-01

Genetic alterations can unpredictably compromise the wellbeing of animals. Thus, more or less harmful phenotypes might appear in the animals used in research projects even when they are not subjected to experimental treatments. The severity classification of suffering has become an important issue since the implementation of Directive 2010/63/EU on the protection of animals used for scientific purposes. Accordingly, the breeding and maintenance of genetically altered (GA) animals which are likely to develop a harmful phenotype has to be authorized. However, a determination of the degree of severity is rather challenging due to the large variety of phenotypes. Here, the Working Group of Berlin Animal Welfare Officers (WG Berlin AWO) provides field-tested guidelines on severity assessment and classification of GA rodents. With a focus on basic welfare assessment and severity classification we provide a list of symptoms that have been classified as non-harmful, mild, moderate or severe burdens. Corresponding monitoring and refinement strategies as well as specific housing requirements have been compiled and are strongly recommended to improve hitherto applied breeding procedures and conditions. The document serves as a guide to determine the degree of severity for an observed phenotype. The aim is to support scientists, animal care takers, animal welfare bodies and competent authorities with this task, and thereby make an important contribution to a European harmonization of severity assessments for the continually increasing number of GA rodents.

American Pancreatic Association Practice Guidelines in Chronic Pancreatitis: evidence-based report on diagnostic guidelines.

PubMed

Conwell, Darwin L; Lee, Linda S; Yadav, Dhiraj; Longnecker, Daniel S; Miller, Frank H; Mortele, Koenraad J; Levy, Michael J; Kwon, Richard; Lieb, John G; Stevens, Tyler; Toskes, Phillip P; Gardner, Timothy B; Gelrud, Andres; Wu, Bechien U; Forsmark, Christopher E; Vege, Santhi S

2014-11-01

The diagnosis of chronic pancreatitis remains challenging in early stages of the disease. This report defines the diagnostic criteria useful in the assessment of patients with suspected and established chronic pancreatitis. All current diagnostic procedures are reviewed, and evidence-based statements are provided about their utility and limitations. Diagnostic criteria for chronic pancreatitis are classified as definitive, probable, or insufficient evidence. A diagnostic (STEP-wise; survey, tomography, endoscopy, and pancreas function testing) algorithm is proposed that proceeds from a noninvasive to a more invasive approach. This algorithm maximizes specificity (low false-positive rate) in subjects with chronic abdominal pain and equivocal imaging changes. Furthermore, a nomenclature is suggested to further characterize patients with established chronic pancreatitis based on TIGAR-O (toxic, idiopathic, genetic, autoimmune, recurrent, and obstructive) etiology, gland morphology (Cambridge criteria), and physiologic state (exocrine, endocrine function) for uniformity across future multicenter research collaborations. This guideline will serve as a baseline manuscript that will be modified as new evidence becomes available and our knowledge of chronic pancreatitis improves.

Noonan syndrome.

PubMed

Bhambhani, Vikas; Muenke, Maximilian

2014-01-01

Noonan syndrome is a common genetic disorder that causes multiple congenital abnormalities and a large number of potential health conditions. Most affected individuals have characteristic facial features that evolve with age; a broad, webbed neck; increased bleeding tendency; and a high incidence of congenital heart disease, failure to thrive, short stature, feeding difficulties, sternal deformity, renal malformation, pubertal delay, cryptorchidism, developmental or behavioral problems, vision problems, hearing loss, and lymphedema. Familial recurrence is consistent with an autosomal dominant mode of inheritance, but most cases are due to de novo mutations. Diagnosis can be made on the basis of clinical features, but may be missed in mildly affected patients. Molecular genetic testing can confirm diagnosis in 70% of cases and has important implications for genetic counseling and management. Most patients with Noonan syndrome are intellectually normal as adults, but some may require multidisciplinary evaluation and regular follow-up care. Age-based Noonan syndrome-specific growth charts and treatment guidelines are available.

Do Health Professionals Need Additional Competencies for Stratified Cancer Prevention Based on Genetic Risk Profiling?

PubMed Central

Chowdhury, Susmita; Henneman, Lidewij; Dent, Tom; Hall, Alison; Burton, Alice; Pharoah, Paul; Pashayan, Nora; Burton, Hilary

2015-01-01

There is growing evidence that inclusion of genetic information about known common susceptibility variants may enable population risk-stratification and personalized prevention for common diseases including cancer. This would require the inclusion of genetic testing as an integral part of individual risk assessment of an asymptomatic individual. Front line health professionals would be expected to interact with and assist asymptomatic individuals through the risk stratification process. In that case, additional knowledge and skills may be needed. Current guidelines and frameworks for genetic competencies of non-specialist health professionals place an emphasis on rare inherited genetic diseases. For common diseases, health professionals do use risk assessment tools but such tools currently do not assess genetic susceptibility of individuals. In this article, we compare the skills and knowledge needed by non-genetic health professionals, if risk-stratified prevention is implemented, with existing competence recommendations from the UK, USA and Europe, in order to assess the gaps in current competences. We found that health professionals would benefit from understanding the contribution of common genetic variations in disease risk, the rationale for a risk-stratified prevention pathway, and the implications of using genomic information in risk-assessment and risk management of asymptomatic individuals for common disease prevention. PMID:26068647

Multi-gene panel testing in Korean patients with common genetic generalized epilepsy syndromes.

PubMed

Lee, Cha Gon; Lee, Jeehun; Lee, Munhyang

2018-01-01

Genetic heterogeneity of common genetic generalized epilepsy syndromes is frequently considered. The present study conducted a focused analysis of potential candidate or susceptibility genes for common genetic generalized epilepsy syndromes using multi-gene panel testing with next-generation sequencing. This study included patients with juvenile myoclonic epilepsy, juvenile absence epilepsy, and epilepsy with generalized tonic-clonic seizures alone. We identified pathogenic variants according to the American College of Medical Genetics and Genomics guidelines and identified susceptibility variants using case-control association analyses and family analyses for familial cases. A total of 57 patients were enrolled, including 51 sporadic cases and 6 familial cases. Twenty-two pathogenic and likely pathogenic variants of 16 different genes were identified. CACNA1H was the most frequently observed single gene. Variants of voltage-gated Ca2+ channel genes, including CACNA1A, CACNA1G, and CACNA1H were observed in 32% of variants (n = 7/22). Analyses to identify susceptibility variants using case-control association analysis indicated that KCNMA1 c.400G>C was associated with common genetic generalized epilepsy syndromes. Only 1 family (family A) exhibited a candidate pathogenic variant p.(Arg788His) on CACNA1H, as determined via family analyses. This study identified candidate genetic variants in about a quarter of patients (n = 16/57) and an average of 2.8 variants was identified in each patient. The results reinforced the polygenic disorder with very high locus and allelic heterogeneity of common GGE syndromes. Further, voltage-gated Ca2+ channels are suggested as important contributors to common genetic generalized epilepsy syndromes. This study extends our comprehensive understanding of common genetic generalized epilepsy syndromes.

Randomized noninferiority trial of telephone versus in-person genetic counseling for hereditary breast and ovarian cancer.

PubMed

Schwartz, Marc D; Valdimarsdottir, Heiddis B; Peshkin, Beth N; Mandelblatt, Jeanne; Nusbaum, Rachel; Huang, An-Tsun; Chang, Yaojen; Graves, Kristi; Isaacs, Claudine; Wood, Marie; McKinnon, Wendy; Garber, Judy; McCormick, Shelley; Kinney, Anita Y; Luta, George; Kelleher, Sarah; Leventhal, Kara-Grace; Vegella, Patti; Tong, Angie; King, Lesley

2014-03-01

Although guidelines recommend in-person counseling before BRCA1/BRCA2 gene testing, genetic counseling is increasingly offered by telephone. As genomic testing becomes more common, evaluating alternative delivery approaches becomes increasingly salient. We tested whether telephone delivery of BRCA1/2 genetic counseling was noninferior to in-person delivery. Participants (women age 21 to 85 years who did not have newly diagnosed or metastatic cancer and lived within a study site catchment area) were randomly assigned to usual care (UC; n = 334) or telephone counseling (TC; n = 335). UC participants received in-person pre- and post-test counseling; TC participants completed all counseling by telephone. Primary outcomes were knowledge, satisfaction, decision conflict, distress, and quality of life; secondary outcomes were equivalence of BRCA1/2 test uptake and costs of delivering TC versus UC. TC was noninferior to UC on all primary outcomes. At 2 weeks after pretest counseling, knowledge (d = 0.03; lower bound of 97.5% CI, -0.61), perceived stress (d = -0.12; upper bound of 97.5% CI, 0.21), and satisfaction (d = -0.16; lower bound of 97.5% CI, -0.70) had group differences and confidence intervals that did not cross their 1-point noninferiority limits. Decision conflict (d = 1.1; upper bound of 97.5% CI, 3.3) and cancer distress (d = -1.6; upper bound of 97.5% CI, 0.27) did not cross their 4-point noninferiority limit. Results were comparable at 3 months. TC was not equivalent to UC on BRCA1/2 test uptake (UC, 90.1%; TC, 84.2%). TC yielded cost savings of $114 per patient. Genetic counseling can be effectively and efficiently delivered via telephone to increase access and decrease costs.

[Primary hyperparathyroidism - new clinical forms of the disease].

PubMed

Zajíčková, Kateřina

Primary hyperparathyroidism (PHPT) has been increasingly diagnosed incidentally in its asymptomatic form owing to calcium screening tests. This form of PHPT represents 80% in developed countries. Although PHPT patients are asym-ptomatic, target organ (bone and kidney) involvement is frequently observed. Mild PHPT is associated with a reduction of bone mineral densityand, moreover, with increased risk of vertebral fractures. The extent of a patient evaluation and indications for parathyroidectomy are based on expert guidelines from 2014. Normocalcemic variant of PHPT has been recently recognized, possibly with higher prevalence in general population than the hypercalcemic form of PHPT. Normal but with respect to hypercalcemia inadequately high parathormon levels characterize normohormonal PHPT. If a hereditary form of PHPT is suspected, genetic testing is recommended. Although there are new clinical forms of PHPT, parathyroidectomy still represents the only curative approach to PHPT followed by substantial osteoprotective effect.Key words: asymptomatic form - normocalcemic form - normohormonal form - parathyroidectomy - primary hyperparathyroidism - recent guidelines for the management PHPT.

Barriers for integrating personalized medicine into clinical practice: a qualitative analysis.

PubMed

Najafzadeh, Mehdi; Davis, Jennifer C; Joshi, Pamela; Marra, Carlo

2013-04-01

Personalized medicine-tailoring interventions based on individual's genetic information-will likely change routine clinical practice in the future. Yet, how practitioners plan to apply genetic information to inform medical decision making remains unclear. We aimed to investigate physician's perception about the future role of personalized medicine, and to identify the factors that influence their decision in using genetic testing in their practice. We conducted three semi-structured focus groups in three health regions (Fraser, Vancouver coastal, and Interior) in British Columbia, Canada. In the focus groups, participants discussed four topics on personalized medicine: (i) physicians' general understanding, (ii) advantages and disadvantages, (iii) potential impact and role in future clinical practice, and (iv) perceived barriers to integrating personalized medicine into clinical practice. Approximately 36% (n = 9) of physicians self-reported that they were not familiar with the concept of personalized medicine. After introducing the concept, the majority of physicians (68%, n = 19 of 28) were interested in incorporating personalized medicine in their practice, provided they have access to the necessary knowledge and tools. Participants mostly believed that genetic developments will directly affect their practice in the future. The key concerns highlighted were physician's access to clinical guidelines and training opportunities for the use of genetic testing and data interpretation. Despite the challenges that personalized medicine can create, in general, physicians in the focus groups expressed strong interest in using genetic information in their practice if they have access to the necessary knowledge and tools. Copyright © 2013 Wiley Periodicals, Inc.

"For all my family's sake, I should go and find out": an Australian report on genetic counseling and testing uptake in individuals at high risk of breast and/or ovarian cancer.

PubMed

Wakefield, Claire E; Ratnayake, Paboda; Meiser, Bettina; Suthers, Graeme; Price, Melanie A; Duffy, Jessica; Tucker, Kathy

2011-06-01

Despite proven benefits, the uptake of genetic counseling and testing by at-risk family members of BRCA1 and BRCA2 mutation carriers remains low. This study aimed to examine at-risk individuals' reported reasons for and against familial cancer clinic (FCC) attendance and genetic testing. Thirty-nine telephone interviews were conducted with relatives of high-risk mutation carriers, 23% (n = 9) of whom had not previously attended an FCC. Interview responses were analyzed using the frameworks of Miles and Huberman. The reasons most commonly reported for FCC attendance were for clarification of risk status and to gain access to testing. While disinterest in testing was one reason for FCC nonattendance, several individuals were unaware of their risk (n = 3) or their eligibility to attend an FCC (n = 2), despite being notified of their risk status through their participation in a large-scale research project. Individuals' reasons for undergoing testing were in line with that reported elsewhere; however, concerns about discrimination and insurance were not reported in nontestees. Current guidelines regarding notifying individuals discovered to be at increased risk in a research, rather than clinical setting, take a largely nondirective approach. However, this study demonstrates that individuals who receive a single letter notifying them of their risk may not understand/value the information they receive.

Guidelines on the use of molecular genetics in reintroduction programs

Treesearch

Michael K. Schwartz

2005-01-01

The use of molecular genetics can play a key role in reintroduction efforts. Prior to the introduction of any individuals, molecular genetics can be used to identify the most appropriate source population for the reintroduction, ensure that no relic populations exist in the reintroduction area, and guide captive breeding programs. The use of molecular genetics post-...

Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C9 and HLA‐B Genotypes and Phenytoin Dosing

PubMed Central

Rettie, A E; Whirl‐Carrillo, M; Smith, L H; Mintzer, S; Lee, M T M; Klein, T E; Callaghan, J T

2014-01-01

Phenytoin is a widely used antiepileptic drug with a narrow therapeutic index and large interpatient variability, partly due to genetic variations in the gene encoding cytochrome P450 (CYP)2C9 (CYP2C9). Furthermore, the variant allele HLA‐B*15:02, encoding human leukocyte antigen, is associated with an increased risk of Stevens–Johnson syndrome and toxic epidermal necrolysis in response to phenytoin treatment. We summarize evidence from the published literature supporting these associations and provide recommendations for the use of phenytoin based on CYP2C9 and/or HLA‐B genotype (also available on PharmGKB: http://www.pharmgkb.org). The purpose of this guideline is to provide information for the interpretation of HLA‐B and/or CYP2C9 genotype tests so that the results can guide dosing and/or use of phenytoin. Detailed guidelines for the use of phenytoin as well as analyses of cost‐effectiveness are out of scope. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines are periodically updated at http://www.pharmgkb.org. Clinical Pharmacology & Therapeutics (2014); 96 5, 542–548. doi:10.1038/clpt.2014.159 PMID:25099164

Limitations and Pitfalls of Using Family Letters to Communicate Genetic Risk: a Qualitative Study with Patients and Healthcare Professionals.

PubMed

Dheensa, Sandi; Lucassen, Anneke; Fenwick, Angela

2018-06-01

European genetic testing guidelines recommend that healthcare professionals (HCPs) discuss the familial implications of any test with a patient and offer written material to help them share the information with family members. Giving patients these "family letters" to alert any relatives of their risk has become part of standard practice and has gone relatively unquestioned over the years. Communication with at-risk relatives will become an increasingly pressing issue as mainstream and routine practice incorporates broad genome tests and as the number of findings potentially relevant to relatives increases. This study therefore explores problems around the use of family letters to communicate about genetic risk. We conducted 16 focus groups with 80 HCPs, and 35 interviews with patients, recruited from across the UK. Data were analyzed thematically and we constructed four themes: 1) HCPs writing family letters: how to write them and why?, 2) Patients' issues with handing out family letters, 3) Dissemination becomes an uncontrolled form of communication, and 4) When the relative has the letter, is the patient's and HCP's duty discharged? We conclude by suggesting alternative and supplementary methods of communication, for example through digital tools, and propose that in comparison to communication by family letter, direct contact by HCPs might be a more appropriate and successful option.

Design Recommendations for Pharmacogenomics Clinical Decision Support Systems

PubMed Central

Khelifi, Maher; Tarczy-Hornoch, Peter; Devine, Emily B.; Pratt, Wanda

2017-01-01

The use of pharmacogenomics (PGx) in clinical practice still faces challenges to fully adopt genetic information in targeting drug therapy. To incorporate genetics into clinical practice, many support the use of Pharmacogenomics Clinical Decision Support Systems (PGx-CDS) for medication prescriptions. This support was fueled by new guidelines to incorporate genetics for optimizing drug dosage and reducing adverse events. In addition, the complexity of PGx led to exploring CDS outside the paradigm of the basic CDS tools embedded in commercial electronic health records. Therefore, designing the right CDS is key to unleashing the full potential of pharmacogenomics and making it a part of clinicians’ daily workflow. In this work, we 1) identify challenges and barriers of the implementation of PGx-CDS in clinical settings, 2) develop a new design approach to CDS with functional characteristics that can improve the adoption of pharmacogenomics guidelines and thus patient safety, and 3) create design guidelines and recommendations for such PGx-CDS tools. PMID:28815136

Lynch Syndrome: A Primer for Urologists and Panel Recommendations.

PubMed

Mork, Maureen; Hubosky, Scott G; Rouprêt, Morgan; Margulis, Vitaly; Raman, Jay; Lotan, Yair; O'Brien, Timothy; You, Nancy; Shariat, Shahrokh F; Matin, Surena F

2015-07-01

Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer, is a common genetic disease. The predisposition of patients with Lynch syndrome to urological cancer, particularly upper tract urothelial carcinoma, is underappreciated. Urologists may be involved in several aspects of care involving Lynch syndrome, including identifying undiagnosed patients, surveillance of those with established Lynch syndrome or screening family members, in addition to treating patients with Lynch syndrome in whom upper tract urothelial carcinoma develops. We sought to increase awareness in the urological community about Lynch syndrome and provide some guidance where little currently exists. Using the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement we reviewed the available published literature and guidelines from 1998 to 2014 on Lynch syndrome and its association with upper tract urothelial carcinoma. Recommendations based on the literature and the consensus of expert opinion are provided. No randomized or prospective study has been done to evaluate Lynch syndrome in the setting of urological cancer. All data were based on retrospective studies. Lynch syndrome is an autosomal dominant genetic disease caused by germline mutations in 4 mismatch repair genes, leading to the accumulation of DNA errors in microsatellite regions. Upper tract urothelial carcinoma develops in up to 28% of patients with known Lynch syndrome. The diagnosis of Lynch syndrome is established by clinical criteria, tumor tissue testing and genetic evaluation. Urologists should suspect Lynch syndrome when a patient with upper tract urothelial carcinoma presents before age 60 years or meets the 3-2-1 rule. Screening patients with Lynch syndrome for upper tract urothelial carcinoma presents a particular challenge. While no ideal screening test exists, at a minimum routine urinalysis is recommended using the American Urological Association guideline of 3 or more red blood cells per high power field as a trigger for further assessment. Upper tract urothelial carcinoma associated with Lynch syndrome presents at a younger age than sporadic upper tract urothelial carcinoma. It shows a higher proportion of ureteral cancer with a female preponderance and a possible predisposition to bilaterality. Lynch syndrome is a common genetic disease that is an underappreciated cause of upper tract urothelial carcinoma and possibly other urological cancers. Optimal screening for upper tract urothelial carcinoma in this population is unclear. Further study is needed to identify the best screening test and interval of testing. Urologists should consider routine tissue testing of de novo upper tract urothelial carcinoma tissue in individuals at risk. Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Asilomar Decision: Unprecedented Guidelines for Gene-Transplant Research

ERIC Educational Resources Information Center

Science News, 1975

1975-01-01

The hazards posed by new techniques of genetic manipulation have prompted scientists to regulate and in some cases restrict their own basic investigations. Describes some possible applications of the new techniques and outlines the established research guidelines. (GS)

Genetic Misdiagnoses and the Potential for Health Disparities.

PubMed

Manrai, Arjun K; Funke, Birgit H; Rehm, Heidi L; Olesen, Morten S; Maron, Bradley A; Szolovits, Peter; Margulies, David M; Loscalzo, Joseph; Kohane, Isaac S

2016-08-18

For more than a decade, risk stratification for hypertrophic cardiomyopathy has been enhanced by targeted genetic testing. Using sequencing results, clinicians routinely assess the risk of hypertrophic cardiomyopathy in a patient's relatives and diagnose the condition in patients who have ambiguous clinical presentations. However, the benefits of genetic testing come with the risk that variants may be misclassified. Using publicly accessible exome data, we identified variants that have previously been considered causal in hypertrophic cardiomyopathy and that are overrepresented in the general population. We studied these variants in diverse populations and reevaluated their initial ascertainments in the medical literature. We reviewed patient records at a leading genetic-testing laboratory for occurrences of these variants during the near-decade-long history of the laboratory. Multiple patients, all of whom were of African or unspecified ancestry, received positive reports, with variants misclassified as pathogenic on the basis of the understanding at the time of testing. Subsequently, all reported variants were recategorized as benign. The mutations that were most common in the general population were significantly more common among black Americans than among white Americans (P<0.001). Simulations showed that the inclusion of even small numbers of black Americans in control cohorts probably would have prevented these misclassifications. We identified methodologic shortcomings that contributed to these errors in the medical literature. The misclassification of benign variants as pathogenic that we found in our study shows the need for sequencing the genomes of diverse populations, both in asymptomatic controls and the tested patient population. These results expand on current guidelines, which recommend the use of ancestry-matched controls to interpret variants. As additional populations of different ancestry backgrounds are sequenced, we expect variant reclassifications to increase, particularly for ancestry groups that have historically been less well studied. (Funded by the National Institutes of Health.).

Genetic sex determination assays in 53 mammalian species: Literature analysis and guidelines for reporting standardization.

PubMed

Hrovatin, Karin; Kunej, Tanja

2018-01-01

Erstwhile, sex was determined by observation, which is not always feasible. Nowadays, genetic methods are prevailing due to their accuracy, simplicity, low costs, and time-efficiency. However, there is no comprehensive review enabling overview and development of the field. The studies are heterogeneous, lacking a standardized reporting strategy. Therefore, our aim was to collect genetic sexing assays for mammals and assemble them in a catalogue with unified terminology. Publications were extracted from online databases using key words such as sexing and molecular. The collected data were supplemented with species and gene IDs and the type of sex-specific sequence variant (SSSV). We developed a catalogue and graphic presentation of diagnostic tests for molecular sex determination of mammals, based on 58 papers published from 2/1991 to 10/2016. The catalogue consists of five categories: species, genes, SSSVs, methods, and references. Based on the analysis of published literature, we propose minimal requirements for reporting, consisting of: species scientific name and ID, genetic sequence with name and ID, SSSV, methodology, genomic coordinates (e.g., restriction sites, SSSVs), amplification system, and description of detected amplicon and controls. The present study summarizes vast knowledge that has up to now been scattered across databases, representing the first step toward standardization regarding molecular sexing, enabling a better overview of existing tests and facilitating planned designs of novel tests. The project is ongoing; collecting additional publications, optimizing field development, and standardizing data presentation are needed.

Global gene mining and the pharmaceutical industry

DOE Office of Scientific and Technical Information (OSTI.GOV)

Knudsen, Lisbeth E.

2005-09-01

Worldwide efforts are ongoing in optimizing medical treatment by searching for the right medicine at the right dose for the individual. Metabolism is regulated by polymorphisms, which may be tested by relatively simple SNP analysis, however requiring DNA from the test individuals. Target genes for the efficiency of a given medicine or predisposition of a given disease are also subject to population studies, e.g., in Iceland, Estonia, Sweden, etc. For hypothesis testing and generation, several bio-banks with samples from patients and healthy persons within the pharmaceutical industry have been established during the past 10 years. Thus, more than 100,000 samplesmore » are stored in the freezers of either the pharmaceutical companies or their contractual partners at universities and test institutions. Ethical issues related to data protection of the individuals providing samples to bio-banks are several: nature and extent of information prior to consent, coverage of the consent given by the study person, labeling and storage of the sample and data (coded or anonymized). In general, genetic test data, once obtained, are permanent and cannot be changed. The test data may imply information that is not beneficial to the patient and his/her family (e.g., employment opportunities, insurance, etc.). Furthermore, there may be a long latency between the analysis of the genetic test and the clinical expression of the disease and wide differences in the disease patterns. Consequently, information about some genetic test data may stigmatize patients leading to poor quality of life. This has raised the issue of 'genetic exceptionalism' justifying specific regulation of use of genetic information. Discussions on how to handle sampling and data are ongoing within the industry and the regulatory sphere, the European Agency for the Evaluation of Medicinal Products (EMEA) having issued a position paper, the Council for International Organizations of Medical Sciences (CIOMS) having a working group on this issue, and the European Society of Human Genetics preparing background paper on 'Polymorphic sequence variants in medicine: Technical, social, legal and ethical issues. Pharmacogenetics as an example'. Within the European project Privacy in Research Ethics and Law (PRIVIREAL), recommendations for common European guidelines for membership in research ethical committees have been discussed, balancing the interests and assuring independence and legal competence. Good decision making, assuring legality of protocols and assessment of data protection is suggested to be part of any evaluation of protocols.« less

Should the Bt brinjal controversy concern healthcare professionals and bioethicists?

PubMed

Seetharam, Sridevi

2010-01-01

The Genetic Engineering Approval Committee's approval of Bt brinjal, the first genetically modified crop for human consumption in India, has sparked off protests across the country. This article questions the so-called benefits of GM crops and highlights some major concerns. These include: inadequately addressed health and environmental risks, inadequate safety guidelines, a lack of transparency in sharing test data, the implications to seed sovereignty of farmers and the lack of informed choice for consumers. Some concerns about field testing by Mahyco, the developer of Bt-brinjal, and the process of evaluation by GEAC remain unresolved. With inadequate information about the crop's long-term safety, a precautionary approach is advocated before national policy allows commercial release of the seeds. A fair process is also needed in the public consultations being proposed by the minister of state for environment and forests. In addition to issues of procedural justice, a basic ethical question remains: do humans have a right to dominate the land and make expendable those creatures that they deem "undesirable"?

Cystic fibrosis screening in assisted reproduction.

PubMed

Gazvani, Rafet; Lewis-Jones, Iwan

2006-06-01

The purpose of this review is to discuss the incidence of cystic fibrosis in the general population, in ethnically diverse populations and specifically in couples needing assisted reproduction caused by male factor subfertility. We review the current understanding of risks for reproductive couples and discuss ideal screening strategies. In ethnically diverse populations, a large difference in clinical sensitivity and birth prevalence exists between the broad racial/ethnic groups examined. Extensive data clearly demonstrate the cost-effectiveness of cystic fibrosis screening. Testing for cystic fibrosis gene mutations is reliable and, with a 26-mutation panel, nearly 90% of possible severe mutations can be detected. To halve the incidence of cystic fibrosis in the community, by offering genetic testing of the fetus if both partners are carrier positive, may also be possible. Recent guidelines suggest that all couples contemplating pregnancy should be informed of molecular screening for cystic fibrosis carrier status for purposes of genetic counselling. In ethnically diverse populations, ethnic-specific mutations should be included in the mutation panels.

POLE and POLD1 mutations in 529 kindred with familial colorectal cancer and/or polyposis: review of reported cases and recommendations for genetic testing and surveillance

PubMed Central

Bellido, Fernando; Pineda, Marta; Aiza, Gemma; Valdés-Mas, Rafael; Navarro, Matilde; Puente, Diana A.; Pons, Tirso; González, Sara; Iglesias, Silvia; Darder, Esther; Piñol, Virginia; Soto, José Luís; Valencia, Alfonso; Blanco, Ignacio; Urioste, Miguel; Brunet, Joan; Lázaro, Conxi; Capellá, Gabriel; Puente, Xose S.; Valle, Laura

2016-01-01

Purpose: Germ-line mutations in the exonuclease domains of POLE and POLD1 have been recently associated with polyposis and colorectal cancer (CRC) predisposition. Here, we aimed to gain a better understanding of the phenotypic characteristics of this syndrome to establish specific criteria for POLE and POLD1 mutation screening and to help define the clinical management of mutation carriers. Genet Med 18 4, 325–332. Methods: The exonuclease domains of POLE and POLD1 were studied in 529 kindred, 441 with familial nonpolyposis CRC and 88 with polyposis, by using pooled DNA amplification and massively parallel sequencing. Genet Med 18 4, 325–332. Results: Seven novel or rare genetic variants were identified. In addition to the POLE p.L424V recurrent mutation in a patient with polyposis, CRC and oligodendroglioma, six novel or rare POLD1 variants (four of them, p.D316H, p.D316G, p.R409W, and p.L474P, with strong evidence for pathogenicity) were identified in nonpolyposis CRC families. Phenotypic data from these and previously reported POLE/POLD1 carriers point to an associated phenotype characterized by attenuated or oligo-adenomatous colorectal polyposis, CRC, and probably brain tumors. In addition, POLD1 mutations predispose to endometrial and breast tumors. Genet Med 18 4, 325–332. Conclusion: Our results widen the phenotypic spectrum of the POLE/POLD1-associated syndrome and identify novel pathogenic variants. We propose guidelines for genetic testing and surveillance recommendations. Genet Med 18 4, 325–332. PMID:26133394

Incorporating Social Media into your Support Tool Box: Points to Consider from Genetics-Based Communities.

PubMed

Rocha, Heather Mae; Savatt, Juliann M; Riggs, Erin Rooney; Wagner, Jennifer K; Faucett, W Andrew; Martin, Christa Lese

2018-04-01

Patients with newly-described or rare genetic findings are turning to social media to find and connect with others. Blogs, Facebook groups, and Twitter have all been reported as tools for patients to connect with one another. However, the preferences for social media use and privacy among patients, their families, and these communities have not been well characterized. To explore preferences about privacy and membership guidelines, an online survey was administered to two web-based patient registries, Simons Variation in Individuals Project ( www.simonsvipconnect.org ) and GenomeConnect ( www.genomeconnect.org ). Over a three-month period, invitations were sent to 2524 individuals and 103 responses (4%) were received and analyzed. Responses indicate that Facebook is the most popular resource accessed within this sample population (99%). Participants used social media to look for information about their diagnosis or test results (83%), read posts from rare disease groups or organizations (73%), participate in conversations about their diagnosis (67%), and connect with others to find support (58%). Focusing on privacy issues in social media, respondents indicate that membership and access impact the level of comfort in sharing personal or medical information. Nearly 60% of respondents felt uncomfortable sharing photos or medical information within a public Facebook group, whereas only 12% of respondents felt uncomfortable sharing in private group targeted to families alone. Using this preliminary data concerning social media use and privacy, we developed points for genetic counselors to incorporate when discussing available support resources for patients with a new, or rare, genetic diagnosis or genetic test result. Genetic counselors are trained to provide anticipatory guidance to families adapting to new genetic information, and are well-equipped to help patients consider their preferences about using social media as a source of information and support.

American Pancreatic Association Practice Guidelines in Chronic Pancreatitis: Evidence-Based Report on Diagnostic Guidelines

PubMed Central

Conwell, Darwin L.; Lee, Linda S.; Yadav, Dhiraj; Longnecker, Daniel S.; Miller, Frank H.; Mortele, Koenraad J.; Levy, Michael J.; Kwon, Richard; Lieb, John G.; Stevens, Tyler; Toskes, Philip P.; Gardner, Timothy B.; Gelrud, Andres; Wu, Bechien U.; Forsmark, Christopher E.; Vege, Santhi S.

2016-01-01

The diagnosis of chronic pancreatitis remains challenging in early stages of the disease. This report defines the diagnostic criteria useful in the assessment of patients with suspected and established chronic pancreatitis. All current diagnostic procedures are reviewed and evidence based statements are provided about their utility and limitations. Diagnostic criteria for chronic pancreatitis are classified as definitive, probable or insufficient evidence. A diagnostic (STEP-wise; S-survey, T-tomography, E-endoscopy and P-pancreas function testing) algorithm is proposed that proceeds from a non-invasive to a more invasive approach. This algorithm maximizes specificity (low false positive rate) in subjects with chronic abdominal pain and equivocal imaging changes. Futhermore, a nomenclature is suggested to further characterize patients with established chronic pancreatitis based on TIGAR-O (T-toxic, I-idiopathic, G-genetic, A- autoimmune, R-recurrent and O-obstructive) etiology, gland morphology (Cambridge criteria) and physiologic state (exocrine, endocrine function) for uniformity across future multi-center research collaborations. This guideline will serve as a baseline manuscript that will be modified as new evidence becomes available and our knowledge of chronic pancreatitis improves. PMID:25333398

Nutrition management guideline for maple syrup urine disease: an evidence- and consensus-based approach.

PubMed

Frazier, Dianne M; Allgeier, Courtney; Homer, Caroline; Marriage, Barbara J; Ogata, Beth; Rohr, Frances; Splett, Patricia L; Stembridge, Adrya; Singh, Rani H

2014-07-01

In an effort to increase harmonization of care and enable outcome studies, the Genetic Metabolic Dietitians International (GMDI) and the Southeast Regional Newborn Screening and Genetics Collaborative (SERC) are partnering to develop nutrition management guidelines for inherited metabolic disorders (IMD) using a model combining both evidence- and consensus-based methodology. The first guideline to be completed is for maple syrup urine disease (MSUD). This report describes the methodology used in its development: formulation of five research questions; review, critical appraisal and abstraction of peer-reviewed studies and unpublished practice literature; and expert input through Delphi surveys and a nominal group process. This report includes the summary statements for each research question and the nutrition management recommendations they generated. Each recommendation is followed by a standardized rating based on the strength of the evidence and consensus used. The application of technology to build the infrastructure for this project allowed transparency during development of this guideline and will be a foundation for future guidelines. Online open access of the full, published guideline allows utilization by health care providers, researchers, and collaborators who advise, advocate and care for individuals with MSUD and their families. There will be future updates as warranted by developments in research and clinical practice. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Guidelines for the Primary Prevention of Stroke

PubMed Central

Meschia, James F.; Bushnell, Cheryl; Boden-Albala, Bernadette; Braun, Lynne T.; Bravata, Dawn M.; Chaturvedi, Seemant; Creager, Mark A.; Eckel, Robert H.; Elkind, Mitchell S.V.; Fornage, Myriam; Goldstein, Larry B.; Greenberg, Steven M.; Horvath, Susanna E.; Iadecola, Costantino; Jauch, Edward C.; Moore, Wesley S.; Wilson, John A.

2016-01-01

The aim of this updated statement is to provide comprehensive and timely evidence-based recommendations on the prevention of stroke among individuals who have not previously experienced a stroke or transient ischemic attack. Evidence-based recommendations are included for the control of risk factors, interventional approaches to atherosclerotic disease of the cervicocephalic circulation, and antithrombotic treatments for preventing thrombotic and thromboembolic stroke. Further recommendations are provided for genetic and pharmacogenetic testing and for the prevention of stroke in a variety of other specific circumstances, including sickle cell disease and patent foramen ovale. PMID:25355838

Genetics of Combined Pituitary Hormone Deficiency: Roadmap into the Genome Era.

PubMed

Fang, Qing; George, Akima S; Brinkmeier, Michelle L; Mortensen, Amanda H; Gergics, Peter; Cheung, Leonard Y M; Daly, Alexandre Z; Ajmal, Adnan; Pérez Millán, María Ines; Ozel, A Bilge; Kitzman, Jacob O; Mills, Ryan E; Li, Jun Z; Camper, Sally A

2016-12-01

The genetic basis for combined pituitary hormone deficiency (CPHD) is complex, involving 30 genes in a variety of syndromic and nonsyndromic presentations. Molecular diagnosis of this disorder is valuable for predicting disease progression, avoiding unnecessary surgery, and family planning. We expect that the application of high throughput sequencing will uncover additional contributing genes and eventually become a valuable tool for molecular diagnosis. For example, in the last 3 years, six new genes have been implicated in CPHD using whole-exome sequencing. In this review, we present a historical perspective on gene discovery for CPHD and predict approaches that may facilitate future gene identification projects conducted by clinicians and basic scientists. Guidelines for systematic reporting of genetic variants and assigning causality are emerging. We apply these guidelines retrospectively to reports of the genetic basis of CPHD and summarize modes of inheritance and penetrance for each of the known genes. In recent years, there have been great improvements in databases of genetic information for diverse populations. Some issues remain that make molecular diagnosis challenging in some cases. These include the inherent genetic complexity of this disorder, technical challenges like uneven coverage, differing results from variant calling and interpretation pipelines, the number of tolerated genetic alterations, and imperfect methods for predicting pathogenicity. We discuss approaches for future research in the genetics of CPHD.

Huntington's disease predictive testing: the case for an assessment approach to requests from adolescents.

PubMed Central

Binedell, J; Soldan, J R; Scourfield, J; Harper, P S

1996-01-01

Adolescents who are actively requesting Huntington's predictive testing of their own accord pose a dilemma to those providing testing. In the absence of empirical evidence as regards the impact of genetic testing on minors, current policy and guidelines, based on the ethical principles of non-maleficence and respect for individual autonomy and confidentiality, generally exclude the testing of minors. It is argued that adherence to an age based exclusion criterion in Huntington's disease predictive testing protocols is out of step with trends in UK case law concerning minors' consent to medical treatment. Furthermore, contributions from developmental psychology and research into adolescents' decision making competence suggest that adolescents can make informed choices about their health and personal lives. Criteria for developing an assessment approach to such requests are put forward and the implications of a case by case evaluation of competence to consent in terms of clinicians' tolerance for uncertainty are discussed. PMID:8950670

The role of genetics in improving forest health

Treesearch

Mary F. Mahalovich

1995-01-01

An often ignored tool to improve forest health is the application of genetics-Tree improvement programs in the Inland West utilize genetic principles to develop-seed transfer guidelines to avoid the problems associated with off-site plantings and to improve characteristics in conifers related to forest health. PC-based expert systems have been developed to aid in seed...

Annual Research Review: Impact of Advances in Genetics in Understanding Developmental Psychopathology

ERIC Educational Resources Information Center

Addington, Anjene M.; Rapoport, Judith L.

2012-01-01

It was hoped that diagnostic guidelines for, and treatment of, child psychiatric disorders in DSM-5 would be informed by the wealth of clinical genetic research related to neurodevelopmental disorders. In spite of remarkable advances in genetic technology, this has not been the case. Candidate gene, genome-wide association, and rare copy number…

Update: new guidelines for the treatment of infants with sickle cell disease. Agency for Health Care Policy and Research.

PubMed

Selekman, J

1993-01-01

These clinical practice guidelines set forth a comprehensive program for identifying, diagnosing, and treating newborns and infants with sickle cell disease and recommend education and counseling strategies for their parents. Sickle cell disease comprises a group of genetic disorders characterized by the production of hemoglobin S, anemia, and acute and chronic tissue damage secondary to the blockage of blood flow by abnormally shaped red cells. Sickle cell anemia is the most common form of the disease, and it affects approximately 1 in 375 African-American infants. Although in the United States sickle cell disease is most commonly found in persons of African ancestry, it also affects other populations. The panel recommends screening of all newborns for sickle cell disease, since targeting specific groups will miss some infected infants. Samples of dried blood on filter paper or liquid blood samples should be used for hemoglobinopathy screening. Hemoglobin electrophoresis, isoelectric focusing, and high performance liquid chromatography are acceptable, reliable, and accurate testing methods. Infants identified on initial screening must be retested to establish a definitive diagnosis. Affected infants must be given twice-daily oral penicillin beginning at 2 months of age to reduce pneumococcal, conjugated Haemophilus influenzae, and hepatitis B vaccines. Infants with sickle cell disease require the same well-child care as infants without the disease. Education and nondirective genetic counseling should be offered to all parents of infants with sickle cell disease. The guidelines stress the need for a comprehensive and fully integrated approach to reduce morbidity and mortality from sickle cell disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Implementation of Good Clinical Laboratory Practice (GCLP) guidelines within the External Quality Assurance Program Oversight Laboratory (EQAPOL).

PubMed

Todd, Christopher A; Sanchez, Ana M; Garcia, Ambrosia; Denny, Thomas N; Sarzotti-Kelsoe, Marcella

2014-07-01

The EQAPOL contract was awarded to Duke University to develop and manage global proficiency testing programs for flow cytometry-, ELISpot-, and Luminex bead-based assays (cytokine analytes), as well as create a genetically diverse panel of HIV-1 viral cultures to be made available to National Institutes of Health (NIH) researchers. As a part of this contract, EQAPOL was required to operate under Good Clinical Laboratory Practices (GCLP) that are traditionally used for laboratories conducting endpoint assays for human clinical trials. EQAPOL adapted these guidelines to the management of proficiency testing programs while simultaneously incorporating aspects of ISO/IEC 17043 which are specifically designed for external proficiency management. Over the first two years of the contract, the EQAPOL Oversight Laboratories received training, developed standard operating procedures and quality management practices, implemented strict quality control procedures for equipment, reagents, and documentation, and received audits from the EQAPOL Central Quality Assurance Unit. GCLP programs, such as EQAPOL, strengthen a laboratory's ability to perform critical assays and provide quality assessments of future potential vaccines. © 2013.

Position Statement Executive Summary: Guidelines and Recommendations for Laboratory Analysis in the Diagnosis and Management of Diabetes Mellitus

PubMed Central

Arnold, Mark; Bakris, George L.; Bruns, David E.; Horvath, Andrea Rita; Kirkman, M. Sue; Lernmark, Ake; Metzger, Boyd E.; Nathan, David M.

2011-01-01

BACKGROUND Multiple laboratory tests are used in the diagnosis and management of patients with diabetes mellitus. The quality of the scientific evidence supporting the use of these assays varies substantially. APPROACH An expert committee compiled evidence-based recommendations for the use of laboratory analysis in patients with diabetes. A new system was developed to grade the overall quality of the evidence and the strength of the recommendations. A draft of the guidelines was posted on the Internet, and the document was modified in response to comments. The guidelines were reviewed by the joint Evidence-Based Laboratory Medicine Committee of the AACC and the National Academy of Clinical Biochemistry and were accepted after revisions by the Professional Practice Committee and subsequent approval by the Executive Committee of the American Diabetes Association. CONTENT In addition to the long-standing criteria based on measurement of venous plasma glucose, diabetes can be diagnosed by demonstrating increased hemoglobin A1c (HbA1c) concentrations in the blood. Monitoring of glycemic control is performed by the patients measuring their own plasma or blood glucose with meters and by laboratory analysis of HbA1c. The potential roles of noninvasive glucose monitoring, genetic testing, and measurement of autoantibodies, urine albumin, insulin, proinsulin, C-peptide, and other analytes are addressed. SUMMARY The guidelines provide specific recommendations based on published data or derived from expert consensus. Several analytes are found to have minimal clinical value at the present time, and measurement of them is not recommended. PMID:21617111

Position statement executive summary: guidelines and recommendations for laboratory analysis in the diagnosis and management of diabetes mellitus.

PubMed

Sacks, David B; Arnold, Mark; Bakris, George L; Bruns, David E; Horvath, Andrea Rita; Kirkman, M Sue; Lernmark, Ake; Metzger, Boyd E; Nathan, David M

2011-06-01

Multiple laboratory tests are used in the diagnosis and management of patients with diabetes mellitus. The quality of the scientific evidence supporting the use of these assays varies substantially. An expert committee compiled evidence-based recommendations for the use of laboratory analysis in patients with diabetes. A new system was developed to grade the overall quality of the evidence and the strength of the recommendations. A draft of the guidelines was posted on the Internet, and the document was modified in response to comments. The guidelines were reviewed by the joint Evidence-Based Laboratory Medicine Committee of the AACC and the National Academy of Clinical Biochemistry and were accepted after revisions by the Professional Practice Committee and subsequent approval by the Executive Committee of the American Diabetes Association. In addition to the long-standing criteria based on measurement of venous plasma glucose, diabetes can be diagnosed by demonstrating increased hemoglobin A(1c) (HbA(1c)) concentrations in the blood. Monitoring of glycemic control is performed by the patients measuring their own plasma or blood glucose with meters and by laboratory analysis of HbA(1c). The potential roles of noninvasive glucose monitoring, genetic testing, and measurement of autoantibodies, urine albumin, insulin, proinsulin, C-peptide, and other analytes are addressed. The guidelines provide specific recommendations based on published data or derived from expert consensus. Several analytes are found to have minimal clinical value at the present time, and measurement of them is not recommended.

BRCA Genetic Testing and Receipt of Preventive Interventions Among Women Aged 18-64 Years with Employer-Sponsored Health Insurance in Nonmetropolitan and Metropolitan Areas - United States, 2009-2014.

PubMed

Kolor, Katherine; Chen, Zhuo; Grosse, Scott D; Rodriguez, Juan L; Green, Ridgely Fisk; Dotson, W David; Bowen, M Scott; Lynch, Julie A; Khoury, Muin J

2017-09-08

Genetic testing for breast cancer 1 (BRCA1) and breast cancer 2 (BRCA2) gene mutations can identify women at increased risk for breast and ovarian cancer. These testing results can be used to select preventive interventions and guide treatment. Differences between nonmetropolitan and metropolitan populations in rates of BRCA testing and receipt of preventive interventions after testing have not previously been examined. 2009-2014. Medical claims data from Truven Health Analytics MarketScan Commercial Claims and Encounters databases were used to estimate rates of BRCA testing and receipt of preventive interventions after BRCA testing among women aged 18-64 years with employer-sponsored health insurance in metropolitan and nonmetropolitan areas of the United States, both nationally and regionally. From 2009 to 2014, BRCA testing rates per 100,000 women aged 18-64 years with employer-sponsored health insurance increased 2.3 times (102.7 to 237.8) in metropolitan areas and 3.0 times (64.8 to 191.3) in nonmetropolitan areas. The relative difference in BRCA testing rates between metropolitan and nonmetropolitan areas decreased from 37% in 2009 (102.7 versus 64.8) to 20% in 2014 (237.8 versus 191.3). The relative difference in BRCA testing rates between metropolitan and nonmetropolitan areas decreased more over time in younger women than in older women and decreased in all regions except the West. Receipt of preventive services 90 days after BRCA testing in metropolitan versus nonmetropolitan areas throughout the period varied by service: the percentage of women who received a mastectomy was similar, the percentage of women who received magnetic resonance imaging of the breast was lower in nonmetropolitan areas (as low as 5.8% in 2014 to as high as 8.2% in 2011) than metropolitan areas (as low as 7.3% in 2014 to as high as 10.3% in 2011), and the percentage of women who received mammography was lower in nonmetropolitan areas in earlier years but was similar in later years. Possible explanations for the 47% decrease in the relative difference in BRCA testing rates over the study period include increased access to genetic services in nonmetropolitan areas and increased demand nationally as a result of publicity. The relative differences in metropolitan and nonmetropolitan BRCA testing rates were smaller among women at younger ages compared with older ages. Improved data sources and surveillance tools are needed to gather comprehensive data on BRCA testing in the United States, monitor adherence to evidence-based guidelines for BRCA testing, and assess receipt of preventive interventions for women with BRCA mutations. Programs can build on the recent decrease in geographic disparities in receipt of BRCA testing while simultaneously educating the public and health care providers about U.S. Preventive Services Task Force recommendations and other clinical guidelines for BRCA testing and counseling.

The current situation regarding the establishment of national ethical guidelines for biomedical research in Thailand and its neighboring countries.

PubMed

Kojima, Somei; Waikagul, Jitra; Rojekittikhun, Wichit; Keicho, Naoto

2005-05-01

This study discusses the establishment of ethical guidelines for ethical review for biomedical research performed in Thailand, and to some extent, in neighboring countries. There are differences, from country to country, at national and institutional levels regarding guidelines for ethical review committees. Only a handbook issued by Mahidol University describes guidelines for human genetic research and on research dealing with reproductive technology. Both these areas require special consideration to avoid violating human dignity, rights, and confidentiality. This indicates that further efforts should be made to establish research guidelines and/or principles dealing with the human genome.

Methodological issues of genetic association studies.

PubMed

Simundic, Ana-Maria

2010-12-01

Genetic association studies explore the association between genetic polymorphisms and a certain trait, disease or predisposition to disease. It has long been acknowledged that many genetic association studies fail to replicate their initial positive findings. This raises concern about the methodological quality of these reports. Case-control genetic association studies often suffer from various methodological flaws in study design and data analysis, and are often reported poorly. Flawed methodology and poor reporting leads to distorted results and incorrect conclusions. Many journals have adopted guidelines for reporting genetic association studies. In this review, some major methodological determinants of genetic association studies will be discussed.

Ethical Concerns About Human Genetic Enhancement in the Malay Science Fiction Novels.

PubMed

Isa, Noor Munirah; Hj Safian Shuri, Muhammad Fakhruddin

2018-02-01

Advancements in science and technology have not only brought hope to humankind to produce disease-free offspring, but also offer possibilities to genetically enhance the next generation's traits and capacities. Human genetic enhancement, however, raises complex ethical questions, such as to what extent should it be allowed? It has been a great challenge for humankind to develop robust ethical guidelines for human genetic enhancement that address both public concerns and needs. We believe that research about public concerns is necessary prior to developing such guidelines, yet the issues have not been thoroughly investigated in many countries, including Malaysia. Since the novel often functions as a medium for the public to express their concerns, this paper explores ethical concerns about human genetic enhancement expressed in four Malay science fiction novels namely Klon, Leksikon Ledang, Transgenesis Bisikan Rimba and Transgenik Sifar. Religion has a strong influence on the worldview of the Malays therefore some concerns such as playing God are obviously religious. Association of the negative image of scientists as well as the private research companies with the research on human genetic enhancement reflects the authors' concerns about the main motivations for conducting such research and the extent to which such research will benefit society.

Genetic diseases associated with an increased risk of skin cancer development in childhood.

PubMed

Fogel, Alexander L; Sarin, Kavita Y; Teng, Joyce M C

2017-08-01

Childhood skin cancers are relatively rare and may indicate an underlying genetic disorder. The increasing elucidation of genetic pathways is changing the diagnosis and management of genetic skin cancer susceptibility syndromes. In this review, we provide an overview of genetic conditions that predispose to skin cancer development in childhood and signs that providers should assess when evaluating affected individuals. In basal cell nevus syndrome (BCNS), the patched2 (PTCH2) and suppressor of fused (SUFU) genes have been implicated in disease pathogenesis. The sonic hedgehog (SHH) pathway inhibitor vismodegib was shown in a placebo-controlled phase III randomized trial to reduce the tumor burden in patients with BCNS. Epidermolysis bullosa (EB) has been classified into four major types and more than 30 subtypes based partly on specific mutations, and best clinical practice guidelines for the management of cutaneous squamous cell carcinoma in EB have been developed. Oculocutaneous albinism (OCA) has been associated with new mutations in genes named OCA5, OCA6, and OCA7, bringing to the total number of culprit genes to seven (OCA1-OCA7). Advances in our understanding of genetic conditions that predispose to childhood skin cancer include new disease classification systems, management guidelines, and treatment options.

Genetic analysis of sudden cardiac death victims: a survey of current forensic autopsy practices.

PubMed

Michaud, Katarzyna; Mangin, Patrice; Elger, Bernice S

2011-05-01

Autopsy-negative sudden cardiac deaths (SCD) seen in forensic practice are most often thought to be the result of sudden arrhythmic death syndrome. Postmortem genetic analysis is recommended in such cases, but is currently performed in only a few academic centers. In order to determine actual current practice, an on-line questionnaire was sent by e-mail to members of various forensic medical associations. The questions addressed routine procedures employed in cases of sudden cardiac death (autopsy ordering, macroscopic and microscopic cardiac examination, conduction tissue examination, immunohistochemistry and electron microscopy, biochemical markers, sampling and storage of material for genetic analyses, toxicological analyses, and molecular autopsy). Some questions concerned the legal and ethical aspects of genetic analyses in postmortem examinations, as well as any existing multidisciplinary collaborations in SCD cases. There were 97 respondents, mostly from European countries. Genetic testing in cases of sudden cardiac death is rarely practiced in routine forensic investigation. Approximately 60% of respondents reported not having the means to perform genetic postmortem testing and 40% do not collect adequate material to perform these investigations at a later date, despite working at university hospitals. The survey demonstrated that many of the problems involved in the adequate investigation of SCD cases are often financial in origin, due to the fact that activities in forensic medicine are often paid by and dependent on the judicial authorities. Problems also exist concerning the contact with family members and/or the family doctor, as well as the often-nonexistent collaboration with others clinicians with special expertise beneficial in the investigation of SCD cases, such as cardiologists and geneticists. This study highlights the importance in establishing guidelines for molecular autopsies in forensic medicine.

Applying Cystic Fibrosis Transmembrane Conductance Regulator Genetics and CFTR2 Data to Facilitate Diagnoses.

PubMed

Sosnay, Patrick R; Salinas, Danieli B; White, Terry B; Ren, Clement L; Farrell, Philip M; Raraigh, Karen S; Girodon, Emmanuelle; Castellani, Carlo

2017-02-01

As a Mendelian disease, genetics plays an integral role in the diagnosis of cystic fibrosis (CF). The identification of 2 disease-causing mutations in the CF transmembrane conductance regulator (CFTR) in an individual with a phenotype provides evidence that the disease is CF. However, not all variations in CFTR always result in CF. Therefore, for CFTR genotype to provide the same level of evidence of CFTR dysfunction as shown by direct tests such as sweat chloride or nasal potential difference, the mutations identified must be known to always result in CF. The use of CFTR genetics in CF diagnosis, therefore, relies heavily on mutation interpretation. Progress that has been made on mutation interpretation and annotation was reviewed at the recent CF Foundation Diagnosis Consensus Conference. A modified Delphi method was used to identify consensus statements on the use of genetic analysis in CF diagnosis. The largest recent advance in CF genetics has come through the Clinical and Functional Translation of CFTR (CFTR2) project. This undertaking seeks to characterize CFTR mutations from patients with CF around the world. The project also established guidelines for the clinical, functional, and population/penetrance criteria that can be used to interpret mutations not yet included in CFTR2's review. The use of CFTR genetics to aid in diagnosis of CF requires that the mutations identified have a known disease liability. The demonstration of 2 in trans mutations known to always result in CF is satisfactory evidence of CFTR dysfunction. However, if the identified mutations are known to be associated with variable outcomes, or have unknown consequence, that genotype may not result in a CF phenotype. In these cases, other tests of CFTR function may help. Copyright © 2016 Elsevier Inc. All rights reserved.

Reference intervals: current status, recent developments and future considerations.

PubMed

Ozarda, Yesim

2016-01-01

Reliable and accurate reference intervals (RIs) for laboratory analyses are an integral part of the process of correct interpretation of clinical laboratory test results. RIs given in laboratory reports have an important role in aiding the clinician in interpreting test results in reference to values for healthy populations. Since the 1980s, the International Federation of Clinical Chemistry (IFCC) has been proactive in establishing recommendations to clarify the true significance of the term 'RIs, to select the appropriate reference population and statistically analyse the data. The C28-A3 guideline published by the Clinical and Laboratory Standards Institute (CLSI) and IFCC is still the most widely-used source of reference in this area. In recent years, protocols additional to the Guideline have been published by the IFCC, Committee on Reference Intervals and Decision Limits (C-RIDL), including all details of multicenter studies on RIs to meet the requirements in this area. Multicentric RIs studies are the most important development in the area of RIs. Recently, the C-RIDL has performed many multicentric studies to obtain common RIs. Confusion of RIs and clinical decision limits (CDLs) remains an issue and pediatric and geriatric age groups are a significant problem. For future studies of RIs, the genetic effect would seem to be the most challenging area. 
The aim of the review is to present the current theory and practice of RIs, with special emphasis given to multicenter RIs studies, RIs studies for pediatric and geriatric age groups, clinical decision limits and partitioning by genetic effects on RIs.

Reference intervals: current status, recent developments and future considerations

PubMed Central

Ozarda, Yesim

2016-01-01

Reliable and accurate reference intervals (RIs) for laboratory analyses are an integral part of the process of correct interpretation of clinical laboratory test results. RIs given in laboratory reports have an important role in aiding the clinician in interpreting test results in reference to values for healthy populations. Since the 1980s, the International Federation of Clinical Chemistry (IFCC) has been proactive in establishing recommendations to clarify the true significance of the term ‘RIs, to select the appropriate reference population and statistically analyse the data. The C28-A3 guideline published by the Clinical and Laboratory Standards Institute (CLSI) and IFCC is still the most widely-used source of reference in this area. In recent years, protocols additional to the Guideline have been published by the IFCC, Committee on Reference Intervals and Decision Limits (C-RIDL), including all details of multicenter studies on RIs to meet the requirements in this area. Multicentric RIs studies are the most important development in the area of RIs. Recently, the C-RIDL has performed many multicentric studies to obtain common RIs. Confusion of RIs and clinical decision limits (CDLs) remains an issue and pediatric and geriatric age groups are a significant problem. For future studies of RIs, the genetic effect would seem to be the most challenging area.
The aim of the review is to present the current theory and practice of RIs, with special emphasis given to multicenter RIs studies, RIs studies for pediatric and geriatric age groups, clinical decision limits and partitioning by genetic effects on RIs. PMID:26981015

Can sexual selection theory inform genetic management of captive populations? A review

PubMed Central

Chargé, Rémi; Teplitsky, Céline; Sorci, Gabriele; Low, Matthew

2014-01-01

Captive breeding for conservation purposes presents a serious practical challenge because several conflicting genetic processes (i.e., inbreeding depression, random genetic drift and genetic adaptation to captivity) need to be managed in concert to maximize captive population persistence and reintroduction success probability. Because current genetic management is often only partly successful in achieving these goals, it has been suggested that management insights may be found in sexual selection theory (in particular, female mate choice). We review the theoretical and empirical literature and consider how female mate choice might influence captive breeding in the context of current genetic guidelines for different sexual selection theories (i.e., direct benefits, good genes, compatible genes, sexy sons). We show that while mate choice shows promise as a tool in captive breeding under certain conditions, for most species, there is currently too little theoretical and empirical evidence to provide any clear guidelines that would guarantee positive fitness outcomes and avoid conflicts with other genetic goals. The application of female mate choice to captive breeding is in its infancy and requires a goal-oriented framework based on the needs of captive species management, so researchers can make honest assessments of the costs and benefits of such an approach, using simulations, model species and captive animal data. PMID:25553072

Implementation of genetic conservation practices in a muskellunge propagation and stocking program

USGS Publications Warehouse

Jennings, Martin J.; Sloss, Brian L.; Hatzenbeler, Gene R.; Kampa, Jeffrey M.; Simonson, Timothy D.; Avelallemant, Steven P.; Lindenberger, Gary A.; Underwood, Bruce D.

2010-01-01

Conservation of genetic resources is a challenging issue for agencies managing popular sport fishes. To address the ongoing potential for genetic risks, we developed a comprehensive set of recommendations to conserve genetic diversity of muskellunge (Esox masquinongy) in Wisconsin, and evaluated the extent to which the recommendations can be implemented. Although some details are specific to Wisconsin's muskellunge propagation program, many of the practical issues affecting implementation are applicable to other species and production systems. We developed guidelines to restrict future broodstock collection operations to lakes with natural reproduction and to develop a set of brood lakes to use on a rotational basis within regional stock boundaries, but implementation will require considering lakes with variable stocking histories. Maintaining an effective population size sufficient to minimize the risk of losing alleles requires limiting broodstock collection to large lakes. Recommendations to better approximate the temporal distribution of spawning in hatchery operations and randomize selection of brood fish are feasible. Guidelines to modify rearing and distribution procedures face some logistic constraints. An evaluation of genetic diversity of hatchery-produced fish during 2008 demonstrated variable success representing genetic variation of the source population. Continued evaluation of hatchery operations will optimize operational efficiency while moving toward genetic conservation goals.

Implementation of genetic conservation practices in a muskellunge propagation and stocking program

USGS Publications Warehouse

Jennings, Martin J.; Sloss, Brian L.; Hatzenbeler, Gene R.; Kampa, Jeffrey M.; Simonson, Timothy D.; Avelallemant, Steven P.; Lindenberger, Gary A.; Underwood, Bruce D.

2010-01-01

Conservation of genetic resources is a challenging issue for agencies managing popular sport fishes. To address the ongoing potential for genetic risks, we developed a comprehensive set of recommendations to conserve genetic diversity of muskellunge (Esox masquinongy) in Wisconsin, and evaluated the extent to which the recommendations can be implemented. Although some details are specific to Wisconsin's muskellunge propagation program, many of the practical issues affecting implementation are applicable to other species and production systems. We developed guidelines to restrict future brood stock collection operations to lakes with natural reproduction and to develop a set of brood lakes to use on a rotational basis within regional stock boundaries, but implementation will require considering lakes with variable stocking histories. Maintaining an effective population size sufficient to minimize the risk of losing alleles requires limiting brood stock collection to large lakes. Recommendations to better approximate the temporal distribution of spawning in hatchery operations and randomize selection of brood fish are feasible. Guidelines to modify rearing and distribution procedures face some logistic constraints. An evaluation of genetic diversity of hatchery-produced fish during 2008 demonstrated variable success representing genetic variation of the source population. Continued evaluation of hatchery operations will optimize operational efficiency while moving toward genetic conservation goals.

Genetic Counselling, BRCA1/2 Status and Clinico-pathologic Characteristics of Patients with Ovarian Cancer before 50 Years of Age

PubMed Central

Cvelbar, Mirjam; Hocevar, Marko; Novakovic, Srdjan; Stegel, Vida; Perhavec, Andraz

2017-01-01

Abstract Background In Slovenia like in other countries, till recently, personal history of epithelial ovarian cancer (EOC) has not been included among indications for genetic counselling. Recent studies reported up to 17% rate of germinal BRCA1/2 mutation (gBRCA1/2m) within the age group under 50 years at diagnosis. The original aim of this study was to invite to the genetic counselling still living patients with EOC under 45 years, to offer gBRCA1/2m testing and to perform analysis of gBRCA1/2m rate and of clinico-pathologic characteristics. Later, we added also the data of previously genetically tested patients with EOC aged 45 to 49 years. Patients and methods All clinical data have to be interpreted in the light of many changes happened in the field of EOC just in the last few years: new hystology stage classification (FIGO), new hystology types and differentiation grades classification, new therapeutic possibilities (PARP inhibitors available, also in Slovenia) and new guidelines for genetic counselling of EOC patients (National Comprehensive Cancer Network, NCCN), together with next-generation sequencing possibilities. Results Compliance rate at the invitation was 43.1%. In the group of 27 invited or previously tested patients with EOC diagnosed before the age of 45 years, five gBRCA1/2 mutations were found. The gBRCA1/2m detection rate within the group was 18.5%. There were 4 gBRCA1 and 1 gBRCA2 mutations detected. In the extended group of 42 tested patients with EOC diagnosed before the age of 50 years, 14 gBRCA1/2 mutations were found. The gBRCA1/2m detection rate within this extended, partially selected group was 33.3%. There were 11 gBRCA1 and 3 gBRCA2 mutations detected. Conclusions The rate of gBRCA1/2 mutation in tested unselected EOC patients under the age of 50 years was higher than 10%, namely 18.5%. Considering also a direct therapeuthic benefit of PARP inhibitors for BRCA positive patients, there is a double reason to offer genetic testing to all EOC patients younger than 50 years. Regarding clinical data, it is important to perform their re-interpretation in everyday clinical practice, because this may influence therapeutic possibilities to be offered. PMID:28740454

Genetic diversity, genetic structure and demographic history of Cycas simplicipinna (Cycadaceae) assessed by DNA sequences and SSR markers

PubMed Central

2014-01-01

Background Cycas simplicipinna (T. Smitinand) K. Hill. (Cycadaceae) is an endangered species in China. There were seven populations and 118 individuals that we could collect were genotyped in this study. Here, we assessed the genetic diversity, genetic structure and demographic history of this species. Results Analyses of data of DNA sequences (two maternally inherited intergenic spacers of chloroplast, cpDNA and one biparentally inherited internal transcribed spacer region ITS4-ITS5, nrDNA) and sixteen microsatellite loci (SSR) were conducted in the species. Of the 118 samples, 86 individuals from the seven populations were used for DNA sequencing and 115 individuals from six populations were used for the microsatellite study. We found high genetic diversity at the species level, low genetic diversity within each of the seven populations and high genetic differentiation among the populations. There was a clear genetic structure within populations of C. simplicipinna. A demographic history inferred from DNA sequencing data indicates that C. simplicipinna experienced a recent population contraction without retreating to a common refugium during the last glacial period. The results derived from SSR data also showed that C. simplicipinna underwent past effective population contraction, likely during the Pleistocene. Conclusions Some genetic features of C. simplicipinna such as having high genetic differentiation among the populations, a clear genetic structure and a recent population contraction could provide guidelines for protecting this endangered species from extinction. Furthermore, the genetic features with population dynamics of the species in our study would help provide insights and guidelines for protecting other endangered species effectively. PMID:25016306

Prevalence of BRCA1 and BRCA2 mutations in women with carcinoma in situ of the breast referred for genetic testing

PubMed Central

Hall, Michael J.; Reid, Julia E.; Wenstrup, Richard J.

2010-01-01

Background Carcinoma in situ (CIS) of the breast will account for 62,280 (24.5%) of new breast cancer diagnoses in 2009. Management guidelines for BRCA1/2 mutation carriers advise close follow-up, intensive screening, and consideration of prophylactic surgeries to lower cancer risk. The prevalence of BRCA1/2 mutations in women with a history of CIS using comprehensive DNA sequencing and rearrangement testing has not been definitively documented. Methods The prevalence of mutations in non-Ashkenazi Jewish women with CIS was assessed by way of a cross-sectional analysis of the Myriad Genetic Laboratories, Inc. BRCA1/2 database. Women reporting any diagnosis of CIS were included. All statistical tests are two-sided, and confidence intervals are reported at the 95% level (α =0.05). Results Among the test population (N=64717), 11.3%(n=7295) reported a history of CIS (any reported CIS). For women without personal history of invasive cancer (CIS alone+CIS and any family history subgroups), those with early-onset CIS had a significantly increased risk of a BRCA1/2 mutation compared to women with late-onset disease (≥50 years)(OR 1.5, 95% CI 1.1–2.1). Among women reporting only a history of CIS and no personal or family history (CIS alone), mutation prevalence was 2.3% (17/738). Conclusions In patients referred for genetic testing, early-onset CIS is associated with BRCA1/2. When a family history of breast and/or ovarian cancer are also present, testing women with early-onset CIS may increase the likelihood of BRCA1/2 mutation detection, and the opportunity for carriers to consider additional cancer prevention strategies. PMID:21149333

Documentation of guideline adherence in antenatal records across maternal weight categories: a chart review.

PubMed

McDonald, Sarah D; Machold, Clea A; Marshall, Laura; Kingston, Dawn

2014-06-13

Documentation in medical records fulfills key functions, including management of care, communication, quality assurance and record keeping. We sought to describe: 1) rates of standard prenatal care as documented in medical charts, and given the higher risks with excess weight, whether this documentation varied among normal weight, overweight and obese women; and 2) adherence to obesity guidelines for obese women as documented in the chart. We conducted a chart review of 300 consecutive charts of women who delivered a live singleton at an academic tertiary centre from January to March 2012, computing Analysis of Variance and Chi Square tests. The proportion of completed fields on the mandatory antenatal forms varied from 100% (maternal age) to 52.7% (pre-pregnancy body mass index). Generally, documentation of care was similar across all weight categories for maternal and prenatal genetic screening tests, ranging from 54.0% (documentation of gonorrhea/chlamydia tests) to 85.0% (documentation of anatomy scan). Documentation of education topics varied widely, from fetal movement in almost all charts across all weight categories but discussion of preterm labour in only 20.6%, 12.7% and 13.4% of normal weight, overweight and obese women's charts (p = 0.224). Across all weight categories, documentation of discussion of exercise, breastfeeding and pain management occurred in less than a fifth of charts. Despite a predominance of excess weight in our region, as well as increasing perinatal risks with increasing maternal weight, weight-related issues and other elements of prenatal care were suboptimally documented across all maternal weight categories, despite an obesity guideline.

European guidelines for workplace drug and alcohol testing in hair.

PubMed

Salomone, A; Tsanaclis, L; Agius, R; Kintz, P; Baumgartner, M R

2016-10-01

Guidelines for Legally Defensible Workplace Drug Testing have been prepared and updated by the European Workplace Drug Testing Society (EWDTS). They are based on the 2010 version published by Pascal Kintz and Ronald Agius (Guidelines for European workplace drug and alcohol testing in hair. Drug Test. Anal. 2010, 2, 367) and in concordance with the Society of Hair Testing guidelines (Society of Hair Testing guidelines for drug testing in hair. Forensic Sci. Int. 2012, 218, 20-24). The European Guidelines are designed to establish best practice procedures whilst allowing individual countries to operate within the requirements of national customs and legislation. The EWDTS recommends that all European laboratories that undertake legally defensible workplace drug testing use these guidelines as a template for accreditation. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Effective population size and genetic conservation criteria for bull trout

Treesearch

Bruce E. Rieman; F. W. Allendorf

2001-01-01

Effective population size (Ne) is an important concept in the management of threatened species like bull trout Salvelinus confluentus. General guidelines suggest that effective population sizes of 50 or 500 are essential to minimize inbreeding effects or maintain adaptive genetic variation, respectively....

Assessment of a Competency-Based Undergraduate Course on Genetic and Genomics.

PubMed

Kronk, Rebecca; Colbert, Alison; Lengetti, Evelyn

2017-08-24

In response to new demands in the nursing profession, an innovative undergraduate genetics course was designed based on the Essential Nursing Competencies and Curricula Guidelines for Genetics and Genomics. Reflective journaling and storytelling were used as major pedagogies, alongside more traditional approaches. Thematic content analysis of student reflections revealed transformational learning as the major theme emerging from genomic and genetic knowledge acquisition. Quantitative analyses of precourse/postcourse student self-assessments of competencies revealed significant findings.

Genetics of Combined Pituitary Hormone Deficiency: Roadmap into the Genome Era

PubMed Central

Fang, Qing; George, Akima S.; Brinkmeier, Michelle L.; Mortensen, Amanda H.; Gergics, Peter; Cheung, Leonard Y. M.; Daly, Alexandre Z.; Ajmal, Adnan; Pérez Millán, María Ines; Ozel, A. Bilge; Kitzman, Jacob O.; Mills, Ryan E.; Li, Jun Z.

2016-01-01

The genetic basis for combined pituitary hormone deficiency (CPHD) is complex, involving 30 genes in a variety of syndromic and nonsyndromic presentations. Molecular diagnosis of this disorder is valuable for predicting disease progression, avoiding unnecessary surgery, and family planning. We expect that the application of high throughput sequencing will uncover additional contributing genes and eventually become a valuable tool for molecular diagnosis. For example, in the last 3 years, six new genes have been implicated in CPHD using whole-exome sequencing. In this review, we present a historical perspective on gene discovery for CPHD and predict approaches that may facilitate future gene identification projects conducted by clinicians and basic scientists. Guidelines for systematic reporting of genetic variants and assigning causality are emerging. We apply these guidelines retrospectively to reports of the genetic basis of CPHD and summarize modes of inheritance and penetrance for each of the known genes. In recent years, there have been great improvements in databases of genetic information for diverse populations. Some issues remain that make molecular diagnosis challenging in some cases. These include the inherent genetic complexity of this disorder, technical challenges like uneven coverage, differing results from variant calling and interpretation pipelines, the number of tolerated genetic alterations, and imperfect methods for predicting pathogenicity. We discuss approaches for future research in the genetics of CPHD. PMID:27828722

International Guidelines on Computer-Based and Internet-Delivered Testing

ERIC Educational Resources Information Center

International Journal of Testing, 2006

2006-01-01

Developed by the International Test Commission, the International Guidelines on Computer-Based and Internet-Delivered Testing are a set of guidelines specifically developed to highlight good practice issues in relation to computer/Internet tests and testing. These guidelines have been developed from an international perspective and are directed at…

Predictive genetic testing in children: constitutional mismatch repair deficiency cancer predisposing syndrome.

PubMed

Bruwer, Zandrè; Algar, Ursula; Vorster, Alvera; Fieggen, Karen; Davidson, Alan; Goldberg, Paul; Wainwright, Helen; Ramesar, Rajkumar

2014-04-01

Biallelic germline mutations in mismatch repair genes predispose to constitutional mismatch repair deficiency syndrome (CMMR-D). The condition is characterized by a broad spectrum of early-onset tumors, including hematological, brain and bowel and is frequently associated with features of Neurofibromatosis type 1. Few definitive screening recommendations have been suggested and no published reports have described predictive testing. We report on the first case of predictive testing for CMMR-D following the identification of two non-consanguineous parents, with the same heterozygous mutation in MLH1: c.1528C > T. The genetic counseling offered to the family, for their two at-risk daughters, is discussed with a focus on the ethical considerations of testing children for known cancer-causing variants. The challenges that are encountered when reporting on heterozygosity in a child younger than 18 years (disclosure of carrier status and risk for Lynch syndrome), when discovered during testing for homozygosity, are addressed. In addition, the identification of CMMR-D in a three year old, and the recommended clinical surveillance that was proposed for this individual is discussed. Despite predictive testing and presymptomatic screening, the sudden death of the child with CMMR-D syndrome occurred 6 months after her last surveillance MRI. This report further highlights the difficulty of developing guidelines, as a result of the rarity of cases and diversity of presentation.

Competency-Based Education for the Molecular Genetic Pathology Fellow

PubMed Central

Talbert, Michael L.; Dunn, S. Terence; Hunt, Jennifer; Hillyard, David R.; Mirza, Imran; Nowak, Jan A.; Van Deerlin, Vivianna; Vnencak-Jones, Cindy L.

2009-01-01

The following report represents guidelines for competency-based fellowship training in Molecular Genetic Pathology (MGP) developed by the Association for Molecular Pathology Training and Education Committee and Directors of MGP Programs in the United States. The goals of the effort were to describe each of the Accreditation Council for Graduate Medical Education competencies as they apply to MGP fellowship training, provide a summary of goals and objectives, and recommend assessment tools. These guidelines are particularly pertinent to MGP training, which is a relatively new specialty that operates within a rapidly changing scientific and technological arena. It is hoped that this document will provide additional material for directors of existing MGP programs to consider for improvement of program objectives and enhancement of evaluation tools already in place. In addition, the guidelines should provide a valuable framework for the development of new MGP programs. PMID:19797613

International Guidelines for the Management and Treatment of Morquio A Syndrome

PubMed Central

Hendriksz, Christian J; Berger, Kenneth I; Giugliani, Roberto; Harmatz, Paul; Kampmann, Christoph; Mackenzie, William G; Raiman, Julian; Villarreal, Martha Solano; Savarirayan, Ravi

2015-01-01

Morquio A syndrome (mucopolysaccharidosis IVA) is a lysosomal storage disorder associated with skeletal and joint abnormalities and significant non-skeletal manifestations including respiratory disease, spinal cord compression, cardiac disease, impaired vision, hearing loss, and dental problems. The clinical presentation, onset, severity and progression rate of clinical manifestations of Morquio A syndrome vary widely between patients. Because of the heterogeneous and progressive nature of the disease, the management of patients with Morquio A syndrome is challenging and requires a multidisciplinary approach, involving an array of specialists. The current paper presents international guidelines for the evaluation, treatment and symptom-based management of Morquio A syndrome. These guidelines were developed during two expert meetings by an international panel of specialists in pediatrics, genetics, orthopedics, pulmonology, cardiology, and anesthesia with extensive experience in managing Morquio A syndrome. © 2014 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals, Inc. PMID:25346323

Challenges in testing genetically modified crops for potential increases in endogenous allergen expression for safety.

PubMed

Panda, R; Ariyarathna, H; Amnuaycheewa, P; Tetteh, A; Pramod, S N; Taylor, S L; Ballmer-Weber, B K; Goodman, R E

2013-02-01

Premarket, genetically modified (GM) plants are assessed for potential risks of food allergy. The major risk would be transfer of a gene encoding an allergen or protein nearly identical to an allergen into a different food source, which can be assessed by specific serum testing. The potential that a newly expressed protein might become an allergen is evaluated based on resistance to digestion in pepsin and abundance in food fractions. If the modified plant is a common allergenic source (e.g. soybean), regulatory guidelines suggest testing for increases in the expression of endogenous allergens. Some regulators request evaluating endogenous allergens for rarely allergenic plants (e.g. maize and rice). Since allergic individuals must avoid foods containing their allergen (e.g. peanut, soybean, maize, or rice), the relevance of the tests is unclear. Furthermore, no acceptance criteria are established and little is known about the natural variation in allergen concentrations in these crops. Our results demonstrate a 15-fold difference in the major maize allergen, lipid transfer protein between nine varieties, and complex variation in IgE binding to various soybean varieties. We question the value of evaluating endogenous allergens in GM plants unless the intent of the modification was production of a hypoallergenic crop. © 2012 John Wiley & Sons A/S.

New clinical practice guidelines on the classification, evaluation and management of childhood interstitial lung disease in infants: what do they mean?

PubMed

Wambach, Jennifer A; Young, Lisa R

2014-12-01

The American Thoracic Society (ATS) recently published a clinical practice guideline regarding the classification, evaluation, and management of childhood interstitial lung disease in infancy (chILD). As disease entities among infants with ILD are often distinct from forms seen in older children and adults, the guideline encourages an age-based classification system and focuses on the diagnostic approach to neonates and infants <2 years of age. The guideline reviews current evidence and recommendations for the evaluation, relevant genetic studies, and management of symptomatic infants. Here, we summarize the ATS guideline, highlight the major concepts, and discuss future strategies aimed at addressing current gaps in knowledge.

Effect of test concentration in the ready biodegradability test for chemical substances: Improvement of OECD test guideline 301C.

PubMed

Nabeoka, Ryosuke; Taruki, Masanori; Kayashima, Takakazu; Yoshida, Tomohiko; Kameya, Takashi

2016-01-01

In Japan, understanding the environmental persistence of chemicals is very important for risk assessment, and ready biodegradability tests are mainly conducted according to the Organisation for Economic Co-operation and Development test guideline 301C. However, the highest test concentration specified in test guideline 301C, 100 mg/L, may cause microbial toxicity and incomplete biodegradation. The authors performed test guideline 301C tests at test concentrations of 30 mg/L for 13 substances that were readily biodegradable in ready biodegradability tests but not in test guideline 301C tests. Of the 5 substances with potential to cause microbial toxicity at 100 mg/L, the percentage of biodegradation of sodium dimethyldithiocarbamate, 4-chloro-3-cresol (CC), thymol (THY), and p-tert-butyl-α-methylbenzenepropionaldehyde measured by biochemical oxygen demand (BOD) increased in the test guideline 301C test at 30 mg/L, suggesting a reduction in toxicity effects. Furthermore, CC and THY met the criteria for ready biodegradability, which are more than 60% of biodegradation by BOD and a 10-d window. Of the 8 substances with a low potential for causing microbial toxicity at 100 mg/L, the percentage of biodegradation of only 2-(diethylamino)ethanol increased in the test guideline 301C test at 30 mg/L. Employing a lower test concentration in the standard test guideline 301C test will contribute to improvement of consistency between results of a test guideline 301C test and other ready biodegradability tests. © 2015 SETAC.

40 CFR 799.11 - Availability of test guidelines.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 31 2010-07-01 2010-07-01 true Availability of test guidelines. 799.11... General Provisions § 799.11 Availability of test guidelines. (a) The TSCA and FIFRA guidelines for the...-487-4650). (b) The OECD guidelines for the various study plans are available from the following...

Experiences with the in vivo and in vitro comet assay in regulatory testing.

PubMed

Frötschl, Roland

2015-01-01

The in vivo comet assay has recently been implemented into regulatory genotoxicity testing of pharmaceuticals with inclusion into the ICH S2R1 guidance. Regulatory genotoxicity testing aims to detect DNA alterations in form of gene mutations, larger scale chromosomal damage and recombination and aneuploidy. The ICH S2R1 guideline offers two options of standard batteries of tests for the detection of these endpoints. Both options start with an AMES assay and option 1 includes an in vitro mammalian cell assay and an in vivo micronucleus assay in rodent, whereas option 2 includes an in vivo micronucleus assay in bone marrow in rodent and a second in vivo assay in a second tissue with a second endpoint. The test recommended as second in vivo test is the comet assay in rat liver. The in vivo comet assay is considered as mature enough to ensure reliable detection of relevant in vivo genotoxicants in combination with the micronucleus test in bone marrow and the AMES assay. Although lots of research papers have been published using the in vitro comet assay, the in vitro version has not been implemented into official regulatory testing guidelines. A survey of the years 1999-2014 revealed 27 in vivo comet assays submitted to BfArM with market authorisation procedures, European and national advice procedures and clinical trial applications. In three procedures, in vitro comet assays had been submitted within the genetic toxicology packages. © The Author 2014. Published by Oxford University Press on behalf of the Mutagenesis Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Colorectal Cancer Screening: Stool DNA and Other Noninvasive Modalities.

PubMed

Bailey, James R; Aggarwal, Ashish; Imperiale, Thomas F

2016-03-01

Colorectal cancer screening dates to the discovery of precancerous adenomatous tissue. Screening modalities and guidelines directed at prevention and early detection have evolved and resulted in a significant decrease in the prevalence and mortality of colorectal cancer via direct visualization or using specific markers. Despite continued efforts and an overall reduction in deaths attributed to colorectal cancer over the last 25 years, colorectal cancer remains one of the most common causes of malignancy-associated deaths. In attempt to further reduce the prevalence of colorectal cancer and associated deaths, continued improvement in screening quality and adherence remains key. Noninvasive screening modalities are actively being explored. Identification of specific genetic alterations in the adenoma-cancer sequence allow for the study and development of noninvasive screening modalities beyond guaiac-based fecal occult blood testing which target specific alterations or a panel of alterations. The stool DNA test is the first noninvasive screening tool that targets both human hemoglobin and specific genetic alterations. In this review we discuss stool DNA and other commercially available noninvasive colorectal cancer screening modalities in addition to other targets which previously have been or are currently under study.

75 FR 22400 - Draft Test Guidelines; Reopening of Comment Period

Federal Register 2010, 2011, 2012, 2013, 2014

2010-04-28

... ENVIRONMENTAL PROTECTION AGENCY [EPA-HQ-OPP-2009-0681; FRL-8822-3] Draft Test Guidelines... draft test guidelines for product performance of public health uses of antimicrobial agents. EPA...-8437-2). In that document, EPA announced the availability of four draft test guidelines for product...

77 FR 15750 - Final Test Guidelines; OCSPP 810 Series; Notice of Availability

Federal Register 2010, 2011, 2012, 2013, 2014

2012-03-16

... ENVIRONMENTAL PROTECTION AGENCY [EPA-HQ-OPP-2009-0681; FRL-9332-4] Final Test Guidelines; OCSPP.... SUMMARY: EPA is announcing the availability of the final test guidelines for Series 810--Product Performance Test Guidelines, specifically public health uses of antimicrobial agents (OCSPP 810.2000...

Cystic Fibrosis: A Review of Associated Phenotypes, Use of Molecular Diagnostic Approaches, Genetic Characteristics, Progress, and Dilemmas.

PubMed

Brennan, Marie-Luise; Schrijver, Iris

2016-01-01

Cystic fibrosis (CF) is an autosomal recessive disease with significant associated morbidity and mortality. It is now appreciated that the broad phenotypic CF spectrum is not explained by obvious genotype-phenotype correlations, suggesting that CF transmembrane conductance regulator (CFTR)-related disease may occur because of multiple additive effects. These contributing effects include complex CFTR alleles, modifier genes, mutations in alternative genes that produce CF-like phenotypes, epigenetic factors, and environmental influences. Most patients in the United States are now diagnosed through newborn screening and use of molecular testing methods. We review the molecular testing approaches and laboratory guidelines for carrier screening, prenatal testing, newborn screening, and clinical diagnostic testing, as well as recent developments in CF treatment, and reasons for the lack of a molecular diagnosis in some patients. Copyright © 2016 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.

Transparency of genetic testing services for 'health, wellness and lifestyle': analysis of online prepurchase information for UK consumers.

PubMed

Hall, Jacqueline A; Gertz, Rena; Amato, Joan; Pagliari, Claudia

2017-08-01

The declining cost of DNA sequencing has been accompanied by a proliferation of companies selling 'direct-to-consumer genetic testing' (DTC-GT) services. Many of these are marketed online as tools for enabling citizens to make more informed decisions about their health, wellness and lifestyle. We assessed the 'information for consumers' provided by these companies at the prepurchase stage, which could influence initial decisions to part with money, data or tissue samples. A scoping exercise revealed 65 DTC-GT companies advertising their services online to consumers in the United Kingdom, of which 15 met our inclusion criteria. We benchmarked their consumer information against the good practice principles developed by the UK Human Genetics Commission (HGC). No provider complied with all the HGC principles and overall levels of compliance varied considerably. Although consent for testing was discussed by all but one company, information about data reuse for research or other purposes was often sparse and consent options limited or unclear. Most did not provide supplementary support services to help users better understand or cope with the implications of test results. We provide recommendations for updating the preconsumer transparency aspects of the HGC guidelines to ensure their fitness-for-purpose in this rapidly changing market. We also recommend improving coordination between relevant governance bodies to ensure minimum standards of transparency, quality and accountability. Although DTC-GT has many potential benefits, close partnership between consumers, industry and government, along with interdisciplinary science input, are essential to ensure that these innovations are used ethically and responsibly.

Ascending Aortic Aneurysm Is an Inherited Disease: A Contemporary Literature Review Based on Hill's Criteria of Specificity, Strength of Association, and Biological Coherence.

PubMed

Ahmad, Mirza Mujadil; Kiani, Immad Arif; Ammar, Khawaja Afzal; Ahmad, Mirza Nubair; Khandheria, Bijoy K; Paterick, Timothy E; Jain, Renuka; Tajik, A Jamil

There is growing evidence of a differential etiological basis for thoracic aortic aneurysms (TAA), with ascending (As) TAAs being genetically mediated and descending (Des) TAAs more strongly related to acquired pathologies. A comprehensive literature review of this hypothesis has not been carried out. We carried out a systematic literature review based on the latest guidelines on TAA endorsed by the American Heart Association. The etiologies were classified as genetic and inherited, the studies were tabulated accordingly, and Hill's epidemiological criteria of causality were applied. We found 38 studies addressing the etiology of TAAs. Out of these, 17 were about genetic causes, 9 about acquired causes, and 4 had information regarding both etiologies. Multiple genetic studies showed a strong association of As TAA with different genetic mutations. Contrary to commonly held beliefs, acquired causes, that is, dyslipidemia, diabetes, and atherosclerosis, were negatively associated with As TAA and positively associated with Des TAA. Hypertension was only associated with Des TAA and dissections (TAAD), not with As TAA. Multiple studies fulfilled the criteria of strength of association (n = 4), consistency (n = 9), specificity (n = 5), temporality (24), biological gradient (n = 3), plausibility (n = 38), biological coherence (n = 25), experiment (n = 4), and analogy (n = 6). Our literature review supports the hypothesis that As TAA is genetically mediated and Des TAA is predominantly an acquired pathology, and supports the argument for genetic testing in all cases of As TAA.

European guidelines for workplace drug testing in oral fluid.

PubMed

Brcak, Michaela; Beck, Olof; Bosch, Tessa; Carmichael, Duncan; Fucci, Nadia; George, Claire; Piper, Mark; Salomone, Alberto; Schielen, Wim; Steinmeyer, Stefan; Taskinen, Sanna; Weinmann, Wolfgang

2018-03-01

These guidelines for Legally Defensible Workplace Drug Testing have been prepared and updated by the European Workplace Drug Testing Society (EWDTS). The European Guidelines are designed to establish best practice procedures whilst allowing individual countries to operate within the requirements of national customs and legislation. The EWDTS recommends that all European laboratories that undertake legally defensible workplace drug testing should use these guidelines as a template for accreditation. These guidelines are relevant to laboratory-based testing only. These guidelines follow current best practices and are constantly under review. Copyright © 2017 John Wiley & Sons, Ltd.

USDA forest service southern region – It’s all about GRITS

Treesearch

Barbara S. Crane; Kevin M. Potter

2017-01-01

Genetic resource management programs across the U.S. Department of Agriculture Forest Service (USDA FS) play a key role in supporting successful land management activities. The programs are responsible for developing and providing plant material for revegetation, seed management guidelines, emergency fire recovery assistance, genetic conservation strategies, climate...

Genetic monitoring as a promising tool for conservation and management

Treesearch

Michael K. Schwartz; Gordon Luikart; Robin S. Waples

2007-01-01

In response to ever-increasing anthropogenic changes to natural ecosystems, regional, national and international organizations have established guidelines for monitoring biological diversity. Most monitoring programs, however, do not take full advantage of the potential afforded by molecular genetic markers, which can provide information relevant to both ecological and...

European guidelines for workplace drug testing in urine.

PubMed

Taskinen, Sanna; Beck, Olof; Bosch, Tessa; Brcak, Michaela; Carmichael, Duncan; Fucci, Nadia; George, Claire; Piper, Mark; Salomone, Alberto; Schielen, Wim; Steinmeyer, Stefan; Weinmann, Wolfgang

2017-06-01

These European Guidelines for Workplace Drug Testing in Urine have been prepared and updated by the European Workplace Drug Testing Society (EWDTS). The first version of these urine guidelines was published in 2002. Since then, the guidelines have been followed by many laboratories in different European countries and their role has been essential particularly in countries lacking legislation for workplace drug testing. In 2014, the EWDTS started a guidelines updating project and published a new version of the urine guidelines in 2015. Here we represent this updated version of the urine guidelines. The European Guidelines are designed to establish best practice procedures whilst allowing individual countries to operate within the requirements of national customs and legislation. The EWDTS recommends that all European laboratories that undertake legally defensible workplace drug testing should use these guidelines as a template for accreditation. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

Responsible implementation of expanded carrier screening

PubMed Central

Henneman, Lidewij; Borry, Pascal; Chokoshvili, Davit; Cornel, Martina C; van El, Carla G; Forzano, Francesca; Hall, Alison; Howard, Heidi C; Janssens, Sandra; Kayserili, Hülya; Lakeman, Phillis; Lucassen, Anneke; Metcalfe, Sylvia A; Vidmar, Lovro; de Wert, Guido; Dondorp, Wybo J; Peterlin, Borut

2016-01-01

This document of the European Society of Human Genetics contains recommendations regarding responsible implementation of expanded carrier screening. Carrier screening is defined here as the detection of carrier status of recessive diseases in couples or persons who do not have an a priori increased risk of being a carrier based on their or their partners' personal or family history. Expanded carrier screening offers carrier screening for multiple autosomal and X-linked recessive disorders, facilitated by new genetic testing technologies, and allows testing of individuals regardless of ancestry or geographic origin. Carrier screening aims to identify couples who have an increased risk of having an affected child in order to facilitate informed reproductive decision making. In previous decades, carrier screening was typically performed for one or few relatively common recessive disorders associated with significant morbidity, reduced life-expectancy and often because of a considerable higher carrier frequency in a specific population for certain diseases. New genetic testing technologies enable the expansion of screening to multiple conditions, genes or sequence variants. Expanded carrier screening panels that have been introduced to date have been advertised and offered to health care professionals and the public on a commercial basis. This document discusses the challenges that expanded carrier screening might pose in the context of the lessons learnt from decades of population-based carrier screening and in the context of existing screening criteria. It aims to contribute to the public and professional discussion and to arrive at better clinical and laboratory practice guidelines. PMID:26980105

Warfarin Pharmacogenetics

PubMed Central

Johnson, Julie A.; Cavallari, Larisa H.

2014-01-01

The cytochrome P450 (CYP) 2C9 and vitamin K epoxide reductase complex 1 (VKORC1) genotypes have been strongly and consistently associated with warfarin dose requirements, and dosing algorithms incorporating genetic and clinical information have been shown to be predictive of stable warfarin dose. However, clinical trials evaluating genotype-guided warfarin dosing produced mixed results, calling into question the utility of this approach. Recent trials used surrogate markers as endpoints rather than clinical endpoints, further complicating translation of the data to clinical practice. The present data do not support genetic testing to guide warfarin dosing, but in the setting where genotype data are available, use of such data in those of European ancestry is reasonable. Outcomes data are expected from an on-going trial, observational studies continue, and more work is needed to define dosing algorithms that incorporate appropriate variants in minority populations; all these will further shape guidelines and recommendations on the clinical utility of genotype-guided warfarin dosing. PMID:25282448

Clinical application of next-generation sequencing for Mendelian diseases.

PubMed

Jamuar, Saumya Shekhar; Tan, Ene-Choo

2015-06-16

Over the past decade, next-generation sequencing (NGS) has led to an exponential increase in our understanding of the genetic basis of Mendelian diseases. NGS allows for the analysis of multiple regions of the genome in one single reaction and has been shown to be a cost-effective and efficient tool in investigating patients with Mendelian diseases. More recently, NGS has been successfully deployed in the clinics, with a reported diagnostic yield of ~25 %. However, recommendations on clinical implementation of NGS are still evolving with numerous key challenges that impede the widespread use of genetics in everyday medicine. These challenges include when to order, on whom to order, what type of test to order, and how to interpret and communicate the results, including incidental findings, to the patient and family. In this review, we discuss these challenges and suggest guidelines on implementing NGS in the routine clinical workflow.

Machine learning in genetics and genomics

PubMed Central

Libbrecht, Maxwell W.; Noble, William Stafford

2016-01-01

The field of machine learning promises to enable computers to assist humans in making sense of large, complex data sets. In this review, we outline some of the main applications of machine learning to genetic and genomic data. In the process, we identify some recurrent challenges associated with this type of analysis and provide general guidelines to assist in the practical application of machine learning to real genetic and genomic data. PMID:25948244

Biological sample collections from minors for genetic research: a systematic review of guidelines and position papers

PubMed Central

Hens, Kristien; Nys, Herman; Cassiman, Jean-Jacques; Dierickx, Kris

2009-01-01

Stored tissue samples are an important resource for epidemiological genetic research. Genetic research on biological material from minors can yield valuable information on the development and genesis of early-onset genetic disorders and the early interaction of environmental and genetic factors. The use of such tissue raises some specific ethical and governance questions, which are not completely covered by the discussion on biological materials from adults. We have retrieved 29 guidelines and position papers pertaining to the storage and use of biological tissue samples for genetic research, originating from 27 different organizations. Five documents have an international scope, three have an European scope and 21 have a national scope. We discovered that 11 of these documents did not contain a section on biological materials from minors. The content of the remaining 18 documents was categorized according to four themes: consent, principles of non-therapeutic research on vulnerable populations, ethics committee approval and difference between anonymous and identifiable samples. We found out that these themes are not consistently mentioned by each document, but that documents discussing the same themes were mostly in agreement with their recommendations. However, a systematic reflection on the ethical and policy issues arising from the participation of minors in biobank research is missing. PMID:19223929

Biological sample collections from minors for genetic research: a systematic review of guidelines and position papers.

PubMed

Hens, Kristien; Nys, Herman; Cassiman, Jean-Jacques; Dierickx, Kris

2009-08-01

Stored tissue samples are an important resource for epidemiological genetic research. Genetic research on biological material from minors can yield valuable information on the development and genesis of early-onset genetic disorders and the early interaction of environmental and genetic factors. The use of such tissue raises some specific ethical and governance questions, which are not completely covered by the discussion on biological materials from adults. We have retrieved 29 guidelines and position papers pertaining to the storage and use of biological tissue samples for genetic research, originating from 27 different organizations. Five documents have an international scope, three have an European scope and 21 have a national scope. We discovered that 11 of these documents did not contain a section on biological materials from minors. The content of the remaining 18 documents was categorized according to four themes: consent, principles of non-therapeutic research on vulnerable populations, ethics committee approval and difference between anonymous and identifiable samples. We found out that these themes are not consistently mentioned by each document, but that documents discussing the same themes were mostly in agreement with their recommendations. However, a systematic reflection on the ethical and policy issues arising from the participation of minors in biobank research is missing.

Genetic management guidelines for captive propagation of freshwater mussels (unionoidea)

USGS Publications Warehouse

Jones, J.W.; Hallerman, E.M.; Neves, R.J.

2006-01-01

Although the greatest global diversity of freshwater mussels (???300 species) resides in the United States, the superfamily Unionoidea is also the most imperiled taxon of animals in the nation. Thirty-five species are considered extinct, 70 species are listed as endangered or threatened, and approximately 100 more are species of conservation concern. To prevent additional species losses, biologists have developed methods for propagating juvenile mussels for release into the wild to restore or augment populations. Since 1997, mussel propagation facilities in the United States have released over 1 million juveniles of more than a dozen imperiled species, and survival of these juveniles in the wild has been documented. With the expectation of continued growth of these programs, agencies and facilities involved with mussel propagation must seriously consider the genetic implications of releasing captive-reared progeny. We propose 10 guidelines to help maintain the genetic resources of cultured and wild populations. Preservation of genetic diversity will require robust genetic analysis of source populations to define conservation units for valid species, subspecies, and unique populations. Hatchery protocols must be implemented that minimize risks of artificial selection and other genetic hazards affecting adaptive traits of progeny subsequently released to the wild. We advocate a pragmatic, adaptive approach to species recovery that incorporates the principles of conservation genetics into breeding programs, and prioritizes the immediate demographic needs of critically endangered mussel species.

Anticipating issues related to increasing preimplantation genetic diagnosis use: a research agenda.

PubMed

Klitzman, Robert; Appelbaum, Paul S; Chung, Wendy; Sauer, Mark

2008-01-01

Increasing use of preimplantation genetic diagnosis (PGD) poses numerous clinical, social, psychological, ethical, legal and policy dilemmas, many of which have received little attention. Patients and providers are now considering and using PGD for a widening array of genetic disorders, and patients may increasingly seek 'designer babies.' In the USA, although governmental oversight policies have been discussed, few specific guidelines exist. Hence, increasingly, patients and providers will face challenging ethical and policy questions of when and for whom to use PGD, and how it should be financed. These issues should be better clarified and addressed through collection of data concerning the current use of PGD in the USA, including factors involved in decision making about PGD use, as well as the education of the various communities that are, and should be, involved in its implementation. Improved understanding of these issues will ultimately enhance the development and implementation of future clinical guidelines and policies.

The emergence of an ethical duty to disclose genetic research results: international perspectives.

PubMed

Knoppers, Bartha Maria; Joly, Yann; Simard, Jacques; Durocher, Francine

2006-11-01

The last decade has witnessed the emergence of international ethics guidelines discussing the importance of disclosing global and also, in certain circumstances, individual genetic research results to participants. This discussion is all the more important considering the advent of pharmacogenomics and the increasing incidence of 'translational' genetic research in the post-genomic era. We surveyed both the literature and the ethical guidelines using selective keywords. We then analyzed our data using a qualitative method approach and singled out countries or policies that were representative of certain positions. From our findings, we conclude that at the international level, there now exists an ethical duty to return individual genetic research results subject to the existence of proof of validity, significance and benefit. Even where these criteria are met, the right of the research participant not to know also has to be taken into consideration. The existence of an ethical duty to return individual genetic research results begs several other questions: Who should have the responsibility of disclosing such results and when? To whom should the results be disclosed? How? Finally, will this ethical 'imperative' become a legally recognized duty as well?

Draft Test Guideline: Daphnid Chronic Toxicity Test

EPA Pesticide Factsheets

The following draft test guideline is part of a series of test guidelines that have been developed by EPA for use in the testing of pesticides and toxic substances, and the development of test data for submission to the Agency for review.

Draft Test Guideline: Gammarid Acute Toxicity Test

EPA Pesticide Factsheets

The following draft test guideline is part of a series of test guidelines that have been developed by EPA for use in the testing of pesticides and toxic substances, and the development of test data for submission to the Agency for review.

Draft Test Guideline: Chironomid Sediment Toxicity Test

EPA Pesticide Factsheets

The following draft test guideline is part of a series of test guidelines that have been developed by EPA for use in the testing of pesticides and toxic substances, and the development of test data for submission to the Agency for review.

Draft Test Guideline: Mysid Acute Toxicity Test

EPA Pesticide Factsheets

The following draft test guideline is part of a series of test guidelines that have been developed by EPA for use in the testing of pesticides and toxic substances, and the development of test data for submission to the Agency for review.

Draft Test Guideline: Penaeid Acute Toxicity Test

EPA Pesticide Factsheets

The following draft test guideline is part of a series of test guidelines that have been developed by EPA for use in the testing of pesticides and toxic substances, and the development of test data for submission to the Agency for review.

Draft Test Guideline: Mysid Chronic Toxicity Test

EPA Pesticide Factsheets

The following draft test guideline is part of a series of test guidelines that have been developed by EPA for use in the testing of pesticides and toxic substances, and the development of test data for submission to the Agency for review.

Contribution of extended family history in assessment of risk for breast and colon cancer.

PubMed

Solomon, Benjamin L; Whitman, Todd; Wood, Marie E

2016-09-01

Family history is important for identifying candidates for high risk cancer screening and referral for genetic counseling. We sought to determine the percentage of individuals who would be eligible for high risk cancer screening or genetic referral and testing if family history includes an extended (vs limited) family history. Family histories were obtained from 626 women at UVMMC associated mammography centers from 2001 to 2002. ACS guidelines were used to determine eligibility for high risk breast or colon cancer screening. Eligibility for referral for genetic counseling for hereditary breast and colon cancer was determined using the Referral Screening Tool and Amsterdam II screening criteria, respectively. All family histories were assessed for eligibility by a limited history (first degree relatives only) and extended history (first and second degree relatives). Four hundred ninety-nine histories were eligible for review. 18/282 (3.6 %) and 62/123 (12 %) individuals met criteria for high risk breast and colon cancer screening, respectively. 13/18 (72 %) in the high risk breast cancer screening group and 12/62 (19 %) in the high risk colon cancer screening group met criteria based upon an extended family history. 9/282 (1.8 %) and 31/123 (6.2 %) individuals met criteria for genetic counseling referral and testing for breast and colon cancer, respectively. 2/9 (22 %) of individuals in the genetic breast cancer screening group and 21/31 (68 %) individuals in the genetic colon cancer screening group met criteria based upon extended family history. This is one of the first studies to suggest that first degree family history alone is not adequate for identification of candidates for high risk screening and referral for genetic counseling for hereditary breast and colon cancer syndromes. A larger population is needed to further validate this data.

American Association of Clinical Endocrinologists Medical Guidelines for clinical practice for the evaluation and treatment of hypogonadism in adult male patients--2002 update.

PubMed

Petak, Steven M; Nankin, Howard R; Spark, Richard F; Swerdloff, Ronald S; Rodriguez-Rigau, Luis J

2002-01-01

In these clinical practice guidelines, specific recommendations are made for determining the most effective methods of diagnosing and treating hypogonadism in adult male patients. The target populations for these guidelines include the following: (1) men with primary testicular failure requiring testosterone replacement (hypergonadotropic hypogonadism); (2) male patients with gonadotropin deficiency or dysfunction who may have received testosterone replacement therapy or treatment for infertility (hypogonadotropic hypogonadism); and (3) aging men with symptoms relating to testosterone deficiency who could benefit from testosterone replacement therapy. Initial hormonal evaluation generally consists of a testosterone determination, in conjunction with a free testosterone or sex hormone-binding globulin level, inpatients with clear symptoms and signs but normal-range total testosterone, follicle-stimulating hormone, luteinizing hormone, and prolactin levels. Other possible tests include semen analysis, pituitary imaging studies, genetic studies, bone densitometry, testicular ultrasonography,testicular biopsy, and specialized hormonal dynamic testing. Therapeutic options generally consist of testosterone replacement by injections, patches, or topically applied gel in hypergonadotropic patients and in hypogonadotropic patients not interested in fertility. In hypogonadotropic patients interested in fertility, gonadal stimulation option scan be considered, including human chorionic gonadotropin stimulation therapy with or without human menopausal gonadotropin (or follicle-stimulating hormone) or gonadotropin-releasing hormone pump therapy. These therapies may be combined with assisted reproductive technologies such as in vitro fertilization with intracytoplasmic sperm injection, which may allow pregnancy to occur with very low numbers of sperm.

Following the giant's paces-governance issues and bioethical reflections in China.

PubMed

Wang, Zhaochen; Zhang, Di; Ng, Vincent H; Lie, Reidar; Zhai, Xiaomei

2014-10-31

China has become a global player in the field of biosamples research and analysis of genetic data. The Beijing Genomics Institute is a genetics factory where enormous amounts of biosamples/data from all over the world are being analyzed. Most of the global bioethics discussions focused on research conducted by scientists from industrialized countries with subjects from poorer countries. Today, however, samples from industrialized nations are being analyzed in China on an unprecedented scale. This means that one should not just focus on bioethics developments in western countries, but also should pay attention to the situation in China. Under this era of rapid advancement in genomics, reassessing the conventionally accepted bioethical principles is strongly needed. In this paper, we will analyze the case of BGI in the context of the Chinese regulatory system in order to identify methods to regulate genetic research more effectively and to strengthen BGI's role in international collaborative research projects. Three main issues concerning sample collection and samples/data management are addressed. Firstly, an ambiguous definition of research, which does not specifically include biosamples/data, when applied to genetic research, may cause confusion and leave loopholes in governance. Secondly, the current regulations do not provide sufficient guidelines on the details of what information to present to prospective subjects, and how to combine informed consent with strategies of re-consent, withdrawal and feedback from research. Finally, the existing regulations do not adequately address issues of genetic privacy and data protection. Bioethical issues related to genetic research in China may be partially due to the nature of genetic research and partially stems from the strategy of simply adopting general international guidelines into the Chinese context without detailed considerations of the local needs. However, there are no perfect readymade ethical solutions for everyone; every country faces different open questions and challenges behind what appears to be unified guidelines. Given the importance of China in international genetic research, other countries ought to be concerned about the bioethical developments in China. China should also have a substantive discussion with the international community on bioethics issues.

Rare-Variant Association Analysis: Study Designs and Statistical Tests

PubMed Central

Lee, Seunggeung; Abecasis, Gonçalo R.; Boehnke, Michael; Lin, Xihong

2014-01-01

Despite the extensive discovery of trait- and disease-associated common variants, much of the genetic contribution to complex traits remains unexplained. Rare variants can explain additional disease risk or trait variability. An increasing number of studies are underway to identify trait- and disease-associated rare variants. In this review, we provide an overview of statistical issues in rare-variant association studies with a focus on study designs and statistical tests. We present the design and analysis pipeline of rare-variant studies and review cost-effective sequencing designs and genotyping platforms. We compare various gene- or region-based association tests, including burden tests, variance-component tests, and combined omnibus tests, in terms of their assumptions and performance. Also discussed are the related topics of meta-analysis, population-stratification adjustment, genotype imputation, follow-up studies, and heritability due to rare variants. We provide guidelines for analysis and discuss some of the challenges inherent in these studies and future research directions. PMID:24995866

Draft Test Guideline: Tadpole/Sediment Subchronic Toxicity Test

EPA Pesticide Factsheets

The following draft test guideline is part of a series of test guidelines that have been developed by EPA for use in the testing of pesticides and toxic substances, and the development of test data for submission to the Agency for review.

Draft Test Guideline: Bivalve Acute Toxicity Test (Embryo Larval)

EPA Pesticide Factsheets

The following draft test guideline is part of a series of test guidelines that have been developed by EPA for use in the testing of pesticides and toxic substances, and the development of test data for submission to the Agency for review.

Draft Test Guideline: Field Testing For Aquatic Organisms

EPA Pesticide Factsheets

The following draft test guideline is part of a series of test guidelines that have been developed by EPA for use in the testing of pesticides and toxic substances, and the development of test data for submission to the Agency for review.

Draft Test Guideline: Oyster Acute Toxicity Test (Shell Deposition)

EPA Pesticide Factsheets

The following draft test guideline is part of a series of test guidelines that have been developed by EPA for use in the testing of pesticides and toxic substances, and the development of test data for submission to the Agency for review.

Draft Test Guideline: Site-Specific Aquatic Microcosm Test, Laboratory

EPA Pesticide Factsheets

The following draft test guideline is part of a series of test guidelines that have been developed by EPA for use in the testing of pesticides and toxic substances, and the development of test data for submission to the Agency for review.

Draft Test Guideline: Generic Freshwater Microcosm Test, Laboratory

EPA Pesticide Factsheets

The following draft test guideline is part of a series of test guidelines that have been developed by EPA for use in the testing of pesticides and toxic substances, and the development of test data for submission to the Agency for review.

Draft Test Guideline: Fish Early-Life Stage Toxicity Test

EPA Pesticide Factsheets

The following draft test guideline is part of a series of test guidelines that have been developed by EPA for use in the testing of pesticides and toxic substances, and the development of test data for submission to the Agency for review.

Comparison of biodegradation performance of OECD test guideline 301C with that of other ready biodegradability tests.

PubMed

Kayashima, Takakazu; Taruki, Masanori; Katagiri, Kazuomi; Nabeoka, Ryosuke; Yoshida, Tomohiko; Tsuji, Toshiaki

2014-02-01

The Organisation for Economic Co-operatoin and development (OECD) Guidelines for the Testing of Chemicals list 7 types of tests for determining the ready biodegradability of chemical compounds (301A-F and 310). The present study compares the biodegradation performance of test guideline 301C, which is applied in Japan's Chemical Substances Control Law, with the performance of the other 6 ready biodegradability tests (RBTs) listed in the guidelines. Test guideline 301C specifies use of activated sludge precultured with synthetic sewage containing glucose and peptone (301C sludge) as a test inoculum; in the other RBTs, however, activated sludge from wastewater treatment plants (WWTP sludge) is frequently employed. Analysis based on percentage of biodegradation and pass levels revealed that the biodegradation intensity of test guideline 301C is relatively weak compared with the intensities of RBTs using WWTP sludge, and the following chemical compounds are probably not biodegraded under test guideline 301C conditions: phosphorus compounds; secondary, tertiary, and quaternary amines; and branched quaternary carbon compounds. The relatively weak biodegradation intensity of test guideline 301C may be related to the markedly different activities of the 301C and WWTP sludges. These findings will be valuable for evaluating RBT data in relation to Japan's Chemical Substances Control Law. © 2013 SETAC.

Draft Test Guideline: Aquatic Invetebrate Acute Toxicity, Test, Freshwater Daphnids

EPA Pesticide Factsheets

The following draft test guideline is part of a series of test guidelines that have been developed by EPA for use in the testing of pesticides and toxic substances, and the development of test data for submission to the Agency for review.

Draft Test Guideline: Fish Acute Toxicity Test, Freshwater And Marine

EPA Pesticide Factsheets

The following draft test guideline is part of a series of test guidelines that have been developed by EPA for use in the testing of pesticides and toxic substances, and the development of test data for submission to the Agency for review.

Preconception Carrier Screening by Genome Sequencing: Results from the Clinical Laboratory.

PubMed

Punj, Sumit; Akkari, Yassmine; Huang, Jennifer; Yang, Fei; Creason, Allison; Pak, Christine; Potter, Amiee; Dorschner, Michael O; Nickerson, Deborah A; Robertson, Peggy D; Jarvik, Gail P; Amendola, Laura M; Schleit, Jennifer; Simpson, Dana Kostiner; Rope, Alan F; Reiss, Jacob; Kauffman, Tia; Gilmore, Marian J; Himes, Patricia; Wilfond, Benjamin; Goddard, Katrina A B; Richards, C Sue

2018-06-07

Advances in sequencing technologies permit the analysis of a larger selection of genes for preconception carrier screening. The study was designed as a sequential carrier screen using genome sequencing to analyze 728 gene-disorder pairs for carrier and medically actionable conditions in 131 women and their partners (n = 71) who were planning a pregnancy. We report here on the clinical laboratory results from this expanded carrier screening program. Variants were filtered and classified using the latest American College of Medical Genetics and Genomics (ACMG) guideline; only pathogenic and likely pathogenic variants were confirmed by orthologous methods before being reported. Novel missense variants were classified as variants of uncertain significance. We reported 304 variants in 202 participants. Twelve carrier couples (12/71 couples tested) were identified for common conditions; eight were carriers for hereditary hemochromatosis. Although both known and novel variants were reported, 48% of all reported variants were missense. For novel splice-site variants, RNA-splicing assays were performed to aid in classification. We reported ten copy-number variants and five variants in non-coding regions. One novel variant was reported in F8, associated with hemophilia A; prenatal testing showed that the male fetus harbored this variant and the neonate suffered a life-threatening hemorrhage which was anticipated and appropriately managed. Moreover, 3% of participants had variants that were medically actionable. Compared with targeted mutation screening, genome sequencing improves the sensitivity of detecting clinically significant variants. While certain novel variant interpretation remains challenging, the ACMG guidelines are useful to classify variants in a healthy population. Copyright © 2018 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Identification of a Comprehensive Spectrum of Genetic Factors for Hereditary Breast Cancer in a Chinese Population by Next-Generation Sequencing

PubMed Central

Yang, Xiaochen; Wu, Jiong; Lu, Jingsong; Liu, Guangyu; Di, Genhong; Chen, Canming; Hou, Yifeng; Sun, Menghong; Yang, Wentao; Xu, Xiaojing; Zhao, Ying; Hu, Xin; Li, Daqiang; Cao, Zhigang; Zhou, Xiaoyan; Huang, Xiaoyan; Liu, Zhebin; Chen, Huan; Gu, Yanzi; Chi, Yayun; Yan, Xia; Han, Qixia; Shen, Zhenzhou; Shao, Zhimin; Hu, Zhen

2015-01-01

The genetic etiology of hereditary breast cancer has not been fully elucidated. Although germline mutations of high-penetrance genes such as BRCA1/2 are implicated in development of hereditary breast cancers, at least half of all breast cancer families are not linked to these genes. To identify a comprehensive spectrum of genetic factors for hereditary breast cancer in a Chinese population, we performed an analysis of germline mutations in 2,165 coding exons of 152 genes associated with hereditary cancer using next-generation sequencing (NGS) in 99 breast cancer patients from families of cancer patients regardless of cancer types. Forty-two deleterious germline mutations were identified in 21 genes of 34 patients, including 18 (18.2%) BRCA1 or BRCA2 mutations, 3 (3%) TP53 mutations, 5 (5.1%) DNA mismatch repair gene mutations, 1 (1%) CDH1 mutation, 6 (6.1%) Fanconi anemia pathway gene mutations, and 9 (9.1%) mutations in other genes. Of seven patients who carried mutations in more than one gene, 4 were BRCA1/2 mutation carriers, and their average onset age was much younger than patients with only BRCA1/2 mutations. Almost all identified high-penetrance gene mutations in those families fulfill the typical phenotypes of hereditary cancer syndromes listed in the National Comprehensive Cancer Network (NCCN) guidelines, except two TP53 and three mismatch repair gene mutations. Furthermore, functional studies of MSH3 germline mutations confirmed the association between MSH3 mutation and tumorigenesis, and segregation analysis suggested antagonism between BRCA1 and MSH3. We also identified a lot of low-penetrance gene mutations. Although the clinical significance of those newly identified low-penetrance gene mutations has not been fully appreciated yet, these new findings do provide valuable epidemiological information for the future studies. Together, these findings highlight the importance of genetic testing based on NCCN guidelines and a multi-gene analysis using NGS may be a supplement to traditional genetic counseling. PMID:25927356

Draft Test Guideline: Fish Bioconcentration Factor (BCF)

EPA Pesticide Factsheets

The following draft test guideline is part of a series of test guidelines that have been developed by EPA for use in the testing of pesticides and toxic substances, and the development of test data for submission to the Agency for review.

Draft Test Guideline: Oyster Bioconcentration Factor (BCF)

EPA Pesticide Factsheets

The following draft test guideline is part of a series of test guidelines that have been developed by EPA for use in the testing of pesticides and toxic substances, and the development of test data for submission to the Agency for review.

Draft Test Guideline: Fish Life Cycle Toxicity

EPA Pesticide Factsheets

The following draft test guideline is part of a series of test guidelines that have been developed by EPA for use in the testing of pesticides and toxic substances, and the development of test data for submission to the Agency for review.

Draft Test Guideline: Aquatic Food Chain Transfer

EPA Pesticide Factsheets

The following draft test guideline is part of a series of test guidelines that have been developed by EPA for use in the testing of pesticides and toxic substances, and the development of test data for submission to the Agency for review.

Evaluation of autopsy and police reports in the investigation of sudden unexplained death in the young.

PubMed

Wilms, Heath R; Midgley, David J; Morrow, Paul; Stables, Simon; Crawford, Jackie; Skinner, Jonathan R

2012-12-01

To evaluate police and autopsy reports in sudden unexplained deaths in 0-40 year olds. A structured, blind review of police and autopsy reports send to a cardiac genetic service from before (February 2006-December 2007) and after (January-December 2009) new best practice guidelines were introduced in Australia and New Zealand was performed. The reviews focused on reporting on: (1) presentation and clinical history, (2) cardiac autopsy, (3) histological tests and toxicology, and (4) detailed examination of coronary arteries. 110 reports were evaluated against the guidelines. 100 % reported location, 95 % activity at time of death, and 84 % some clinical history. Less than 25 % reported on family history, presence/absence of illicit drugs or alcohol, recorded a possible arrhythmic trigger, or history of fits/faints or collapses. Over 95 % listed heart weight, valvular examinations, pulmonary and some myocardial histology. Less than 50 % commented on septal, LV (left ventricle) and RV (right ventricle) wall thickness. Less than 50 % mentioned site of histology samples, or gave specific description of LV or RV histology or conduction system. Toxicology was not mentioned in a third. Histology of coronary arteries was described in only 18 %. Post guidelines reporting increased in some areas, e.g. in 1-40 year olds: antecedent symptoms (22-61 %), number and location of histology samples (0-47 %), and histology of coronary arteries (6-50 %). Most police and autopsy reports fall short of best practice guidelines. They have improved somewhat after the new guidelines were introduced, but need to be more consistent and particularly need to include significant negative findings.

Familial Gastric Cancers

PubMed Central

Setia, Namrata; Clark, Jeffrey W.; Duda, Dan G.; Hong, Theodore S.; Kwak, Eunice L.; Mullen, John T.

2015-01-01

Although the majority of gastric carcinomas are sporadic, approximately 10% show familial aggregation, and a hereditary cause is determined in 1%–3% cases. Of these, hereditary diffuse gastric cancer is the most recognized predisposition syndrome. Although rare, the less commonly known syndromes also confer a markedly increased risk for development of gastric cancer. Identification and characterization of these syndromes require a multidisciplinary effort involving oncologists, surgeons, genetic counselors, biologists, and pathologists. This article reviews the molecular genetics, clinical and pathologic features, surveillance guidelines, and preventive measures of common and less common hereditary gastric cancer predisposition syndromes. Implications for Practice: Although the majority of gastric adenocarcinomas are sporadic with many of those related to chronic Helicobacter pylori infection, approximately 10% of the cases show familial aggregation, and a specific hereditary cause is determined in 1%–3% cases. This review describes the molecular genetics, clinical and pathologic features, surveillance guidelines, and preventive measures of common and less common hereditary gastric cancer predisposition syndromes. Ultimately, a better understanding of the biology of these conditions should allow early identification and intervention as part of a multidisciplinary approach involving oncologists, surgeons, genetic counselors, and pathologists. PMID:26424758

An ecological genetic delineation of local seed-source provenance for ecological restoration

PubMed Central

Krauss, Siegfried L; Sinclair, Elizabeth A; Bussell, John D; Hobbs, Richard J

2013-01-01

An increasingly important practical application of the analysis of spatial genetic structure within plant species is to help define the extent of local provenance seed collection zones that minimize negative impacts in ecological restoration programs. Here, we derive seed sourcing guidelines from a novel range-wide assessment of spatial genetic structure of 24 populations of Banksia menziesii (Proteaceae), a widely distributed Western Australian tree of significance in local ecological restoration programs. An analysis of molecular variance (AMOVA) of 100 amplified fragment length polymorphism (AFLP) markers revealed significant genetic differentiation among populations (ΦPT = 0.18). Pairwise population genetic dissimilarity was correlated with geographic distance, but not environmental distance derived from 15 climate variables, suggesting overall neutrality of these markers with regard to these climate variables. Nevertheless, Bayesian outlier analysis identified four markers potentially under selection, although these were not correlated with the climate variables. We calculated a global R-statistic using analysis of similarities (ANOSIM) to test the statistical significance of population differentiation and to infer a threshold seed collection zone distance of ∼60 km (all markers) and 100 km (outlier markers) when genetic distance was regressed against geographic distance. Population pairs separated by >60 km were, on average, twice as likely to be significantly genetically differentiated than population pairs separated by <60 km, suggesting that habitat-matched sites within a 30-km radius around a restoration site genetically defines a local provenance seed collection zone for B. menziesii. Our approach is a novel probability-based practical solution for the delineation of a local seed collection zone to minimize negative genetic impacts in ecological restoration. PMID:23919158

Draft Test Guideline: Whole Sediment Acute Toxicity Invertebrates, Freshwater

EPA Pesticide Factsheets

The following draft test guideline is part of a series of test guidelines that have been developed by EPA for use in the testing of pesticides and toxic substances, and the development of test data for submission to the Agency for review.

Draft Test Guideline: Whole Sediment Acute Toxicity Invertebrates, Marine

EPA Pesticide Factsheets

The following draft test guideline is part of a series of test guidelines that have been developed by EPA for use in the testing of pesticides and toxic substances, and the development of test data for submission to the Agency for review.

Applications of pharmacogenomics in regulatory science: a product life cycle review.

PubMed

Tan-Koi, W C; Leow, P C; Teo, Y Y

2018-05-22

With rapid developments of pharmacogenomics (PGx) and regulatory science, it is important to understand the current PGx integration in product life cycle, impact on clinical practice thus far and opportunities ahead. We conducted a cross-sectional review on PGx-related regulatory documents and implementation guidelines in the United States and Europe. Our review found that although PGx-related guidance in both markets span across the entire product life cycle, the scope of implementation guidelines varies across two continents. Approximately one-third of Food and Drug Administration (FDA)-approved drugs with PGx information in drug labels and half of the European labels posted on PharmGKB website contain recommendations on genetic testing. The drugs affected 19 and 15 World Health Organization Anatomical Therapeutic Chemical drug classes (fourth level) in the United States and Europe, respectively, with protein kinase inhibitors (13 drugs in the United States and 16 drugs in Europe) being most prevalent. Topics of emerging interest were novel technologies, adaptive design in clinical trial and sample collection.

Factors precipitating acute ulcerative colitis.

PubMed

Puri, A S; Chaubal, C C; Midha, Vandana

2014-08-01

Ulcerative colitis is characterized by mucosal inflammation of a variable length of the colon starting from the rectum. The precise etiopathogenesis is unknown but it occurs in genetically susceptible individuals who manifest an abnormal immunological response against gut commensal bacteria. The disease course is-characterized by multiple spontaneous relapses and remissions. Two pathogens namely CMV and C. difficile have been associated with disease exacerbation in specific clinical situations. Whereas C. difficile may produce worsening of the disease in those exposed to broad spectrum antibiotics, CMV reactivation is seen only in patients with moderate to severe steroid refractory disease. The importance of these two super-infections can be gauged by the fact that both the ACG and the ECCO recommend testing for these two pathogens in appropriate clinical situations. The applicability of these guidelines in the Indian scenario has yet to be determined in view of the bacterial and parasitic infections endemic in tropical countries. The guidelines for diagnosis and management of these two super-infections in the presence of ulcerative colitis are discussed in this review.

Guidelines for testing and release procedures

NASA Technical Reports Server (NTRS)

Molari, R.; Conway, M.

1984-01-01

Guidelines and procedures are recommended for the testing and release of the types of computer software efforts commonly performed at NASA/Ames Research Center. All recommendations are based on the premise that testing and release activities must be specifically selected for the environment, size, and purpose of each individual software project. Guidelines are presented for building a Test Plan and using formal Test Plan and Test Care Inspections on it. Frequent references are made to NASA/Ames Guidelines for Software Inspections. Guidelines are presented for selecting an Overall Test Approach and for each of the four main phases of testing: (1) Unit Testing of Components, (2) Integration Testing of Components, (3) System Integration Testing, and (4) Acceptance Testing. Tools used for testing are listed, including those available from operating systems used at Ames, specialized tools which can be developed, unit test drivers, stub module generators, and the use of format test reporting schemes.

77 FR 22282 - Draft Guidelines on Biologics Quality Monitoring: Testing for the Detection of Mycoplasma...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-04-13

...] Draft Guidelines on Biologics Quality Monitoring: Testing for the Detection of Mycoplasma Contamination... Detection of Mycoplasma Contamination.'' This draft guideline identifies stages of manufacture where... contamination. Because the guidelines apply to final product and master seed/cell testing in veterinary vaccines...

Phylogeographic pattern suggests a general northeastward dispersal in the distribution of Machilus pauhoi in South China

PubMed Central

Zhu, Qin; Liao, Bo-Yong; Li, Pei; Li, Jun-Cheng; Deng, Xiao-Mei; Chen, Xiao-Yang

2017-01-01

Machilus pauhoi Kanehira is an important timber species in China. A provenance trial was recently set up to evaluate the growth performance of trees from different localities, with the aim of designing seed transfer guidelines. Here, we tested twelve nuclear microsatellite markers derived from other species of the Lauraceae family and investigated population genetic structure in M. pauhoi. Both the number of observed alleles per locus (Na) and the polymorphic information content (PIC) significantly decreased against the latitude, but showed an insignificant decrease against the longitude. Heterozygosity (Ho) and gene diversity (h) exhibited a weak correlation with geographic location. Private alleles were present in multiple populations, and a moderate level of population genetic differentiation was detected (Gst = 0.1691). The joint pattern of genetic diversity (Na, PIC, Ho, and h) suggests that general northeastward dispersal led to the current distribution of M. pauhoi. Significant but weak effects of isolation-by-distance (IBD) occurred, implicating the mountain ranges as the major barrier to gene flow. Both STRUCTURE and hierarchical clustering analyses showed three distinct groups of populations related to the physical connectivity among mountain ranges. A priority in designing genetic conservation should be given to the populations at the southwest side of the species’ distribution. This conservation strategy can also be combined with the pattern of adaptive genetic variation from the provenance trial for comprehensive genetic resource management of native M. pauhoi. PMID:28886133

Benefits, issues, and recommendations for personalized medicine in oncology in Canada.

PubMed

Butts, C; Kamel-Reid, S; Batist, G; Chia, S; Blanke, C; Moore, M; Sawyer, M B; Desjardins, C; Dubois, A; Pun, J; Bonter, K; Ashbury, F D

2013-10-01

The burden of cancer for Canadian citizens and society is large. New technologies have the potential to increase the use of genetic information in clinical decision-making, furthering prevention, surveillance, and safer, more effective drug therapies for cancer patients. Personalized medicine can have different meanings to different people. The context for personalized medicine in the present paper is genetic testing, which offers the promise of refining treatment decisions for those diagnosed with chronic and life-threatening illnesses. Personalized medicine and genetic characterization of tumours can also give direction to the development of novel drugs. Genetic testing will increasingly become an essential part of clinical decision-making. In Canada, provinces are responsible for health care, and most have unique policies and programs in place to address cancer control. The result is inconsistency in access to and delivery of therapies and other interventions, beyond the differences expected because of demographic factors and clinical education. Inconsistencies arising from differences in resources, policy, and application of evidence-informed personalized cancer medicine exacerbate patient access to appropriate testing and quality care. Geographic variations in cancer incidence and mortality rates in Canada-with the Atlantic provinces and Quebec having higher rates, and British Columbia having the lowest rates-are well documented. Our purpose here is to provide an understanding of current and future applications of personalized medicine in oncology, to highlight the benefits of personalized medicine for patients, and to describe issues and opportunities for improvement in the coordination of personalized medicine in Canada. Efficient and more rapid adoption of personalized medicine in oncology in Canada could help overcome those issues and improve cancer prevention and care. That task might benefit from the creation of a National Genetics Advisory Panel that would review research and provide recommendations on tests for funding or reimbursement, guidelines, service delivery models, laboratory quality assurance, education, and communication. More has to be known about the current state of personalized cancer medicine in Canada, and strategies have to be developed to inform and improve understanding and appropriate coordination and delivery. Our hope is that the perspectives emphasized in this paper will stimulate discussion and further research to create a more informed response.

Draft Test Guideline: Fish Acute Toxicity Mitigated By Humic Acid

EPA Pesticide Factsheets

The following draft test guideline is part of a series of test guidelines that have been developed by EPA for use in the testing of pesticides and toxic substances, and the development of test data for submission to the Agency for review.

Draft Test Guideline: Special Considerations for Conducting Aquatic Laboratory Studies

EPA Pesticide Factsheets

The following draft test guideline is part of a series of test guidelines that have been developed by EPA for use in the testing of pesticides and toxic substances, and the development of test data for submission to the Agency for review.

Review of achievements of the OECD Working Party on Manufactured Nanomaterials' Testing and Assessment Programme. From exploratory testing to test guidelines.

PubMed

Rasmussen, Kirsten; González, Mar; Kearns, Peter; Sintes, Juan Riego; Rossi, François; Sayre, Phil

2016-02-01

This paper charts the almost ten years of history of OECD's work on nanosafety, during which the programme of the OECD on the Testing and Assessment of Manufactured Nanomaterials covered the testing of eleven nanomaterials for about 59 end-points addressing physical-chemical properties, mammalian and environmental toxicity, environmental fate and material safety. An overview of the materials tested, the test methods applied and the discussions regarding the applicability of the OECD test guidelines, which are recognised methods for regulatory testing of chemicals, are given. The results indicate that many existing OECD test guidelines are suitable for nanomaterials and consequently, hazard data collected using such guidelines will fall under OECD's system of Mutual Acceptance of Data (MAD) which is a legally binding instrument to facilitate the international acceptance of information for the regulatory safety assessment of chemicals. At the same time, some OECD test guidelines and guidance documents need to be adapted to address nanomaterials while new test guidelines and guidance documents may be needed to address endpoints that are more relevant to nanomaterials. This paper presents examples of areas where test guidelines or guidance for nanomaterials are under development. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Development of a molecular test of Paget's disease of bone.

PubMed

Guay-Bélanger, Sabrina; Simonyan, David; Bureau, Alexandre; Gagnon, Edith; Albert, Caroline; Morissette, Jean; Siris, Ethel S; Orcel, Philippe; Brown, Jacques P; Michou, Laëtitia

2016-03-01

Depending on populations, 15 to 40% of patients have a familial form of Paget's disease of bone (PDB), which is transmitted in an autosomal-dominant mode of inheritance with incomplete penetrance. To date, only SQSTM1 gene mutations have been linked to the disease. Several single nucleotide polymorphisms (SNPs) have been associated with PDB in patient non-carriers of SQSTM1 mutations, but they have minor size effects. The current clinical practice guidelines still recommend to measure total serum alkaline phosphatase (sALP) for PDB screening. However, genetic or bone biomarkers alone may lack sensitivity to detect PDB. Thus, the objective of this study was to develop a molecular test of PDB, combining genetic and bone biomarkers, in order to detect PDB, which is frequently asymptomatic. We genotyped 35 SNPs previously associated with PDB in 305 patients, and 292 healthy controls. In addition, serum levels of 14 bone biomarkers were assayed in 51 patients and 151 healthy controls. Bivariate and multivariate logistic regression models with adjustment for age and sex were fitted to search for a combination of SNPs and/or bone biomarkers that could best detect PDB in patient non-carriers of SQSTM1 mutations. First, a combination of five genetic markers gave rise to the highest area under the ROC curve (AUC) with 95% confidence interval [95% CI] of 0.731 [0.688; 0.773], which allowed us to detect 81.5% of patients with PDB. Second, a combination of two bone biomarkers had an AUC of 0.822 [0.726; 0.918], and was present in 81.5% of patients with PDB. Then, the combination of the five genetic markers and the two bone biomarkers increased the AUC up to 0.892 [0.833; 0.951], and detected 88.5% of patients with PDB. These results suggested that an algorithm integrating first a screen for SQSTM1 gene mutations, followed by either a genetic markers combination or a combined genetic and biochemical markers test in patients non-carrier of any SQSTM1 mutation, may detect the PDB phenotype better than biomarkers already available in the clinical practice. Copyright © 2016 Amgen Inc. Published by Elsevier Inc. All rights reserved.

Computational allergenicity prediction of transgenic proteins expressed in genetically modified crops.

PubMed

Verma, Alok Kumar; Misra, Amita; Subash, Swarna; Das, Mukul; Dwivedi, Premendra D

2011-09-01

Development of genetically modified (GM) crops is on increase to improve food quality, increase harvest yields, and reduce the dependency on chemical pesticides. Before their release in marketplace, they should be scrutinized for their safety. Several guidelines of different regulatory agencies like ILSI, WHO Codex, OECD, and so on for allergenicity evaluation of transgenics are available and sequence homology analysis is the first test to determine the allergenic potential of inserted proteins. Therefore, to test and validate, 312 allergenic, 100 non-allergenic, and 48 inserted proteins were assessed for sequence similarity using 8-mer, 80-mer, and full FASTA search. On performing sequence homology studies, ~94% the allergenic proteins gave exact matches for 8-mer and 80-mer homology. However, 20 allergenic proteins showed non-allergenic behavior. Out of 100 non-allergenic proteins, seven qualified as allergens. None of the inserted proteins demonstrated allergenic behavior. In order to improve the predictability, proteins showing anomalous behavior were tested by Algpred and ADFS separately. Use of Algpred and ADFS softwares reduced the tendency of false prediction to a great extent (74-78%). In conclusion, routine sequence homology needs to be coupled with some other bioinformatic method like ADFS/Algpred to reduce false allergenicity prediction of novel proteins.

Psychological stress associated with cardiogenetic conditions.

PubMed

Hidayatallah, Nadia; Silverstein, Louise B; Stolerman, Marina; McDonald, Thomas; Walsh, Christine A; Paljevic, Esma; Cohen, Lilian L; Marion, Robert W; Wasserman, David; Hreyo, Sarah; Dolan, Siobhan M

2014-09-01

Genetic testing now makes it possible to identify specific mutations that may lead to life-threatening cardiac arrhythmias. This article presents data from a qualitative research study that explored the subjective experiences of individuals and families with cardiogenetic conditions. We focus on describing patients' experiences of psychological stresses associated with having a cardiogenetic condition, illustrating the importance of integrating psychological and medical care. This integration of care is particularly important as personalized genomic medicine continues to evolve and the implications of genetic testing have a profound effect on individuals and families. The researchers interviewed 50 participants from 32 families. The research team used a systematic, grounded theory procedure to code and analyze interview and focus group transcripts, incorporating multiple coders at several stages of the data analysis process. Three major themes emerged: a bereavement trajectory associated with sudden death in the absence of prior symptoms; high anxiety about transmitting a genetic mutation; and resilience reflected in positive lifestyle changes and participation in support groups. This article identifies patient perspectives on personalized genomic medicine in cardiogenetics that can improve clinical care, including: specialized bereavement counseling; improving education about cardiogenetic conditions for medical professionals; parent guidelines for discussing cardiogenetic conditions with their children; information about support groups; and the routine inclusion of clinical psychologists in interdisciplinary treatment teams. Given recent advances in technology and decreasing costs, whole-genome sequencing is likely to become common practice in the near future. Therefore, these recommendations are likely to be relevant for other genetic conditions, as well as the entire field of personalized genomic medicine.

Comparison of locus-specific databases for BRCA1 and BRCA2 variants reveals disparity in variant classification within and among databases.

PubMed

Vail, Paris J; Morris, Brian; van Kan, Aric; Burdett, Brianna C; Moyes, Kelsey; Theisen, Aaron; Kerr, Iain D; Wenstrup, Richard J; Eggington, Julie M

2015-10-01

Genetic variants of uncertain clinical significance (VUSs) are a common outcome of clinical genetic testing. Locus-specific variant databases (LSDBs) have been established for numerous disease-associated genes as a research tool for the interpretation of genetic sequence variants to facilitate variant interpretation via aggregated data. If LSDBs are to be used for clinical practice, consistent and transparent criteria regarding the deposition and interpretation of variants are vital, as variant classifications are often used to make important and irreversible clinical decisions. In this study, we performed a retrospective analysis of 2017 consecutive BRCA1 and BRCA2 genetic variants identified from 24,650 consecutive patient samples referred to our laboratory to establish an unbiased dataset representative of the types of variants seen in the US patient population, submitted by clinicians and researchers for BRCA1 and BRCA2 testing. We compared the clinical classifications of these variants among five publicly accessible BRCA1 and BRCA2 variant databases: BIC, ClinVar, HGMD (paid version), LOVD, and the UMD databases. Our results show substantial disparity of variant classifications among publicly accessible databases. Furthermore, it appears that discrepant classifications are not the result of a single outlier but widespread disagreement among databases. This study also shows that databases sometimes favor a clinical classification when current best practice guidelines (ACMG/AMP/CAP) would suggest an uncertain classification. Although LSDBs have been well established for research applications, our results suggest several challenges preclude their wider use in clinical practice.

Recent Trends in WRN Gene Mutation Patterns in Individuals with Werner Syndrome.

PubMed

Yamaga, Masaya; Takemoto, Minoru; Takada-Watanabe, Aki; Koizumi, Naoko; Kitamoto, Takumi; Sakamoto, Kenichi; Ishikawa, Takahiro; Koshizaka, Masaya; Maezawa, Yoshiro; Yokote, Koutaro

2017-08-01

To determine recent trends in mutation patterns in the WRN gene, which cause Werner syndrome (WS), a rare, inheritable progeroid syndrome in Japan. Retrospective cohort. Longitudinal survey of WS and literature search for case reports. Individuals whose genetic testing their facilities had requested between 2009 and October 2016 (N = 67). A nationwide epidemiological study was conducted from 2009 to 2011 to improve understanding of the pathology of WS and develop therapeutic guidelines. Since 2009, Chiba University Hospital consecutively evaluated the WRN gene in 67 individuals throughout Japan who had requested genetic testing. A literature search was also conducted for case reports on Japanese WS reported since 1997. A definitive diagnosis of WS was confirmed genetically in 50 of 67 participants. Through the literature search, 16 individuals diagnosed genetically with WS were identified. Of these 66 individuals with WS, 42 were homozygous for a WRN mutation, and 21 were compound heterozygotes. One novel mutant allele was identified in an individual with the compound heterozygous genotype. The proportion of compound heterozygotes (31.8%) was significantly greater than reported previously (14.2%), indicating that the incidence of consanguineous marriage of parents has decreased. The increased frequency of individuals with WS with the compound heterozygous genotype is a recent trend in Japan. A long-term follow-up study on WRN homozygotes and compound heterozygotes will allow the relationship between WRN genotype and clinical severity of WS to be evaluated in the future. © 2017, Copyright the Authors Journal compilation © 2017, The American Geriatrics Society.

Saliva as a diagnostic tool for oral and systemic diseases

PubMed Central

Javaid, Mohammad A.; Ahmed, Ahad S.; Durand, Robert; Tran, Simon D.

2015-01-01

Early disease detection is not only vital to reduce disease severity and prevent complications, but also critical to increase success rate of therapy. Saliva has been studied extensively as a potential diagnostic tool over the last decade due to its ease and non-invasive accessibility along with its abundance of biomarkers, such as genetic material and proteins. This review will update the clinician on recent advances in salivary biomarkers to diagnose autoimmune diseases (Sjogren's syndrome, cystic fibrosis), cardiovascular diseases, diabetes, HIV, oral cancer, caries and periodontal diseases. Considering their accuracy, efficacy, ease of use and cost effectiveness, salivary diagnostic tests will be available in dental offices. It is expected that the advent of sensitive and specific salivary diagnostic tools and the establishment of defined guidelines and results following rigorous testing will allow salivary diagnostics to be used as chair-side tests for several oral and systemic diseases in the near future. PMID:26937373

A Systematic Review on the Existing Screening Pathways for Lynch Syndrome Identification.

PubMed

Tognetto, Alessia; Michelazzo, Maria Benedetta; Calabró, Giovanna Elisa; Unim, Brigid; Di Marco, Marco; Ricciardi, Walter; Pastorino, Roberta; Boccia, Stefania

2017-01-01

Lynch syndrome (LS) is the most common hereditary colon cancer syndrome, accounting for 3-5% of colorectal cancer (CRC) cases, and it is associated with the development of other cancers. Early detection of individuals with LS is relevant, since they can take advantage of life-saving intensive care surveillance. The debate regarding the best screening policy, however, is far from being concluded. This prompted us to conduct a systematic review of the existing screening pathways for LS. We performed a systematic search of MEDLINE, ISI Web of Science, and SCOPUS online databases for the existing screening pathways for LS. The eligibility criteria for inclusion in this review required that the studies evaluated a structured and permanent screening pathway for the identification of LS carriers. The effectiveness of the pathways was analyzed in terms of LS detection rate. We identified five eligible studies. All the LS screening pathways started from CRC cases, of which three followed a universal screening approach. Concerning the laboratory procedures, the pathways used immunohistochemistry and/or microsatellite instability testing. If the responses of the tests indicated a risk for LS, the genetic counseling, performed by a geneticist or a genetic counselor, was mandatory to undergo DNA genetic testing. The overall LS detection rate ranged from 0 to 5.2%. This systematic review reported different existing pathways for the identification of LS patients. Although current clinical guidelines suggest to test all the CRC cases to identify LS cases, the actual implementation of pathways for LS identification has not been realized. Large-scale screening programs for LS have the potential to reduce morbidity and mortality for CRC, but coordinated efforts in educating all key stakeholders and addressing public needs are still required.

Quality of cancer family history and referral for genetic counseling and testing among oncology practices: a pilot test of quality measures as part of the American Society of Clinical Oncology Quality Oncology Practice Initiative.

PubMed

Wood, Marie E; Kadlubek, Pamela; Pham, Trang H; Wollins, Dana S; Lu, Karen H; Weitzel, Jeffrey N; Neuss, Michael N; Hughes, Kevin S

2014-03-10

Family history of cancer (CFH) is important for identifying individuals to receive genetic counseling/testing (GC/GT). Prior studies have demonstrated low rates of family history documentation and referral for GC/GT. CFH quality and GC/GT practices for patients with breast (BC) or colon cancer (CRC) were assessed in 271 practices participating in the American Society of Clinical Oncology Quality Oncology Practice Initiative in fall 2011. A total of 212 practices completed measures regarding CFH and GC/GT practices for 10,466 patients; 77.4% of all medical records reviewed documented presence or absence of CFH in first-degree relatives, and 61.5% of medical records documented presence or absence of CFH in second-degree relatives, with significantly higher documentation for patients with BC compared with CRC. Age at diagnosis was documented for all relatives with cancer in 30.7% of medical records (BC, 45.2%; CRC, 35.4%; P ≤ .001). Referall for GC/GT occurred in 22.1% of all patients with BC or CRC. Of patients with increased risk for hereditary cancer, 52.2% of patients with BC and 26.4% of those with CRC were referred for GC/GT. When genetic testing was performed, consent was documented 77.7% of the time, and discussion of results was documented 78.8% of the time. We identified low rates of complete CFH documentation and low rates of referral for those with BC or CRC meeting guidelines for referral among US oncologists. Documentation and referral were greater for patients with BC compared with CRC. Education and support regarding the importance of accurate CFH and the benefits of proactive high-risk patient management are clearly needed.

An analysis of pharmaceutical experience with decades of rat carcinogenicity testing: support for a proposal to modify current regulatory guidelines.

PubMed

Sistare, Frank D; Morton, Daniel; Alden, Carl; Christensen, Joel; Keller, Douglas; Jonghe, Sandra De; Storer, Richard D; Reddy, M Vijayaraj; Kraynak, Andrew; Trela, Bruce; Bienvenu, Jean-Guy; Bjurström, Sivert; Bosmans, Vanessa; Brewster, David; Colman, Karyn; Dominick, Mark; Evans, John; Hailey, James R; Kinter, Lewis; Liu, Matt; Mahrt, Charles; Marien, Dirk; Myer, James; Perry, Richard; Potenta, Daniel; Roth, Arthur; Sherratt, Philip; Singer, Thomas; Slim, Rabih; Soper, Keith; Fransson-Steen, Ronny; Stoltz, James; Turner, Oliver; Turnquist, Susan; van Heerden, Marjolein; Woicke, Jochen; DeGeorge, Joseph J

2011-06-01

Data collected from 182 marketed and nonmarketed pharmaceuticals demonstrate that there is little value gained in conducting a rat two-year carcinogenicity study for compounds that lack: (1) histopathologic risk factors for rat neoplasia in chronic toxicology studies, (2) evidence of hormonal perturbation, and (3) positive genetic toxicology results. Using a single positive result among these three criteria as a test for outcome in the two-year study, fifty-two of sixty-six rat tumorigens were correctly identified, yielding 79% test sensitivity. When all three criteria were negative, sixty-two of seventy-six pharmaceuticals (82%) were correctly predicted to be rat noncarcinogens. The fourteen rat false negatives had two-year study findings of questionable human relevance. Applying these criteria to eighty-six additional chemicals identified by the International Agency for Research on Cancer as likely human carcinogens and to drugs withdrawn from the market for carcinogenicity concerns confirmed their sensitivity for predicting rat carcinogenicity outcome. These analyses support a proposal to refine regulatory criteria for conducting a two-year rat study to be based on assessment of histopathologic findings from a rat six-month study, evidence of hormonal perturbation, genetic toxicology results, and the findings of a six-month transgenic mouse carcinogenicity study. This proposed decision paradigm has the potential to eliminate over 40% of rat two-year testing on new pharmaceuticals without compromise to patient safety.

Settling the score: variant prioritization and Mendelian disease

PubMed Central

Eilbeck, Karen; Quinlan, Aaron; Yandell, Mark

2018-01-01

When investigating Mendelian disease using exome or genome sequencing, distinguishing disease-causing genetic variants from the multitude of candidate variants is a complex, multidimensional task. Many prioritization tools and online interpretation resources exist, and professional organizations have offered clinical guidelines for review and return of prioritization results. In this Review, we describe the strengths and weaknesses of widely used computational approaches, explain their roles in the diagnostic and discovery process and discuss how they can inform (and misinform) expert reviewers. We place variant prioritization in the wider context of gene prioritization, burden testing and genotype–phenotype association, and we discuss opportunities and challenges introduced by whole-genome sequencing. PMID:28804138

Initial clinical validation of Health Heritage, a patient-facing tool for personal and family history collection and cancer risk assessment.

PubMed

Baumgart, Leigh A; Postula, Kristen J Vogel; Knaus, William A

2016-04-01

Personal and family health histories remain important independent risk factors for cancer; however they are currently not being well collected or used effectively. Health Heritage was designed to address this need. The purpose of this study was to validate the ability of Health Heritage to identify patients appropriate for further genetic evaluation and to accurately stratify cancer risk. A retrospective chart review was conducted on 100 random patients seen at an adult genetics clinic presenting with concern for an inherited predisposition to cancer. Relevant personal and family history obtained from the patients' medical records was entered into Health Heritage. Recommendations by Health Heritage were compared to national guidelines of eligibility for genetic evaluation. Agreement between Health Heritage referral for genetic evaluation and guideline eligibility for genetic evaluation was 97% (sensitivity 98% and specificity 88%). Risk stratification for cancer was also compared between Health Heritage and those documented by a geneticist. For patients at increased risk for breast, ovarian, or colorectal cancer as determined by the geneticist, risk stratification by Health Heritage agreed 90, 93, and 75%, respectively. Discordances in risk stratification were attributed to both complex situations better handled by the geneticist and Health Heritage's adherence to incorporating all information into its algorithms. Health Heritage is a clinically valid tool to identify patients appropriate for further genetic evaluation and to encourage them to confirm the assessment and management recommendations with cancer genetic experts. Health Heritage also provides an estimate of cancer risk that is complementary to a genetics team.

Access and benefits sharing of genetic resources and associated traditional knowledge in northern Canada: understanding the legal environment and creating effective research agreements

PubMed Central

Geary, Janis; Jardine, Cynthia G.; Guebert, Jenilee; Bubela, Tania

2013-01-01

Background Research in northern Canada focused on Aboriginal peoples has historically benefited academia with little consideration for the people being researched or their traditional knowledge (TK). Although this attitude is changing, the complexity of TK makes it difficult to develop mechanisms to preserve and protect it. Protecting TK becomes even more important when outside groups become interested in using TK or materials with associated TK. In the latter category are genetic resources, which may have commercial value and are the focus of this article. Objective This article addresses access to and use of genetic resources and associated TK in the context of the historical power-imbalances in research relationships in Canadian north. Design Review. Results Research involving genetic resources and TK is becoming increasingly relevant in northern Canada. The legal framework related to genetic resources and the cultural shift of universities towards commercial goals in research influence the environment for negotiating research agreements. Current guidelines for research agreements do not offer appropriate guidelines to achieve mutual benefit, reflect unequal bargaining power or take the relationship between parties into account. Conclusions Relational contract theory may be a useful framework to address the social, cultural and legal hurdles inherent in creating research agreements. PMID:23986896

Access and benefits sharing of genetic resources and associated traditional knowledge in northern Canada: understanding the legal environment and creating effective research agreements.

PubMed

Geary, Janis; Jardine, Cynthia G; Guebert, Jenilee; Bubela, Tania

2013-01-01

Research in northern Canada focused on Aboriginal peoples has historically benefited academia with little consideration for the people being researched or their traditional knowledge (TK). Although this attitude is changing, the complexity of TK makes it difficult to develop mechanisms to preserve and protect it. Protecting TK becomes even more important when outside groups become interested in using TK or materials with associated TK. In the latter category are genetic resources, which may have commercial value and are the focus of this article. This article addresses access to and use of genetic resources and associated TK in the context of the historical power-imbalances in research relationships in Canadian north. Review. Research involving genetic resources and TK is becoming increasingly relevant in northern Canada. The legal framework related to genetic resources and the cultural shift of universities towards commercial goals in research influence the environment for negotiating research agreements. Current guidelines for research agreements do not offer appropriate guidelines to achieve mutual benefit, reflect unequal bargaining power or take the relationship between parties into account. Relational contract theory may be a useful framework to address the social, cultural and legal hurdles inherent in creating research agreements.

Personalized medicine: is it a pharmacogenetic mirage?

PubMed Central

Shah, Rashmi R; Shah, Devron R

2012-01-01

The notion of personalized medicine has developed from the application of the discipline of pharmacogenetics to clinical medicine. Although the clinical relevance of genetically-determined inter-individual differences in pharmacokinetics is poorly understood, and the genotype-phenotype association data on clinical outcomes often inconsistent, officially approved drug labels frequently include pharmacogenetic information concerning the safety and/or efficacy of a number of drugs and refer to the availability of the pharmacogenetic test concerned. Regulatory authorities differ in their approach to these issues. Evidence emerging subsequently has generally revealed the pharmacogenetic information included in the label to be premature. Revised drugs labels, together with a flurry of other collateral activities, have raised public expectations of personalized medicine, promoted as ‘the right drug at the right dose the first time.’ These expectations place the prescribing physician in a dilemma and at risk of litigation, especially when evidence-based information on genotype-related dosing schedules is to all intent and purposes non-existent and guidelines, intended to improve the clinical utility of available pharmacogenetic information or tests, distance themselves from any responsibility. Lack of efficacy or an adverse drug reaction is frequently related to non-genetic factors. Phenoconversion, arising from drug interactions, poses another often neglected challenge to any potential success of personalized medicine by mimicking genetically-determined enzyme deficiency. A more realistic promotion of personalized medicine should acknowledge current limitations and emphasize that pharmacogenetic testing can only improve the likelihood of diminishing a specific toxic effect or increasing the likelihood of a beneficial effect and that application of pharmacogenetics to clinical medicine cannot adequately predict drug response in individual patients. PMID:22591598

Now Available – Final Test Guidelines for Ecological Effects

EPA Pesticide Factsheets

EPA's “Guidelines for Aquatic and Sediment-Dwelling Fauna, Aquatic Microcosm and Field Testing” are part of a series of test guidelines established by EPA for use in testing pesticides and other chemical substances.

76 FR 74063 - Mandatory Guidelines for Federal Workplace Drug Testing Programs

Federal Register 2010, 2011, 2012, 2013, 2014

2011-11-30

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Mandatory Guidelines for Federal Workplace Drug Testing... Federal Workplace Drug Testing Programs (Mandatory Guidelines), effective on October 1, 2010, addresses... for physicians performing a review of Federal employee drug testing results that seek approval by the...

Adherence to multiple cancer screening tests among women living in Appalachia Ohio

PubMed Central

Katz, Mira L.; Reiter, Paul L.; Young, Gregory S.; Pennell, Michael L.; Tatum, Cathy M.; Paskett, Electra D.

2015-01-01

Background There is a lack of information about the correlates of completing all three cancer screening tests among women living in Appalachia. Methods Cross-sectional telephone interviews were conducted (April-September 2013) among women (n=637) ages 51-75 from 12 Appalachia Ohio counties. Outcomes of within screening guidelines were verified by medical record. Multivariable logistic regression models identified correlates of being within guidelines for all three cancer screening tests. Results Screening rates were: mammography (32.1%), Pap test (36.1%), and a colorectal cancer test (30.1%). Only 8.6% of women were within guidelines for all tests. Having had a check-up in the past two years and having received a screening recommendation were significantly related to being within guidelines for all three tests (p<0.01). Participants with higher annual household incomes ($60,000+; OR=3.53, 95% CI: 1.49, 8.33) and conditions requiring regular medical visits (OR=3.16, 95% CI: 1.29, 7.74) were more likely to be within guidelines for all three screening tests. Conclusion Less than 10% of women had completed screening within guidelines for all three screening tests. Regular contact with the healthcare system and higher incomes were significant predictors of being within guidelines. Impact Within guidelines rates for the three recommended cancer screening tests is low among women in Appalachia Ohio. This finding illustrates the need for innovative interventions to improve rates of multiple cancer screening tests. PMID:26282630

[Gaucher disease--guidelines for diagnosis and management of adult patients].

PubMed

Merkler, Marijan; Simić, Iveta; Pećin, Ivan; Muacević-Katanec, Diana; Sucur, Nediljko; Reiner, Zeljko

2014-01-01

Gaucher disease is an autosomal recessive disorder, characterized by decreased levels of the lysosomal enzyme glucocerebrosidase. This deficiency results in a decreased breakdown of this glycosphingolipid glucocerebroside, which accumulates in the lysosomes of the monocyte-macrophage system. It is the most common form of sphingolipidosis. Clinically, the principle signs of Gaucher's disease are hepatosplenomegaly, bone involvement, hematological changes and CNS involvement. The diagnosis of Gaucher disease has to be confirmed by the measurement of the activity of the enzyme glucocerebrosidase in leukocytes or fibroblasts and genetic testing. An effective therapy for Gaucher disease has now been available for more than 10 years. It consists of life-long intravenous replacement of the deficient enzyme--glucocerebrosidase. If enzyme replacement therapy is started early enough, it leads to significant improvement in patient's general condition and quality of life. The aim of this document is to provide to the Croatian medical audience the guidelines for diagnosis and management of adult patients with Gaucher disease. These guidelines are produced by specialists who have long lasting experience with patients with rare metabolic diseases working in the Division of Metabolic Diseases, Department of Internal Medicine, University Hospital Center Zagreb which is the Referral Center for Rare and Metabolic diseases of the Ministry of Health, Republic of Croatia. They were endorsed by the Croatian Society for Rare Diseases, Croatian Medical Association. These are the first guidelines published in Croatia on diagnosis, treatment and follow-up of Gaucher disease.

RAI1 Alternate Probe Identifies Additional Breast Cancer Cases as Amplified Following Equivocal HER2 Fluorescence In Situ Hybridization Testing: Experience From a National Reference Laboratory.

PubMed

Hui, Ling; Geiersbach, Katherine B; Downs-Kelly, Erinn; Gulbahce, H Evin

2017-02-01

-In 2013 the American Society of Clinical Oncology and College of American Pathologists updated the HER2 guidelines and changed the equivocal category for HER2 in situ hybridization testing to an average HER2 copy number of 4.0 to 5.9 with a HER2:CEP17 ratio of less than 2.0 and proposed retesting, with an option of using another control probe to avoid false-negative results. RAI1, located at band position 17p11.2, is a popular alternate probe locus for retesting equivocal changes. -To review experience with the RAI1 alternate probe in HER2 fluorescence in situ hybridization equivocal breast cancers. -Primary and metastatic breast cancers with equivocal HER2 fluorescence in situ hybridization, retested with an alternate (RAI1) probe, were identified. HER2, RAI1, and CEP17 copy numbers, HER2 to control probe ratios, and genetic heterogeneity were recorded. Hematoxylin-eosin-stained slides were reviewed for type and grade of cancer. -Of 876 cases tested with CEP17 as the reference probe, 97 (11.1%) had equivocal HER2 fluorescence in situ hybridization results. Additional testing with the RAI1 probe classified 39.2% cases (38 of 97) as amplified with a HER2:RAI1 ratio ranging from 2.0 to 3.2 (mean, 2.37); 3.1% (3 of 97) were still unclassifiable because of a deletion of RAI1. -RAI1 identified close to 40% of original HER2 fluorescence in situ hybridization equivocal cases as amplified, making these patients eligible for targeted therapies. It is not known whether guidelines for US Food and Drug Administration-approved probes can be extrapolated to alternate probes when an alternate control probe shows losses or gains. Because of the lack of guidelines for reporting HER2 status with alternate probes, laboratories face challenges in interpreting results.

Primary care physician management, referral, and relations with specialists concerning patients at risk for cancer due to family history.

PubMed

Wood, M E; Flynn, B S; Stockdale, A

2013-01-01

Risk stratification based on family history is a feature of screening guidelines for a number of cancers and referral guidelines for genetic counseling/testing for cancer risk. Our aim was to describe primary care physician perceptions of their role in managing cancer risk based on family history. Structured interviews were conducted by a medical anthropologist with primary care physicians in 3 settings in 2 north-eastern states. Transcripts were systematically analyzed by a research team to identify major themes expressed by participants. Forty interviews were conducted from May 2003 through May 2006. Physicians provided a diversity of views on roles in management of cancer risk based on family history, management practices and patient responses to risk information. They also provided a wide range of perspectives on criteria used for referral to specialists, types of specialists referred to and expected management roles for referred patients. Some primary care physicians appeared to make effective use of family history information for cancer risk management, but many in this sample did not. Increased focus on efficient assessment tools based on recognized guidelines, accessible guides to management options, and patient education and decision aids may be useful directions to facilitate broader use of family history information for cancer risk management. Copyright © 2013 S. Karger AG, Basel.

76 FR 57031 - Draft Harmonized Test Guidelines; Notice of Availability and Request for Comments

Federal Register 2010, 2011, 2012, 2013, 2014

2011-09-15

...EPA is announcing the availability of the draft test guidelines for Series 810--Product Performance Test Guidelines for Public Health Uses of Antimicrobial Agents, concerning specifically air, textiles, and water.

78 FR 2675 - Mandatory Guidelines for Federal Workplace Drug Testing Programs

Federal Register 2010, 2011, 2012, 2013, 2014

2013-01-14

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Mandatory Guidelines for Federal Workplace Drug Testing... Federal Workplace Drug Testing Programs (Mandatory Guidelines), effective on October 1, 2010, addresses... performing a review of Federal employee drug testing results that seek approval by the Secretary must submit...

75 FR 76478 - Mandatory Guidelines for Federal Workplace Drug Testing Programs

Federal Register 2010, 2011, 2012, 2013, 2014

2010-12-08

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Mandatory Guidelines for Federal Workplace Drug Testing... Drug Testing Programs (Mandatory Guidelines) which took effect on October 1, 2010 address the role and... Federal employee drug testing results that seek approval by the Secretary must submit their qualifications...

Genetic Testing in Pancreatic Ductal Adenocarcinoma: Implications for Prevention and Treatment.

PubMed

Peters, Mary Linton B; Tseng, Jennifer F; Miksad, Rebecca A

2016-07-01

This article reviews the progress to date and future directions for investigation of germline and somatic genetic testing to inform pancreatic adenocarcinoma (PDAC) treatment, screening, and prevention strategies. We searched PubMed to identify recent articles regarding genetic testing in pancreatic cancer, including both germline and somatic testing, and recent genome-wide association studies. References were specifically hand searched as relevant. Guidelines for testing and screening high-risk individuals were included. We searched clinicaltrials.gov to review the current landscape of active clinical trials. Approximately 10% of PDACs are associated with an identified germline mutation. Although germline mutations may inform treatment options and identify high-risk individuals for screening in other cancers, the data on PDAC are only now emerging. For example, poly adenosine diphosphate ribose polymerase (PARP) inhibitors are under investigation for BRCA-associated PDAC. Somatic mutations have also been identified in PDAC. However, current data are limited regarding treatment for potential PDAC somatic driver mutations. Although erlotinib is used in PDAC, its use is not targeted based on a tumor marker. Many tyrosine kinase inhibitors targeted toward potential driver mutations and critical pathways are in development, including BRAF/MEK, ALK, and CDK4/6. A consensus on screening strategies for individuals at high risk for PDAC is still evolving because of the relatively low prevalence of the disease, the relative invasiveness of endoscopic procedures often used as part of screening, and the lack of a clear survival benefit. Pancreatic cancer has been slower to move toward genomic testing, partially because of a lower prevalence of mutations and partially because of a limited effect of results on treatment choices outside a clinical trial. This is an area of active investigation, and we anticipate that there will be both preventive and therapeutic implications of driver mutations in the coming decade. Copyright © 2016 Elsevier HS Journals, Inc. All rights reserved.

Behavioral assays with mouse models of Alzheimer’s disease: practical considerations and guidelines

PubMed Central

Puzzo, Daniela; Lee, Linda; Palmeri, Agostino; Calabrese, Giorgio; Arancio, Ottavio

2014-01-01

In Alzheimer’s disease (AD) basic research and drug discovery, mouse models are essential resources for uncovering biological mechanisms, validating molecular targets and screening potential compounds. Both transgenic and non-genetically modified mouse models enable access to different types of AD-like pathology in vivo. Although there is a wealth of genetic and biochemical studies on proposed AD pathogenic pathways, as a disease that centrally features cognitive failure, the ultimate readout for any interventions should be measures of learning and memory. This is particularly important given the lack of knowledge on disease etiology – assessment by cognitive assays offers the advantage of targeting relevant memory systems without requiring assumptions about pathogenesis. A multitude of behavioral assays are available for assessing cognitive functioning in mouse models, including ones specific for hippocampal-dependent learning and memory. Here we review the basics of available transgenic and non-transgenic AD mouse models and detail three well-established behavioral tasks commonly used for testing hippocampal-dependent cognition in mice – contextual fear conditioning, radial arm water maze and Morris water maze. In particular, we discuss the practical considerations, requirements and caveats of these behavioral testing paradigms. PMID:24462904

Decision making about healthcare-related tests and diagnostic test strategies. Paper 4: International guidelines show variability in their approaches.

PubMed

Mustafa, Reem A; Wiercioch, Wojtek; Arevalo-Rodriguez, Ingrid; Cheung, Adrienne; Prediger, Barbara; Ivanova, Liudmila; Ventresca, Matthew; Brozek, Jan; Santesso, Nancy; Bossuyt, Patrick; Garg, Amit X; Lloyd, Nancy; Lelgemann, Monika; Bühler, Diedrich; Schünemann, Holger J

2017-12-01

The objective of the study was to describe and compare current practices in developing guidelines about the use of healthcare-related tests and diagnostic strategies (HCTDS). We sampled 37 public health and clinical practice guidelines about HCTDS from various sources without language restrictions. Detailed descriptions of the systems used to assess the quality of evidence and develop recommendations were challenging to find within guidelines. We observed much variability among and within organizations with respect to how they develop recommendations about HCTDS. Twenty-four percent of the guidelines did not consider health benefits and harms but based decisions solely on test accuracy. We did not identify guidelines that described the main potential care pathways involving tests for a healthcare problem. In addition, we did not identify guidelines that systematically assessed, described, and referenced the evidence that linked test accuracy and patient-important outcomes. There is considerable variability among the processes used and factors considered in developing recommendations about the use of tests. This variability may be the cause for the disagreement we observed in recommendations about testing for the same condition. Copyright © 2017 Elsevier Inc. All rights reserved.

Current surgical management of carotid body tumors.

PubMed

Davila, Victor J; Chang, James M; Stone, William M; Fowl, Richard J; Bower, Thomas C; Hinni, Michael L; Money, Samuel R

2016-12-01

Carotid body tumors (CBTs) are rare. Management guidelines may include genetic testing for succinate dehydrogenase (SDH) mutations. We performed an institutional review of the surgical management of CBT. A retrospective analysis (1994-2015) of CBT excisions at our institution was performed. Data obtained included demographics, genetic testing (if performed), intraoperative details, postoperative morbidity, and long-term outcomes. Data from the first CBT excision were included in patients with bilateral tumors. Genetic testing was routinely offered in patients with a family history of CBT or multiple paragangliomas. A total of 183 CBTs (124 female [67.7%]) were excised. A neck mass was present in 106 patients (57.9%), 24 patients (12.1%) presented with tenderness or neck pain, and 3 (1.6%) presented with cranial nerve dysfunction. Computed tomography (57.9%) or magnetic resonance imaging (51.3%) were the most commonly used imaging modalities. Preoperative angiography was performed in 73 patients (39.8%), and 62 of them (84.5%) underwent embolization or internal carotid balloon occlusion testing, or both. Mean tumor diameter was 3.2 cm (range, 0.6-7.2 cm). There were 71 (38.8%), 75 (41%), and 37 (20.2%) Shamblin type 1, 2, and 3 tumors, respectively. Average operating time was 224 minutes (range, 52-696 minutes). Average blood loss was 143.9 mL (range, 10-2000 mL). Arterial reconstruction with an interposition graft was required in 10, and patch angioplasty was performed in four. Cranial nerve injury was permanent in 10 (5.5%), and the rate of stroke was 1% (n = 2). A total of 382 lymph nodes were excised, and all were benign. There were no deaths ≤30 days. Only one patient presented with malignant disease 2 years after CBT excision, and this patient did not undergo genetic testing. Thirty-four (18.6%) had a family history of CBT. SDH testing was performed in 18 patients, and 17 tested positive. Positive genetic testing had a correlation with earlier age at operation (P < .0001). Mean age at diagnosis of patients with SDH mutations was 38.0 years, and patients without known SDH mutations presented at a mean age of 50.3 years. In patients with SDH mutations, tumor diameter, operating time, blood loss, and distribution of Shamblin type 1, 2, and 3 lesions were not significantly different compared with the control group. CBT can be treated with minimal morbidity and mortality; however, the subgroup of patients with positive SDH mutations may represent a variant group of younger patients. Vascular surgeons should be aware of genetic testing to identify patients and family members who should undergo additional preoperative testing and monitoring for other paragangliomas. Concomitant lymph node dissection does not appear to add value in absence of clinic suspicion for malignancy. Copyright © 2016. Published by Elsevier Inc.

An Official American Thoracic Society Clinical Practice Guideline: Classification, Evaluation, and Management of Childhood Interstitial Lung Disease in Infancy

PubMed Central

Kurland, Geoffrey; Deterding, Robin R.; Hagood, James S.; Young, Lisa R.; Brody, Alan S.; Castile, Robert G.; Dell, Sharon; Fan, Leland L.; Hamvas, Aaron; Hilman, Bettina C.; Langston, Claire; Nogee, Lawrence M.; Redding, Gregory J.

2013-01-01

Background: There is growing recognition and understanding of the entities that cause interstitial lung disease (ILD) in infants. These entities are distinct from those that cause ILD in older children and adults. Methods: A multidisciplinary panel was convened to develop evidence-based guidelines on the classification, diagnosis, and management of ILD in children, focusing on neonates and infants under 2 years of age. Recommendations were formulated using a systematic approach. Outcomes considered important included the accuracy of the diagnostic evaluation, complications of delayed or incorrect diagnosis, psychosocial complications affecting the patient’s or family’s quality of life, and death. Results: No controlled clinical trials were identified. Therefore, observational evidence and clinical experience informed judgments. These guidelines: (1) describe the clinical characteristics of neonates and infants (<2 yr of age) with diffuse lung disease (DLD); (2) list the common causes of DLD that should be eliminated during the evaluation of neonates and infants with DLD; (3) recommend methods for further clinical investigation of the remaining infants, who are regarded as having “childhood ILD syndrome”; (4) describe a new pathologic classification scheme of DLD in infants; (5) outline supportive and continuing care; and (6) suggest areas for future research. Conclusions: After common causes of DLD are excluded, neonates and infants with childhood ILD syndrome should be evaluated by a knowledgeable subspecialist. The evaluation may include echocardiography, controlled ventilation high-resolution computed tomography, infant pulmonary function testing, bronchoscopy with bronchoalveolar lavage, genetic testing, and/or lung biopsy. Preventive care, family education, and support are essential. PMID:23905526

75 FR 4380 - Draft Test Guidelines; Notice of Availability and Request for Comments

Federal Register 2010, 2011, 2012, 2013, 2014

2010-01-27

... ENVIRONMENTAL PROTECTION AGENCY [EPA-HQ-OPP-2009-0681; FRL-8437-2] Draft Test Guidelines; Notice...: Notice. SUMMARY: EPA is announcing the availability of four draft test guidelines for Product Performance... holidays. The Docket Facility telephone number is (703) 305-5805. Electronic access to the OPPTS Test...

APA's Guidelines for Test User Qualifications: An Executive Summary.

ERIC Educational Resources Information Center

Turner, Samuel M.; DeMers, Stephen T.; Fox, Heather Roberts; Reed, Geoffrey M.

2001-01-01

Describes the American Psychological Association's (APA's) development of the Task Force on Test User Qualifications, explaining the APA's purpose in developing guidelines for the use of psychological tests. Highlights the historical background, the scope of the guidelines, generic knowledge and skills considered important for good test use, and…

75 FR 22809 - Mandatory Guidelines for Federal Workplace Drug Testing Programs

Federal Register 2010, 2011, 2012, 2013, 2014

2010-04-30

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Mandatory Guidelines for Federal Workplace Drug Testing... for Federal Workplace Drug Testing Programs (Mandatory Guidelines) from May 1, 2010, to October 1... drug testing programs as soon as possible that they will not be expected to implement the revisions to...

Genetic variation and seed transfer guidelines for ponderosa pine in central Oregon.

Treesearch

Frank C. Sorensen

1994-01-01

Adaptive genetic variation in seed and seedling traits for ponderosa pine from the east slopes of the Cascade Range in Oregon was analyzed by using 307 families from 227 locations. Factor scores from three principal components based on seed and seedling traits were related by multiple regression to latitude, distance from the Cascade crest, elevation, slope, and...

EFHC1 variants in juvenile myoclonic epilepsy: reanalysis according to NHGRI and ACMG guidelines for assigning disease causality.

PubMed

Bailey, Julia N; Patterson, Christopher; de Nijs, Laurence; Durón, Reyna M; Nguyen, Viet-Huong; Tanaka, Miyabi; Medina, Marco T; Jara-Prado, Aurelio; Martínez-Juárez, Iris E; Ochoa, Adriana; Molina, Yolli; Suzuki, Toshimitsu; Alonso, María E; Wight, Jenny E; Lin, Yu-Chen; Guilhoto, Laura; Targas Yacubian, Elza Marcia; Machado-Salas, Jesús; Daga, Andrea; Yamakawa, Kazuhiro; Grisar, Thierry M; Lakaye, Bernard; Delgado-Escueta, Antonio V

2017-02-01

EFHC1 variants are the most common mutations in inherited myoclonic and grand mal clonic-tonic-clonic (CTC) convulsions of juvenile myoclonic epilepsy (JME). We reanalyzed 54 EFHC1 variants associated with epilepsy from 17 cohorts based on National Human Genome Research Institute (NHGRI) and American College of Medical Genetics and Genomics (ACMG) guidelines for interpretation of sequence variants. We calculated Bayesian LOD scores for variants in coinheritance, unconditional exact tests and odds ratios (OR) in case-control associations, allele frequencies in genome databases, and predictions for conservation/pathogenicity. We reviewed whether variants damage EFHC1 functions, whether efhc1 -/- KO mice recapitulate CTC convulsions and "microdysgenesis" neuropathology, and whether supernumerary synaptic and dendritic phenotypes can be rescued in the fly model when EFHC1 is overexpressed. We rated strengths of evidence and applied ACMG combinatorial criteria for classifying variants. Nine variants were classified as "pathogenic," 14 as "likely pathogenic," 9 as "benign," and 2 as "likely benign." Twenty variants of unknown significance had an insufficient number of ancestry-matched controls, but ORs exceeded 5 when compared with racial/ethnic-matched Exome Aggregation Consortium (ExAC) controls. NHGRI gene-level evidence and variant-level evidence establish EFHC1 as the first non-ion channel microtubule-associated protein whose mutations disturb R-type VDCC and TRPM2 calcium currents in overgrown synapses and dendrites within abnormally migrated dislocated neurons, thus explaining CTC convulsions and "microdysgenesis" neuropathology of JME.Genet Med 19 2, 144-156.

MYSID TWO-GENERATION TEST GUIDELINE

EPA Science Inventory

McKenney, Charles L., Jr. In press. Mysid Two-Generation Test Guideline. OECD Expert Group on Invertebrate Testing for Endocrine Disruptors, Organisation for Economic Co-operation and Development, Paris, France. 17 p. (ERL,GB 1215).

This guideline describes a two-generati...

The improvement of the best practice guidelines for preimplantation genetic diagnosis of cystic fibrosis: toward an international consensus.

PubMed

Girardet, Anne; Viart, Victoria; Plaza, Stéphanie; Daina, Gemma; De Rycke, Martine; Des Georges, Marie; Fiorentino, Francesco; Harton, Gary; Ishmukhametova, Aliya; Navarro, Joaquima; Raynal, Caroline; Renwick, Pamela; Saguet, Florielle; Schwarz, Martin; SenGupta, Sioban; Tzetis, Maria; Roux, Anne-Françoise; Claustres, Mireille

2016-04-01

Cystic fibrosis (CF) is one of the most common indications for preimplantation genetic diagnosis (PGD) for single gene disorders, giving couples the opportunity to conceive unaffected children without having to consider termination of pregnancy. However, there are no available standardized protocols, so that each center has to develop its own diagnostic strategies and procedures. Furthermore, reproductive decisions are complicated by the diversity of disease-causing variants in the CFTR (cystic fibrosis transmembrane conductance regulator) gene and the complexity of correlations between genotypes and associated phenotypes, so that attitudes and practices toward the risks for future offspring can vary greatly between countries. On behalf of the EuroGentest Network, eighteen experts in PGD and/or molecular diagnosis of CF from seven countries attended a workshop held in Montpellier, France, on 14 December 2011. Building on the best practice guidelines for amplification-based PGD established by ESHRE (European Society of Human Reproduction and Embryology), the goal of this meeting was to formulate specific guidelines for CF-PGD in order to contribute to a better harmonization of practices across Europe. Different topics were covered including variant nomenclature, inclusion criteria, genetic counseling, PGD strategy and reporting of results. The recommendations are summarized here, and updated information on the clinical significance of CFTR variants and associated phenotypes is presented.

Ninety-day oral toxicity studies on two genetically modified maize MON810 varieties in Wistar Han RCC rats (EU 7th Framework Programme project GRACE).

PubMed

Zeljenková, Dagmar; Ambrušová, Katarína; Bartušová, Mária; Kebis, Anton; Kovrižnych, Jevgenij; Krivošíková, Zora; Kuricová, Miroslava; Líšková, Aurélia; Rollerová, Eva; Spustová, Viera; Szabová, Elena; Tulinská, Jana; Wimmerová, Soňa; Levkut, Mikuláš; Révajová, Viera; Ševčíková, Zuzana; Schmidt, Kerstin; Schmidtke, Jörg; La Paz, Jose Luis; Corujo, Maria; Pla, Maria; Kleter, Gijs A; Kok, Esther J; Sharbati, Jutta; Hanisch, Carlos; Einspanier, Ralf; Adel-Patient, Karine; Wal, Jean-Michel; Spök, Armin; Pöting, Annette; Kohl, Christian; Wilhelm, Ralf; Schiemann, Joachim; Steinberg, Pablo

2014-12-01

The GMO Risk Assessment and Communication of Evidence (GRACE; www.grace-fp7.eu ) project is funded by the European Commission within the 7th Framework Programme. A key objective of GRACE is to conduct 90-day animal feeding trials, animal studies with an extended time frame as well as analytical, in vitro and in silico studies on genetically modified (GM) maize in order to comparatively evaluate their use in GM plant risk assessment. In the present study, the results of two 90-day feeding trials with two different GM maize MON810 varieties, their near-isogenic non-GM varieties and four additional conventional maize varieties are presented. The feeding trials were performed by taking into account the guidance for such studies published by the EFSA Scientific Committee in 2011 and the OECD Test Guideline 408. The results obtained show that the MON810 maize at a level of up to 33 % in the diet did not induce adverse effects in male and female Wistar Han RCC rats after subchronic exposure, independently of the two different genetic backgrounds of the event.

The genetic polymorphism of merozoite surface protein-1 in Plasmodium falciparum isolates from Aceh province, Indonesia

NASA Astrophysics Data System (ADS)

Jamil, K. F.; Supargiyono, S.; Syafruddin, D.; Pratama, N.; Silvy, S.

2018-03-01

An estimated of 3.3 million Indonesian population were infected with malaria. However, extensive genetic polymorphism of the field isolates msp-1 of P. falciparum represents a major obstacle for the development of malaria treatment. The aim of this study was to investigate the genetic diversity of msp-1 genotype in field isolates of P. falciparum collected in Aceh Province. A total of 90 patients with malaria (+) were selected from eleven district hospitals in Aceh from 2013-2015. Data were collected by anamnesis, complete physical examination and laboratory tests for msp-1. All protocols to diagnose malaria followed the WHO 2010 guideline. All samples were stored in Eijkman Biology Molecular Institute, Jakarta. Among 90 samples, 57.7% were male, and 42.3% were female with the most cases found between 21-30 years old. From the allele typing analysis of P. falciparum from Aceh; K1, MAD20, and RO33 allele types were identified. MAD20 type was the highest allele found in this study (57.9%). It was found in single and mixed infection. A moderate level of the mixed allele was also observed.

Identification and management of women with a family history of breast cancer

PubMed Central

Heisey, Ruth; Carroll, June C.

2016-01-01

Abstract Objective To summarize the best evidence on strategies to identify and manage women with a family history of breast cancer. Sources of information A PubMed search was conducted using the search terms breast cancer, guidelines, risk, family history, management, and magnetic resonance imaging screening from 2000 to 2016. Most evidence is level II. Main message Taking a good family history is essential when assessing breast cancer risk in order to identify women suitable for referral to a genetic counselor for possible genetic testing. Offering risk-reducing surgery (bilateral prophylactic mastectomy, bilateral salpingo-oophorectomy) to women with BRCA genetic mutations can save lives. All women with a family history of breast cancer should be encouraged to stay active and limit alcohol intake to less than 1 drink per day; some will qualify for chemoprevention. Women with a 20% to 25% or greater lifetime risk of breast cancer should be offered enhanced screening with annual magnetic resonance imaging in addition to mammography. Conclusion Healthy living and chemoprevention (for suitable women) could reduce breast cancer incidence; enhanced screening could result in earlier detection. Referring women who carry BRCA mutations for risk-reducing surgery will save lives. PMID:27737975

Drug Development Pipeline

MedlinePlus

... Care Guidelines Newborn Screening Clinical Care Guidelines Sweat Test Clinical Care Guidelines Infection Prevention and Control Care Guidelines Allergic Bronchopulmonary Aspergillosis Clinical Care Guidelines ...

77 FR 38282 - Final Test Guidelines; OCSPP 850 Series; Notice of Availability

Federal Register 2010, 2011, 2012, 2013, 2014

2012-06-27

... conditions. EPA is changing the title of OPPTS 850.4450 ``Aquatic Plants Field Study, Tier III'' test....4300 ``Terrestrial Plants Field Study, Tier III'' test guideline. Public Draft OPPTS 850.4025 ``Target..., OCSPP 850.4300 ``Terrestrial Plants Field Study.'' The target area test guideline covers a special case...

75 FR 75485 - Current List of Laboratories Which Meet Minimum Standards To Engage in Urine Drug Testing for...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-12-03

... Current List of Laboratories Which Meet Minimum Standards To Engage in Urine Drug Testing for Federal... Guidelines for Federal Workplace Drug Testing Programs (Mandatory Guidelines). The Mandatory Guidelines were... Laboratories and Instrumented Initial Testing Facilities (IITF) must meet in order to conduct drug and specimen...

Drug Testing Guidelines and Practices for Juvenile Probation and Parole Agencies.

ERIC Educational Resources Information Center

American Probation and Parole Association, Lexington, KY.

This document, intended as a resource manual, provides guidelines on drug testing. These topics are covered: (1) National Institute on Drug Abuse guidelines applicability; (2) introduction to legal issues, drug testing in juvenile probation and parole, and juvenile law; (3) mission of a juvenile parole agency; (4) purpose of testing; (5) drug…

75 FR 62842 - Current List of Laboratories Which Meet Minimum Standards To Engage in Urine Drug Testing for...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-10-13

... Current List of Laboratories Which Meet Minimum Standards To Engage in Urine Drug Testing for Federal... Guidelines for Federal Workplace Drug Testing Programs (Mandatory Guidelines). The Mandatory Guidelines were... and Instrumented Initial Testing Facilities (IITF) must meet in order to conduct drug and specimen...

ITC Guidelines on Quality Control in Scoring, Test Analysis, and Reporting of Test Scores

ERIC Educational Resources Information Center

Allalouf, Avi

2014-01-01

The Quality Control (QC) Guidelines are intended to increase the efficiency, precision, and accuracy of the scoring, analysis, and reporting process of testing. The QC Guidelines focus on large-scale testing operations where multiple forms of tests are created for use on set dates. However, they may also be used for a wide variety of other testing…

Safety Assessment of Food and Feed from GM Crops in Europe: Evaluating EFSA's Alternative Framework for the Rat 90-day Feeding Study.

PubMed

Hong, Bonnie; Du, Yingzhou; Mukerji, Pushkor; Roper, Jason M; Appenzeller, Laura M

2017-07-12

Regulatory-compliant rodent subchronic feeding studies are compulsory regardless of a hypothesis to test, according to recent EU legislation for the safety assessment of whole food/feed produced from genetically modified (GM) crops containing a single genetic transformation event (European Union Commission Implementing Regulation No. 503/2013). The Implementing Regulation refers to guidelines set forth by the European Food Safety Authority (EFSA) for the design, conduct, and analysis of rodent subchronic feeding studies. The set of EFSA recommendations was rigorously applied to a 90-day feeding study in Sprague-Dawley rats. After study completion, the appropriateness and applicability of these recommendations were assessed using a battery of statistical analysis approaches including both retrospective and prospective statistical power analyses as well as variance-covariance decomposition. In the interest of animal welfare considerations, alternative experimental designs were investigated and evaluated in the context of informing the health risk assessment of food/feed from GM crops.

Fuzzy-logic based strategy for validation of multiplex methods: example with qualitative GMO assays.

PubMed

Bellocchi, Gianni; Bertholet, Vincent; Hamels, Sandrine; Moens, W; Remacle, José; Van den Eede, Guy

2010-02-01

This paper illustrates the advantages that a fuzzy-based aggregation method could bring into the validation of a multiplex method for GMO detection (DualChip GMO kit, Eppendorf). Guidelines for validation of chemical, bio-chemical, pharmaceutical and genetic methods have been developed and ad hoc validation statistics are available and routinely used, for in-house and inter-laboratory testing, and decision-making. Fuzzy logic allows summarising the information obtained by independent validation statistics into one synthetic indicator of overall method performance. The microarray technology, introduced for simultaneous identification of multiple GMOs, poses specific validation issues (patterns of performance for a variety of GMOs at different concentrations). A fuzzy-based indicator for overall evaluation is illustrated in this paper, and applied to validation data for different genetically modified elements. Remarks were drawn on the analytical results. The fuzzy-logic based rules were shown to be applicable to improve interpretation of results and facilitate overall evaluation of the multiplex method.

Genetically modified foods and social concerns.

PubMed

Maghari, Behrokh Mohajer; Ardekani, Ali M

2011-07-01

Biotechnology is providing us with a wide range of options for how we can use agricultural and commercial forestry lands. The cultivation of genetically modified (GM) crops on millions of hectares of lands and their injection into our food chain is a huge global genetic experiment involving all living beings. Considering the fast pace of new advances in production of genetically modified crops, consumers, farmers and policymakers worldwide are challenged to reach a consensus on a clear vision for the future of world food supply. The current food biotechnology debate illustrates the serious conflict between two groups: 1) Agri-biotech investors and their affiliated scientists who consider agricultural biotechnology as a solution to food shortage, the scarcity of environmental resources and weeds and pests infestations; and 2) independent scientists, environmentalists, farmers and consumers who warn that genetically modified food introduces new risks to food security, the environment and human health such as loss of biodiversity; the emergence of superweeds and superpests; the increase of antibiotic resistance, food allergies and other unintended effects. This article reviews major viewpoints which are currently debated in the food biotechnology sector in the world. It also lays the ground-work for deep debate on benefits and risks of Biotech-crops for human health, ecosystems and biodiversity. In this context, although some regulations exist, there is a need for continuous vigilance for all countries involved in producing genetically engineered food to follow the international scientific bio-safety testing guidelines containing reliable pre-release experiments and post-release track of transgenic plants to protect public health and avoid future environmental harm.

Approaching confidentiality at a familial level in genomic medicine: a focus group study with healthcare professionals

PubMed Central

Dheensa, Sandi; Fenwick, Angela; Lucassen, Anneke

2017-01-01

Objectives Clinical genetics guidelines from 2011 conceptualise genetic information as confidential to families, not individuals. The normative consequence of this is that the family's interest is the primary consideration and genetic information is shared unless there are good reasons not to do so. We investigated healthcare professionals' (HCPs') views about, and reasoning around, individual and familial approaches to confidentiality and how such views influenced their practice. Method 16 focus groups with 80 HCPs working in/with clinical genetics services were analysed, drawing on grounded theory. Results Participants raised seven problems with, and arguments against, going beyond the individual approach to confidentiality. These problems fell into two overlapping categories: ‘relationships’ and ‘structures’. Most participants had never considered ways to—or thought it was impossible to—treat familial genetic information and personal information differently. They worried that putting the familial approach into practice could disrupt family dynamics and erode patient trust in the health service. They also thought they had insufficient resources to share information and feared that sharing might change the standard of care and make them more vulnerable to liability. Conclusions A familial approach to confidentiality has not been accepted or adopted as a standard, but wider research suggests that some of the problems HCPs perceived are surmountable and sharing in the interest of the family can be achieved. However, further research is needed to explore how personal and familial genetic information can be separated in practice. Our findings are relevant to HCPs across health services who are starting to use genome tests as part of their routine investigations. PMID:28159847

Genetic Counselors' Experiences Regarding Communication of Reproductive Risks with Autosomal Recessive Conditions found on Cancer Panels.

PubMed

Mets, Sarah; Tryon, Rebecca; Veach, Patricia McCarthy; Zierhut, Heather A

2016-04-01

The development of hereditary cancer genetic testing panels has altered genetic counseling practice. Mutations within certain genes on cancer panels pose not only a cancer risk, but also a reproductive risk for autosomal recessive conditions such as Fanconi anemia, constitutional mismatch repair deficiency syndrome, and ataxia telangiectasia. This study aimed to determine if genetic counselors discuss reproductive risks for autosomal recessive conditions associated with genes included on cancer panels, and if so, under what circumstances these risks are discussed. An on-line survey was emailed through the NSGC list-serv. The survey assessed 189 cancer genetic counselors' experiences discussing reproductive risks with patients at risk to carry a mutation or variant of uncertain significance (VUS) in a gene associated with both an autosomal dominant cancer risk and an autosomal recessive syndrome. Over half (n = 82, 55 %) reported having discussed reproductive risks; the remainder (n = 66, 45 %) had not. Genetic counselors who reported discussing reproductive risks primarily did so when patients had a positive result and were of reproductive age. Reasons for not discussing these risks included when a patient had completed childbearing or when a VUS was identified. Most counselors discussed reproductive risk after obtaining results and not during the informed consent process. There is inconsistency as to if and when the discussion of reproductive risks is taking place. The wide variation in responses suggests a need to develop professional guidelines for when and how discussions of reproductive risk for autosomal recessive conditions identified through cancer panels should occur with patients.

Genetic counselling in the era of genomic medicine

PubMed Central

Middleton, Anna

2018-01-01

Abstract Background Genomic technology can now deliver cost effective, targeted diagnosis and treatment for patients. Genetic counselling is a communication process empowering patients and families to make autonomous decisions and effectively use new genetic information. The skills of genetic counselling and expertise of genetic counsellors are integral to the effective implementation of genomic medicine. Sources of data Original papers, reviews, guidelines, policy papers and web-resources. Areas of agreement An international consensus on the definition of genetic counselling. Genetic counselling is necessary for implementation of genomic medicine. Areas of controversy Models of genetic counselling. Growing points Genomic medicine is a growing and strategic priority for many health care systems. Genetic counselling is part of this. Areas timely for developing research An evidence base is necessary, incorporating implementation and outcome research, to enable health care systems, practitioners, patients and families to maximize the utility (medically and psychologically) of the new genomic possibilities. PMID:29617718

Situation analysis of prenatal diagnosis technology utilization in China: current situation, main issues, and policy implications.

PubMed

Chen, Yingyao; Qian, Xu; Tang, Zhiliu; Banta, H David; Hu, Fangfang; Cao, Jianwen; Huang, Jiayan; Wang, Qian; Lv, Jun; Ying, Xianghua; Chen, Jie

2004-01-01

The purpose of this study is to describe the situation with the distribution and utilization of prenatal diagnosis technology in China, to identify some important barriers to prenatal diagnosis use, and to suggest changes to improve the present situation. The study uses cross-sectional surveys to capture quantitative data from both providers and consumers. Qualitative information based on focus group discussions is also presented. A mail survey of the provincial Bureaus of Health (BOHs) reveals that sixteen provincial prenatal diagnosis centers and twelve city level centers were accredited by the BOHs by July of 2001. These centers were located in thirteen provinces, of thirty in all of China. Of 147 selected institutions surveyed separately, 90.5 percent offer ultrasound examination, 72.1 percent provide pathogen tests (mainly Toxoplasma, rubella virus, cytomegalovirus, and herpes simplex or TORCH), 57.1 percent do biochemical tests, 21.8 percent have genetic counseling, 13.6 percent do karyotype testing, 7.5 percent do enzymology testing, and 5.4 percent carry out molecular genetic testing. Chromosome diseases, congenital diseases, and several gene diseases are the target diseases. According to qualitative data, macromanagement for prenatal diagnosis, supplier provision of tests, and population demand are the main influences on prenatal diagnosis use. From the quantitative and qualitative analysis, it is clear that the technology of prenatal diagnosis is not diffusing well throughout China and is apparently not appropriately used. The situation of prenatal diagnosis has implications for policy-makers, including identification of priorities, regulation of prenatal diagnosis, strategic planning, development of guidelines based on health technology assessment, and consumer orientation.

HIV pre-test information, discussion or counselling? A review of guidance relevant to the WHO European Region.

PubMed

Bell, Stephen A; Delpech, Valerie; Raben, Dorthe; Casabona, Jordi; Tsereteli, Nino; de Wit, John

2016-02-01

In the context of a shift from exceptionalism to normalisation, this study examines recommendations/evidence in current pan-European/global guidelines regarding pre-test HIV testing and counselling practices in health care settings. It also reviews new research not yet included in guidelines. There is consensus that verbal informed consent must be gained prior to testing, individually, in private, confidentially, in the presence of a health care provider. All guidelines recommend pre-test information/discussion delivered verbally or via other methods (information sheet). There is agreement about a minimum standard of information to be provided before a test, but guidelines differ regarding discussion about issues encouraging patients to think about implications of the result. There is heavy reliance on expert consultation in guideline development. Referenced scientific evidence is often more than ten years old and based on US/UK research. Eight new papers are reviewed. Current HIV testing and counselling guidelines have inconsistencies regarding the extent and type of information that is recommended during pre-test discussions. The lack of new research underscores a need for new evidence from a range of European settings to support the process of expert consultation in guideline development. © The Author(s) 2015.

Genetic structure of the threatened Dipterocarpus costatus populations in lowland tropical rainforests of southern Vietnam.

PubMed

Duc, N M; Duy, V D; Xuan, B T T; Thang, B V; Ha, N T H; Tam, N M

2016-10-24

Dipterocarpus costatus is an endangered species restricted to the lowland forests of southern Vietnam. Habitat loss and over-exploitation of D. costatus wood are the major threats to this species. We investigated the level of genetic variability within and among populations of D. costatus in order to provide guidelines for the conservation, management, and restoration of this species to the Forest Protection Department, Vietnam. Nine microsatellite markers were used to analyze 114 samples from four populations representing the natural range of D. costatus in southeast Vietnam. We indicated the low allelic diversity (N A = 2.3) and low genetic diversities with an average observed and expected heterozygosity of 0.130 and 0.151, respectively, in the lowland forests of southeast Vietnam. The low genetic diversity might be a consequence of inbreeding within the small and isolated populations of D. costatus owing to its habitat loss and over-exploitation. All populations deviated from Hardy-Weinberg equilibrium showing reduced heterozygosity. Alleles were lost from the populations by genetic drift. Genetic differentiation among populations was high (average pairwise F ST = 0.405), indicating low gene flow (<1) and isolated populations due to its destructed habitat and large geographical distances (P < 0.05) among populations. Heterozygosity excess tests (except of Bu Gia Map only under infinite allele model) were negative. The high genetic variation (62.7%) was found within populations. The STRUCTURE and neighbor joining tree results suggest strong differentiation among D. costatus populations, with the three genetic clusters, Phu Quoc, Tan Phu and Bu Gia Map, and Lo Go-Xa Mat due to habitat fragmentation and isolation. The threatened status of D. costatus was related to a lack of genetic diversity, with all its populations isolated in small forest patches. We recommend the establishment of an ex situ conservation site for D. costatus with a new big population comprising all genetic groups in order to enhance its survival under different environmental stresses.

Practical guidelines addressing ethical issues pertaining to the curation of human locus-specific variation databases (LSDBs)

PubMed Central

Povey, Sue; Al Aqeel, Aida I; Cambon-Thomsen, Anne; Dalgleish, Raymond; den Dunnen, Johan T; Firth, Helen V; Greenblatt, Marc S; Barash, Carol Isaacson; Parker, Michael; Patrinos, George P; Savige, Judith; Sobrido, Maria-Jesus; Winship, Ingrid; Cotton, Richard GH

2010-01-01

More than 1,000 Web-based locus-specific variation databases (LSDBs) are listed on the Website of the Human Genetic Variation Society (HGVS). These individual efforts, which often relate phenotype to genotype, are a valuable source of information for clinicians, patients, and their families, as well as for basic research. The initiators of the Human Variome Project recently recognized that having access to some of the immense resources of unpublished information already present in diagnostic laboratories would provide critical data to help manage genetic disorders. However, there are significant ethical issues involved in sharing these data worldwide. An international working group presents second-generation guidelines addressing ethical issues relating to the curation of human LSDBs that provide information via a Web-based interface. It is intended that these should help current and future curators and may also inform the future decisions of ethics committees and legislators. These guidelines have been reviewed by the Ethics Committee of the Human Genome Organization (HUGO). Hum Mutat 31:–6, 2010. © 2010 Wiley-Liss, Inc. PMID:20683926

Developing Guidelines for HIV Antibody Testing among Victims of Pediatric Sexual Abuse.

ERIC Educational Resources Information Center

Gellert, George A.; And Others

1990-01-01

An interim set of human immunodeficiency virus (HIV) testing guidelines for victims of pediatric sexual abuse (PSA) is proposed. Guidelines are based on responses of 63 practitioners of PSA assessment to 7 hypothetical clinical profiles with 12 testing criteria. (Author/DB)

Comments from the Developmental Neurotoxicology Committee of the Japanese Teratology Society on the OECD Guideline for the Testing of Chemicals, Proposal for a New Guideline 426, Developmental Neurotoxicity Study, Draft Document (October 2006 version), and on the Draft Document of the Retrospective Performance Assessment of the Draft Test Guideline 426 on Developmental Neurotoxicity.

PubMed

Ema, Makoto; Fukui, Yoshihiro; Aoyama, Hiroaki; Fujiwara, Michio; Fuji, Junichiro; Inouye, Minoru; Iwase, Takayuki; Kihara, Takahide; Oi, Akihide; Otani, Hiroki; Shinomiya, Mitsuhiro; Sugioka, Kozo; Yamano, Tsunekazu; Yamashita, Keisuke H; Tanimura, Takashi

2007-06-01

In October 2006, a new revision of the draft guideline (OECD Guideline for the Testing of Chemicals, Proposal for a New Guideline 426. Developmental Neurotoxicity Study) and Draft Document of the Retrospective Performance Assessment (RPA) of the Draft Test Guideline 426 on Developmental Neurotoxicity were distributed following incorporation of the results of the Expert Consultation Meeting in Tokyo on May 24-26, 2005. The draft guideline consists of 50 paragraphs and an appendix with 102 references; and the draft RPA consists of 37 paragraphs with 109 references. National coordinators were requested to arrange for national expert reviews of these draft documents in their member countries. Members of the Developmental Neurotoxicology (DNT) Committee of the Japanese Teratology Society (JTS) reviewed, discussed, and commented on the draft Test Guideline Proposal. The DNT Committee of the JTS also commented on the draft document of the RPA. These comments were sent to the OECD Secretariat. The DNT Committee of the JTS expects the comments to be useful for the finalization of these draft documents.

A Randomized Trial of Genetic and Environmental Risk Assessment (GERA) for Colorectal Cancer Risk in Primary Care: Trial Design and Baseline Findings

PubMed Central

Myers, Ronald E.; Manne, Sharon L.; Wilfond, Benjamin; Sifri, Randa; Ziring, Barry; Wolf, Thomas A.; Cocroft, James; Ueland, Amy; Petrich, Anett; Swan, Heidi; DiCarlo, Melissa; Weinberg, David S.

2010-01-01

Purpose This paper describes an ongoing randomized controlled trial designed to assess the impact of genetic and environmental risk assessment (GERA) on colorectal cancer (CRC) screening. Methods The trial includes asymptomatic patients who are 50-79 years and are not up-to-date with CRC screening guidelines. Patients who responded to a baseline telephone survey are randomized to a GERA or Control group. GERA Group participants meet with a nurse, decide whether to have a GERA blood test (a combination of genetic polymorphism and folate), and, if tested, receive GERA feedback. Follow-up telephone surveys are conducted at one and six months. A chart audit is performed at six months. Results Of 2,223 eligible patients, 562 (25%) have enrolled. Patients who enrolled in the study were significantly younger than those who did not (p<0.001). Participants tended to be 50-59 years (64%), female (58%), white (52%), married (51%), and have more than a high school education (67%). At baseline, most participants had some knowledge of CRC screening and GERA, viewed CRC screening favorably, and reported that they had decided to do screening. Almost half had worries and concerns about CRC. Conclusions One in four eligible primary care patients enrolled in the study. Age was negatively associated with enrollment. Prospective analyses using data for all participants will provide more definitive information on GERA uptake and the impact of GERA feedback. PMID:20828635

A randomized trial of genetic and environmental risk assessment (GERA) for colorectal cancer risk in primary care: trial design and baseline findings.

PubMed

Myers, Ronald E; Manne, Sharon L; Wilfond, Benjamin; Sifri, Randa; Ziring, Barry; Wolf, Thomas A; Cocroft, James; Ueland, Amy; Petrich, Anett; Swan, Heidi; DiCarlo, Melissa; Weinberg, David S

2011-01-01

This paper describes an ongoing randomized controlled trial designed to assess the impact of genetic and environmental risk assessment (GERA) on colorectal cancer (CRC) screening. The trial includes asymptomatic patients who are 50-79years and are not up-to-date with CRC screening guidelines. Patients who responded to a baseline telephone survey are randomized to a GERA or Control group. GERA group participants meet with a nurse, decide whether to have a GERA blood test (a combination of genetic polymorphism and folate), and, if tested, receive GERA feedback. Follow-up telephone surveys are conducted at 1 and 6months. A chart audit is performed at 6months. Of 2,223 eligible patients, 562 (25%) have enrolled. Patients who enrolled in the study were significantly younger than those who did not (p<0.001). Participants tended to be 50-59years (64%), female (58%), white (52%), married (51%), and have more than a high school education (67%). At baseline, most participants had some knowledge of CRC screening and GERA, viewed CRC screening favorably, and reported that they had decided to do screening. Almost half had worries and concerns about CRC. One in four eligible primary care patients enrolled in the study. Age was negatively associated with enrollment. Prospective analyses using data for all participants will provide more definitive information on GERA uptake and the impact of GERA feedback. Copyright © 2010 Elsevier Inc. All rights reserved.

Competences, education and support for new roles in cancer genetics services: outcomes from the cancer genetics pilot projects.

PubMed

Bennett, Catherine; Burton, Hilary; Farndon, Peter

2007-01-01

In 2004 the Department of Health in collaboration with Macmillan Cancer Support set up service development projects to pilot the integration of genetics in mainstream medicine in the area of cancer genetics.In developing these services, new roles and responsibilities were devised that required supporting programmes of education and training. The NHS National Genetics Education and Development Centre has worked with the projects to draw together their experience in these aspects. New roles include the Cancer Family Nurse Specialist, in which a nurse working in a cancer setting was trained to identify and manage genetic or family history concerns, and the Genetic Risk Assessment Practitioner--a small team of practitioners working within a secondary care setting to deliver a standardised risk assessment pathway. Existing roles were also adapted for a different setting, in particular the use of genetic counsellors working in a community ethnic minority setting. These practitioners undertook a range of clinical activities that can be mapped directly to the 'UK National Workforce Competences for Genetics in Clinical Practice for Non-genetics Healthcare Staff' framework developed by Skills for Health and the NHS National Genetics Education and Development Centre (2007; draft competence framework). The main differences between the various roles were in the ordering of genetic tests and the provision of advice on invasive preventive options such as mastectomy. Those involved in service development also needed to develop competences in project management, business skills, audit and evaluation, working with users, general management (personnel, multi-agency work and marketing), educational supervision, IT, public and professional outreach, and research. Important resources to support the development of new roles and competences included pathways and guidelines, a formal statement of competences, a recognised syllabus, appropriate and timely courses, the availability of a mentor, supervision and opportunities to discuss cases, a formal assessment of learning and continuing support from specialist genetics services. This represents a current resource gap that will be of concern to cancer networks and a challenge to providers of educational resources and regional genetics services.

Item-Writing Guidelines for Physics

ERIC Educational Resources Information Center

Regan, Tom

2015-01-01

A teacher learning how to write test questions (test items) will almost certainly encounter item-writing guidelines--lists of item-writing do's and don'ts. Item-writing guidelines usually are presented as applicable across all assessment settings. Table I shows some guidelines that I believe to be generally applicable and two will be briefly…

Genetic variation and seed transfer guidelines for ponderosa pine in the Ochoco and Malheur National Forests of central Oregon.

Treesearch

Frank C. Sorensen; John C. Weber

1994-01-01

Adaptive genetic variation in seed and seedling traits was evaluated for 280 families from 220 locations. Factor scores from three principal components were related by multiple regression to latitude, longitude, elevation, slope, and aspect of the seed source, and by classification analysis to seed zone and elevation band in seed zone. Location variance was significant...

The Journal of the Naval Postgraduate School Center for Homeland Defense and Security. Volume 6. Issue 3

DTIC Science & Technology

2010-09-01

genetic relationships between kin.33 Regardless of the underlying mechanism, individual symbiotic relationships can confer multiple benefits to the...allocation guidelines for homeland security and emergency management policymakers. The framework provides an operationally relevant rubric for...S. Wells, The Journey of Man: A Genetic Odyssey (Princeton, NJ: Princeton University Press, 2002). 4 A. Jakubowicz, “Anglo-multiculturalism

Standard development at the Human Variome Project.

PubMed

Smith, Timothy D; Vihinen, Mauno

2015-01-01

The Human Variome Project (HVP) is a world organization working towards facilitating the collection, curation, interpretation and free and open sharing of genetic variation information. A key component of HVP activities is the development of standards and guidelines. HVP Standards are systems, procedures and technologies that the HVP Consortium has determined must be used by HVP-affiliated data sharing infrastructure and should be used by the broader community. HVP guidelines are considered to be beneficial for HVP affiliated data sharing infrastructure and the broader community to adopt. The HVP also maintains a process for assessing systems, processes and tools that implement HVP Standards and Guidelines. Recommended System Status is an accreditation process designed to encourage the adoption of HVP Standards and Guidelines. Here, we describe the HVP standards development process and discuss the accepted standards, guidelines and recommended systems as well as those under acceptance. Certain HVP Standards and Guidelines are already widely adopted by the community and there are committed users for the others. © The Author(s) 2015. Published by Oxford University Press.

Standard development at the Human Variome Project

PubMed Central

Smith, Timothy D.; Vihinen, Mauno

2015-01-01

The Human Variome Project (HVP) is a world organization working towards facilitating the collection, curation, interpretation and free and open sharing of genetic variation information. A key component of HVP activities is the development of standards and guidelines. HVP Standards are systems, procedures and technologies that the HVP Consortium has determined must be used by HVP-affiliated data sharing infrastructure and should be used by the broader community. HVP guidelines are considered to be beneficial for HVP affiliated data sharing infrastructure and the broader community to adopt. The HVP also maintains a process for assessing systems, processes and tools that implement HVP Standards and Guidelines. Recommended System Status is an accreditation process designed to encourage the adoption of HVP Standards and Guidelines. Here, we describe the HVP standards development process and discuss the accepted standards, guidelines and recommended systems as well as those under acceptance. Certain HVP Standards and Guidelines are already widely adopted by the community and there are committed users for the others. PMID:25818894

Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome.

PubMed

Yurgelun, Matthew B; Allen, Brian; Kaldate, Rajesh R; Bowles, Karla R; Judkins, Thaddeus; Kaushik, Praveen; Roa, Benjamin B; Wenstrup, Richard J; Hartman, Anne-Renee; Syngal, Sapna

2015-09-01

Multigene panels are commercially available tools for hereditary cancer risk assessment that allow for next-generation sequencing of numerous genes in parallel. However, it is not clear if these panels offer advantages over traditional genetic testing. We investigated the number of cancer predisposition gene mutations identified by parallel sequencing in individuals with suspected Lynch syndrome. We performed germline analysis with a 25-gene, next-generation sequencing panel using DNA from 1260 individuals who underwent clinical genetic testing for Lynch syndrome from 2012 through 2013. All patients had a history of Lynch syndrome-associated cancer and/or polyps. We classified all identified germline alterations for pathogenicity and calculated the frequencies of pathogenic mutations and variants of uncertain clinical significance (VUS). We also analyzed data on patients' personal and family history of cancer, including fulfillment of clinical guidelines for genetic testing. Of the 1260 patients, 1112 met National Comprehensive Cancer Network (NCCN) criteria for Lynch syndrome testing (88%; 95% confidence interval [CI], 86%-90%). Multigene panel testing identified 114 probands with Lynch syndrome mutations (9.0%; 95% CI, 7.6%-10.8%) and 71 with mutations in other cancer predisposition genes (5.6%; 95% CI, 4.4%-7.1%). Fifteen individuals had mutations in BRCA1 or BRCA2; 93% of these met the NCCN criteria for Lynch syndrome testing and 33% met NCCN criteria for BRCA1 and BRCA2 analysis (P = .0017). An additional 9 individuals carried mutations in other genes linked to high lifetime risks of cancer (5 had mutations in APC, 3 had bi-allelic mutations in MUTYH, and 1 had a mutation in STK11); all of these patients met NCCN criteria for Lynch syndrome testing. A total of 479 individuals had 1 or more VUS (38%; 95% CI, 35%-41%). In individuals with suspected Lynch syndrome, multigene panel testing identified high-penetrance mutations in cancer predisposition genes, many of which were unexpected based on patients' histories. Parallel sequencing also detected a high number of potentially uninformative germline findings, including VUS. Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.

Colon cancer screening: which non-invasive filter tests?

PubMed

Pox, Christian

2011-01-01

The following non-invasive stool tests for colorectal cancer (CRC) screening exist: guaiac or immunochemical fecal occult blood testing (FOBT), genetic stool tests and the M2-PK. Currently the most widely used tests are guaiac-based (gFOBT). Several randomized controlled trials have shown that gFOBT are able to achieve a reduction in CRC-related mortality. This reduction is achieved by detecting asymptomatic cancers at an early stage with a better prognosis. However, gFOBT have a low sensitivity for colorectal adenomas and are thus unlikely to be able to reduce the incidence of CRC. Furthermore, gFOBT are not specific for human blood and can be influenced by external factors. Immunochemical tests (iFOBT) only detect human blood in the stool. In two recent randomized studies from the Netherlands comparing guaiac and immunochemical tests in the asymptomatic population, iFOBT were found to detect more cancers than gFOBT. Furthermore, iFOBT were able to detect more advanced adenomas thus having the potential to be able to reduce the incidence of CRC as well as CRC-related mortality. In the recently released European CRC screening guidelines, iFOBT are considered the screening test of choice. Several questions remain however. It is currently unknown what the optimal cut-off value for an iFOBT to be considered positive should be and what the number of stool samples is that are required. Genetic stool tests detect mutations in stool that can be found in CRC. The original test testing for 21 genetic changes was found to be superior to gFOBT for the detection of cancers. However, the sensitivity was moderate (51.6%) and the sensitivity for advanced adenomas was low. In the meantime the test has been modified improving DNA extraction and reducing the number of mutations tested for as well as including a methylation marker. The efficacy of the modified test in the screening population is unknown. M2-PK is an isomer of the enzyme pyruvate kinase that is involved in glycolysis. Studies have found a good sensitivity for cancers, a low sensitivity for advanced adenomas with a specificity of around 80%. Further studies in the screening population are required. Copyright © 2011 S. Karger AG, Basel.

21 CFR 350.60 - Guidelines for effectiveness testing of antiperspirant drug products.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 5 2011-04-01 2011-04-01 false Guidelines for effectiveness testing of antiperspirant drug products. 350.60 Section 350.60 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF... Drug Administration is providing guidelines that manufacturers may use in testing for effectiveness...

21 CFR 350.60 - Guidelines for effectiveness testing of antiperspirant drug products.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 5 2014-04-01 2014-04-01 false Guidelines for effectiveness testing of antiperspirant drug products. 350.60 Section 350.60 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF... Drug Administration is providing guidelines that manufacturers may use in testing for effectiveness...

21 CFR 350.60 - Guidelines for effectiveness testing of antiperspirant drug products.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 5 2012-04-01 2012-04-01 false Guidelines for effectiveness testing of antiperspirant drug products. 350.60 Section 350.60 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF... Drug Administration is providing guidelines that manufacturers may use in testing for effectiveness...

21 CFR 350.60 - Guidelines for effectiveness testing of antiperspirant drug products.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 5 2013-04-01 2013-04-01 false Guidelines for effectiveness testing of antiperspirant drug products. 350.60 Section 350.60 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF... Drug Administration is providing guidelines that manufacturers may use in testing for effectiveness...

Comments from the Behavioral Teratology Committee of the Japanese Teratology Society on OECD guideline for the testing of chemicals, proposal for a new guideline 426, developmental neurotoxicity study, draft document (September 2003).

PubMed

Fukui, Yoshihiro; Ema, Makoto; Fujiwara, Michio; Higuchi, Hashihiro; Inouye, Minoru; Iwase, Takayuki; Kihara, Takahide; Nishimura, Tatsuya; Oi, Akihide; Ooshima, Yojiro; Otani, Hiroki; Shinomiya, Mitsuhiro; Sugioka, Kozo; Yamano, Tsunekazu; Yamashita, Keisuke H; Tanimura, Takashi

2004-09-01

In September 2003, a new revision of the draft guideline (Organization for Economic Co-operation and Development [OECD] Guideline for the Testing of Chemicals, Proposal for a New Guideline 426, Developmental Neurotoxicity Study) was distributed. The draft guideline consists of 51 paragraphs and an appendix. The National Coordinators were requested to arrange national expert reviews of the guideline proposal in their member countries. The member of the Behavioral Teratology (BT) Committee of the Japanese Teratology Society (JTS) reviewed, discussed and commented on the draft Test Guideline proposal. The BT Committee of the JTS also commented that the International Collaborative Study to validate this protocol should be definitely performed. These comments were sent to the OECD Secretariat. The BT Committee of the JTS expects that the comments are useful for further discussion.

Guidelines for investigating causality of sequence variants in human disease

PubMed Central

MacArthur, D. G.; Manolio, T. A.; Dimmock, D. P.; Rehm, H. L.; Shendure, J.; Abecasis, G. R.; Adams, D. R.; Altman, R. B.; Antonarakis, S. E.; Ashley, E. A.; Barrett, J. C.; Biesecker, L. G.; Conrad, D. F.; Cooper, G. M.; Cox, N. J.; Daly, M. J.; Gerstein, M. B.; Goldstein, D. B.; Hirschhorn, J. N.; Leal, S. M.; Pennacchio, L. A.; Stamatoyannopoulos, J. A.; Sunyaev, S. R.; Valle, D.; Voight, B. F.; Winckler, W.; Gunter, C.

2014-01-01

The discovery of rare genetic variants is accelerating, and clear guidelines for distinguishing disease-causing sequence variants from the many potentially functional variants present in any human genome are urgently needed. Without rigorous standards we risk an acceleration of false-positive reports of causality, which would impede the translation of genomic research findings into the clinical diagnostic setting and hinder biological understanding of disease. Here we discuss the key challenges of assessing sequence variants in human disease, integrating both gene-level and variant-level support for causality. We propose guidelines for summarizing confidence in variant pathogenicity and highlight several areas that require further resource development. PMID:24759409

Guidelines for investigating causality of sequence variants in human disease.

PubMed

MacArthur, D G; Manolio, T A; Dimmock, D P; Rehm, H L; Shendure, J; Abecasis, G R; Adams, D R; Altman, R B; Antonarakis, S E; Ashley, E A; Barrett, J C; Biesecker, L G; Conrad, D F; Cooper, G M; Cox, N J; Daly, M J; Gerstein, M B; Goldstein, D B; Hirschhorn, J N; Leal, S M; Pennacchio, L A; Stamatoyannopoulos, J A; Sunyaev, S R; Valle, D; Voight, B F; Winckler, W; Gunter, C

2014-04-24

The discovery of rare genetic variants is accelerating, and clear guidelines for distinguishing disease-causing sequence variants from the many potentially functional variants present in any human genome are urgently needed. Without rigorous standards we risk an acceleration of false-positive reports of causality, which would impede the translation of genomic research findings into the clinical diagnostic setting and hinder biological understanding of disease. Here we discuss the key challenges of assessing sequence variants in human disease, integrating both gene-level and variant-level support for causality. We propose guidelines for summarizing confidence in variant pathogenicity and highlight several areas that require further resource development.

Impact of a clinical guideline for prescribing antibiotics to inpatients reporting penicillin or cephalosporin allergy.

PubMed

Blumenthal, Kimberly G; Shenoy, Erica S; Varughese, Christy A; Hurwitz, Shelley; Hooper, David C; Banerji, Aleena

2015-10-01

Self-reported penicillin allergy infrequently reflects an inability to tolerate penicillins. Inpatients reporting penicillin allergy receive alternative antibiotics that might be broader spectrum, more toxic, or less effective. To develop and assess a clinical guideline for the general inpatient provider that directs taking a history and prescribing antibiotics for patients with penicillin or cephalosporin allergy. A guideline was implemented to assist providers with assessing allergy history and prescribing antibiotics for patients with reported penicillin or cephalosporin allergy. The guideline used a standard 2-step graded challenge or test dose. A quasi-experimental study was performed to assess safety, feasibility, and impact on antibiotic use by comparing treatment 21 months before guideline implementation with 12 months after guideline implementation. Significantly more test doses to β-lactam antibiotics were performed monthly after vs before guideline implementation (median 14.5, interquartile range 13-16.25, vs 2, interquartile range 1-3.25, P < .001). Seven adverse drug reactions occurred during guideline-driven test doses, with no significant difference in rate (3.9% vs 6.1%, P = .44) or severity (P > .5) between periods. Guideline-driven test doses decreased alternative antimicrobial therapy after the test dose, including vancomycin (68.3% vs 37.2%, P < .001), aztreonam (11.5% vs 0.5%, P < .001), aminoglycosides (6.0% vs 1.1%, P = .004), and fluoro quinolones (15.3% vs 3.3%, P < .001). The implementation of an inpatient antibiotic prescribing guideline for patients with penicillin or cephalosporin allergy was associated with an almost 7-fold increase in the number of test doses to β-lactams without increased adverse drug reactions. Patients assessed with guideline-driven test doses were observed to have significantly decreased alternative antibiotic exposure. Copyright © 2015 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Detection by real-time PCR and pyrosequencing of the cry1Ab and cry1Ac genes introduced in genetically modified (GM) constructs.

PubMed

Debode, Frederic; Janssen, Eric; Bragard, Claude; Berben, Gilbert

2017-08-01

The presence of genetically modified organisms (GMOs) in food and feed is mainly detected by the use of targets focusing on promoters and terminators. As some genes are frequently used in genetically modified (GM) construction, they also constitute excellent screening elements and their use is increasing. In this paper we propose a new target for the detection of cry1Ab and cry1Ac genes by real-time polymerase chain reaction (PCR) and pyrosequencing. The specificity, sensitivity and robustness of the real-time PCR method were tested following the recommendations of international guidelines and the method met the expected performance criteria. This paper also shows how the robustness testing was assessed. This new cry1Ab/Ac method can provide a positive signal with a larger number of GM events than do the other existing methods using double dye-probes. The method permits the analysis of results with less ambiguity than the SYBRGreen method recommended by the European Reference Laboratory (EURL) GM Food and Feed (GMFF). A pyrosequencing method was also developed to gain additional information thanks to the sequence of the amplicon. This method of sequencing-by-synthesis can determine the sequence between the primers used for PCR. Pyrosequencing showed that the sequences internal to the primers present differences following the GM events considered and three different sequences were observed. The sensitivity of the pyrosequencing was tested on reference flours with a low percentage GM content and different copy numbers. Improvements in the pyrosequencing protocol provided correct sequences with 50 copies of the target. Below this copy number, the quality of the sequence was more random.

A dizygotic twin pregnancy in a MODY 3-affected woman.

PubMed

Bitterman, O; Iafusco, D; Torcia, F; Tinto, N; Napoli, A

2016-10-01

MODY diabetes includes rare familiar forms due to genetic mutations resulting in β-cell dysfunction. MODY 3 is due to mutations in the gene transcription factor HNF-1α, with diabetes diagnosis in adolescence or early adult life. Few data are available about MODY 3 in pregnancy. A 36-year-old Italian woman came to our unit at the 5th week of pregnancy. She was diagnosed with diabetes at 18 years, with negative autoimmunity and a strong familiarity for diabetes. She was treated with gliclazide and metformin. She had a previous pregnancy in which she was treated with insulin, giving birth at 38 weeks to a 3.210 kg baby girl, who showed neonatal hypoglycemia. We switched her to insulin treatment according to guidelines. We asked for genetic molecular testing, resulting in a HNF-1α gene mutation. A US examination at 7 weeks revealed a twin, bicorial, biamniotic pregnancy. At 37 weeks of gestation, she gave birth to two normal-weight baby girls; only one showed neonatal hypoglycemia and a genetic test revealed that she was affected by HNF-1α gene mutation. Subsequently, entire family of the woman was tested, showing that the father, the sister and the first daughter had the same HNF-1α mutation. A MODY 3 foetus needs a near-normal maternal glycemic control, because the exposure to intrauterine hyperglycemia can lead to an earlier age of diabetes onset. Neonatal hypoglycemia is generally observed in MODY 1 infants, but it is possible to hypothesize that some HNF-1α mutations could lead to a functionally impaired protein that might dysregulate HNF-4α expression determining hypoglycemia.

[Development and validation of event-specific quantitative PCR method for genetically modified maize LY038].

PubMed

Mano, Junichi; Masubuchi, Tomoko; Hatano, Shuko; Futo, Satoshi; Koiwa, Tomohiro; Minegishi, Yasutaka; Noguchi, Akio; Kondo, Kazunari; Akiyama, Hiroshi; Teshima, Reiko; Kurashima, Takeyo; Takabatake, Reona; Kitta, Kazumi

2013-01-01

In this article, we report a novel real-time PCR-based analytical method for quantitation of the GM maize event LY038. We designed LY038-specific and maize endogenous reference DNA-specific PCR amplifications. After confirming the specificity and linearity of the LY038-specific PCR amplification, we determined the conversion factor required to calculate the weight-based content of GM organism (GMO) in a multilaboratory evaluation. Finally, in order to validate the developed method, an interlaboratory collaborative trial according to the internationally harmonized guidelines was performed with blind DNA samples containing LY038 at the mixing levels of 0, 0.5, 1.0, 5.0 and 10.0%. The precision of the method was evaluated as the RSD of reproducibility (RSDR), and the values obtained were all less than 25%. The limit of quantitation of the method was judged to be 0.5% based on the definition of ISO 24276 guideline. The results from the collaborative trial suggested that the developed quantitative method would be suitable for practical testing of LY038 maize.

Biosafety, risk assessment and regulation of plant-made pharmaceuticals.

PubMed

Sparrow, Penelope A C; Twyman, Richard M

2009-01-01

The technology for plant-made pharmaceuticals (PMPs) has progressed significantly over the last few years, with the first commercial products for human use expected to reach the market by 2009 (see Note 1). As part of the 'next generation' of genetically modified (GM) crops, PMPs will be subject to additional biosafety considerations and are set to challenge the complex and overlapping regulations that currently govern GM plants, plant biologics (see Note 2) and 'conventional' pharmaceutical production. The areas of responsibility are being mapped out between the different regulatory agencies (Sparrow, P.A.C., Irwin, J., Dale, P., Twyman, R.M., and Ma, J.K.C. (2007) Pharma-Planta: Road testing the developing regulatory guidelines for plant-made pharmaceuticals. Transgenic Res., 2007), with specific guidelines currently being drawn up for the regulation of PMPs. In this chapter, we provide an overview of the biosafety (see Note 3), risk assessment (see Note 4) and regulation of this emerging technology. While reference will be made to EU regulations, the underlying principles of biosafety and risk assessment are generic to most countries.

Clinical application of ACMG-AMP guidelines in HNF1A and GCK variants in a cohort of MODY families.

PubMed

Santana, L S; Caetano, L A; Costa-Riquetto, A D; Quedas, E P S; Nery, M; Collett-Solberg, P; Boguszewski, M C S; Vendramini, M F; Crisostomo, L G; Floh, F O; Zarabia, Z I; Kohara, S K; Guastapaglia, L; Passone, C G B; Sewaybricker, L E; Jorge, A A L; Teles, M G

2017-10-01

Maturity-onset diabetes of the young (MODY) is a form of monogenic diabetes with autosomal dominant inheritance. GCK -MODY and HNF1A -MODY are the prevalent subtypes. Currently, there is growing concern regarding the correct interpretation of molecular genetic findings. The American College of Medical Genetics and Genomics (ACMG) updated guidelines to interpret and classify molecular variants. This study aimed to determine the prevalence of MODY ( GCK / HNF1A ) in a large cohort of Brazilian families, to report variants related to phenotype, and to classify them according to ACMG guidelines. One hundred and nine probands were investigated, 45% with clinical suspicion of GCK -MODY and 55% with suspicion of HNF1A -MODY. Twenty-five different variants were identified in GCK gene (30 probands-61% of positivity), and 7 variants in HNF1A (10 probands-17% of positivity). Fourteen of them were novel (12- GCK /2- HNF1A ). ACMG guidelines were able to classify a large portion of variants as pathogenic (36%- GCK /86%- HNF1A ) and likely pathogenic (44%- GCK /14%- HNF1A ), with 16% (5/32) as uncertain significance. This allows us to determine the pathogenicity classification more efficiently, and also reinforces the suspected associations with the phenotype among novel variants. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Neurofibromatosis: part 2--clinical management.

PubMed

Batista, Pollyanna Barros; Bertollo, Eny Maria Goloni; Costa, Danielle de Souza; Eliam, Lucas; Cunha, Karin Soares Gonçalves; Cunha-Melo, José Renan; Darrigo Junior, Luiz Guilherme; Geller, Mauro; Gianordoli-Nascimento, Ingrid Faria; Madeira, Luciana Gonçalves; Mendes, Hérika Martins; Miranda, Débora Marques de; Mata-Machado, Nikolas Andre; Morato, Eric Grossi; Pavarino, Érika Cristina; Pereira, Luciana Baptista; Rezende, Nilton Alves de; Rodrigues, Luíza de Oliveira; Sette, Jorge Bezerra Cavalcanti

2015-06-01

Part 1 of this guideline addressed the differential diagnosis of the neurofibromatoses (NF): neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2) and schwannomatosis (SCH). NF shares some features such as the genetic origin of the neural tumors and cutaneous manifestations, and affects nearly 80 thousand Brazilians. Increasing scientific knowledge on NF has allowed better clinical management and reduced rate of complications and morbidity, resulting in higher quality of life for NF patients. Most medical doctors are able to perform NF diagnosis, but the wide range of clinical manifestations and the inability to predict the onset or severity of new features, consequences, or complications make NF management a real clinical challenge, requiring the support of different specialists for proper treatment and genetic counseling, especially in NF2 and SCH. The present text suggests guidelines for the clinical management of NF, with emphasis on NF1.

DNA Commission of the International Society for Forensic Genetics (ISFG): Guidelines on the use of X-STRs in kinship analysis.

PubMed

Tillmar, Andreas O; Kling, Daniel; Butler, John M; Parson, Walther; Prinz, Mechthild; Schneider, Peter M; Egeland, Thore; Gusmão, Leonor

2017-07-01

Forensic genetic laboratories perform an increasing amount of genetic analyses of the X chromosome, in particular to solve complex cases of kinship analysis. For some biological relationships X-chromosomal markers can be more informative than autosomal markers, and there are a large number of markers, methods and databases that have been described for forensic use. Due to their particular mode of inheritance, and their physical location on a single chromosome, some specific considerations are required when estimating the weight of evidence for X-chromosomal marker DNA data. The DNA Commission of the International Society for Forensic Genetics (ISFG) hereby presents guidelines and recommendations for the use of X-chromosomal markers in kinship analysis with a special focus on the biostatistical evaluation. Linkage and linkage disequilibrium (association of alleles) are of special importance for such evaluations and these concepts and the implications for likelihood calculations are described in more detail. Furthermore it is important to use appropriate computer software that accounts for linkage and linkage disequilibrium among loci, as well as for mutations. Even though some software exist, there is still a need for further improvement of dedicated software. Copyright © 2017 Elsevier B.V. All rights reserved.

A new impetus for guideline development and implementation: construction and evaluation of a toolbox.

PubMed

Hilbink, Mirrian A H W; Ouwens, Marielle M T J; Burgers, Jako S; Kool, Rudolf B

2014-03-19

In the last decade, guideline organizations faced a number of problems, including a lack of standardization in guideline development methods and suboptimal guideline implementation. To contribute to the solution of these problems, we produced a toolbox for guideline development, implementation, revision, and evaluation. All relevant guideline organizations in the Netherlands were approached to prioritize the topics. We sent out a questionnaire and discussed the results at an invitational conference. Based on consensus, twelve topics were selected for the development of new tools. Subsequently, working groups were composed for the development of the tools. After development of the tools, their draft versions were pilot tested in 40 guideline projects. Based on the results of the pilot tests, the tools were refined and their final versions were presented. The vast majority of organizations involved in pilot testing of the tools reported satisfaction with using the tools. Guideline experts involved in pilot testing of the tools proposed a variety of suggestions for the implementation of the tools. The tools are available in Dutch and in English at a web-based platform on guideline development and implementation (http://www.ha-ring.nl). A collaborative approach was used for the development and evaluation of a toolbox for development, implementation, revision, and evaluation of guidelines. This approach yielded a potentially powerful toolbox for improving the quality and implementation of Dutch clinical guidelines. Collaboration between guideline organizations within this project led to stronger linkages, which is useful for enhancing coordination of guideline development and implementation and preventing duplication of efforts. Use of the toolbox could improve quality standards in the Netherlands, and might facilitate the development of high-quality guidelines in other countries as well.

Guidelines for the management and treatment of periodic fever syndromes familial Mediterranean fever.

PubMed

Terreri, Maria Teresa R A; Bernardo, Wanderley Marques; Len, Claudio Arnaldo; da Silva, Clovis Artur Almeida; de Magalhães, Cristina Medeiros Ribeiro; Sacchetti, Silvana B; Ferriani, Virgínia Paes Leme; Piotto, Daniela Gerent Petry; de Souza Cavalcanti, André; de Moraes, Ana Júlia Pantoja; Sztajnbok, Flavio Roberto; de Oliveira, Sheila Knupp Feitosa; Campos, Lucia Maria Arruda; Bandeira, Marcia; Santos, Flávia Patricia Sena Teixeira; Magalhães, Claudia Saad

2016-01-01

To establish guidelines based on scientific evidence for the management of familial Mediterranean fever. The Guideline was prepared from 5 clinical questions that were structured through PICO (Patient, Intervention or indicator, Comparison and Outcome), to search key primary scientific information databases. After defining the potential studies to support the recommendations, these were graduated considering their strength of evidence and grade of recommendation. 10,341 articles were retrieved and evaluated by title and abstract; from these, 46 articles were selected to support the recommendations. 1. The diagnosis of FMF is based on clinical manifestations, characterized by recurrent febrile episodes associated with abdominal pain, chest or arthritis of large joints. 2. FMF is a genetic disease presenting an autosomal recessive trait, caused by mutation in the MEFV gene. 3. Laboratory tests are not specific, demonstrating high serum levels of inflammatory proteins in the acute phase of the disease, but also often showing high levels even between attacks. SAA serum levels may be especially useful in monitoring the effectiveness of treatment. 4. The therapy of choice is colchicine; this drug has proven its effectiveness in preventing acute inflammatory episodes and progression toward amyloidosis in adults. 5. Based on the available information, the use of biological drugs appears to be an alternative for patients with FMF who do not respond or are intolerant to therapy with colchicine. Copyright © 2015 Elsevier Editora Ltda. All rights reserved.

Sudden adult death syndrome in m.3243A>G-related mitochondrial disease: an unrecognized clinical entity in young, asymptomatic adults.

PubMed

Ng, Yi Shiau; Grady, John P; Lax, Nichola Z; Bourke, John P; Alston, Charlotte L; Hardy, Steven A; Falkous, Gavin; Schaefer, Andrew G; Radunovic, Aleksandar; Mohiddin, Saidi A; Ralph, Matilda; Alhakim, Ali; Taylor, Robert W; McFarland, Robert; Turnbull, Douglass M; Gorman, Gráinne S

2016-08-21

To provide insight into the mechanism of sudden adult death syndrome (SADS) and to give new clinical guidelines for the cardiac management of patients with the most common mitochondrial DNA mutation, m.3243A>G. These studies were initiated after two young, asymptomatic adults harbouring the m.3243A>G mutation died suddenly and unexpectedly. The m.3243A>G mutation is present in ∼1 in 400 of the population, although the recognized incidence of mitochondrial DNA (mtDNA) disease is ∼1 in 5000. Pathological studies including histochemistry and molecular genetic analyses performed on various post-mortem samples including cardiac tissues (atrium and ventricles) showed marked respiratory chain deficiency and high levels of the m.3243A>G mutation. Systematic review of cause of death in our m.3243A>G patient cohort showed the person-time incidence rate of sudden adult death is 2.4 per 1000 person-years. A further six cases of sudden death among extended family members have been identified from interrogation of family pedigrees. Our findings suggest that SADS is an important cause of death in patients with m.3243A>G and likely to be due to widespread respiratory chain deficiency in cardiac muscle. The involvement of asymptomatic relatives highlights the importance of family tracing in patients with m.3243A>G and the need for specific cardiac arrhythmia surveillance in the management of this common genetic disease. In addition, these findings have prompted the derivation of cardiac guidelines specific to patients with m.3243A>G-related mitochondrial disease. Finally, due to the prevalence of this mtDNA point mutation, we recommend inclusion of testing for m.3243A>G mutations in the genetic autopsy of all unexplained cases of SADS. © The Author 2015. Published by Oxford University Press on behalf of the European Society of Cardiology.

Australian and New Zealand Anaesthetic Allergy Group Perioperative Anaphylaxis Investigation Guidelines.

PubMed

Scolaro, R J; Crilly, H M; Maycock, E J; McAleer, P T; Nicholls, K A; Rose, M A; The, Rih

2017-09-01

These guidelines are a consensus document developed by a working party of the Australian and New Zealand Anaesthetic Allergy Group (ANZAAG) to provide an approach to the investigation of perioperative anaphylaxis. They focus primarily on the use of skin testing as it is the investigation with the greatest clinical utility for the identification of the likely causative agent and potentially safer alternatives. The practicalities and process of skin testing, its limitations, and the place of other tests are discussed. These guidelines also address the roles of graded challenge and in vitro testing. The implications of anaphylaxis associated with neuromuscular blocking agents, beta-lactam antibiotics, local anaesthetic agents and chlorhexidine are discussed. Evidence for the recommendations is derived from literature searches using the words skin test, allergy, anaphylaxis, anaesthesia, and each of the individual agents listed in these guidelines. The individual articles were then reviewed for suitability for inclusion in these guidelines. Where evidence was not strong, as is the situation for many perioperative agents, expert consensus from the ANZAAG working party was used. These guidelines are intended for use by specialists involved in the investigation of perioperative allergy. They have been approved following peer review by members of ANZAAG and are available on the ANZAAG website: http://www.anzaag.com/anaphylaxis-management/testing-guidelines.pdf.

Noonan syndrome - a new survey.

PubMed

Tafazoli, Alireza; Eshraghi, Peyman; Koleti, Zahra Kamel; Abbaszadegan, Mohammadreza

2017-02-01

Noonan syndrome (NS) is an autosomal dominant disorder with vast heterogeneity in clinical and genetic features. Various symptoms have been reported for this abnormality such as short stature, unusual facial characteristics, congenital heart abnormalities, developmental complications, and an elevated tumor incidence rate. Noonan syndrome shares clinical features with other rare conditions, including LEOPARD syndrome, cardio-facio-cutaneous syndrome, Noonan-like syndrome with loose anagen hair, and Costello syndrome. Germline mutations in the RAS-MAPK (mitogen-activated protein kinase) signal transduction pathway are responsible for NS and other related disorders. Noonan syndrome diagnosis is primarily based on clinical features, but molecular testing should be performed to confirm it in patients. Due to the high number of genes associated with NS and other RASopathy disorders, next-generation sequencing is the best choice for diagnostic testing. Patients with NS also have higher risk for leukemia and specific solid tumors. Age-specific guidelines for the management of NS are available.

Noonan syndrome – a new survey

PubMed Central

Tafazoli, Alireza; Eshraghi, Peyman; Koleti, Zahra Kamel

2016-01-01

Noonan syndrome (NS) is an autosomal dominant disorder with vast heterogeneity in clinical and genetic features. Various symptoms have been reported for this abnormality such as short stature, unusual facial characteristics, congenital heart abnormalities, developmental complications, and an elevated tumor incidence rate. Noonan syndrome shares clinical features with other rare conditions, including LEOPARD syndrome, cardio-facio-cutaneous syndrome, Noonan-like syndrome with loose anagen hair, and Costello syndrome. Germline mutations in the RAS-MAPK (mitogen-activated protein kinase) signal transduction pathway are responsible for NS and other related disorders. Noonan syndrome diagnosis is primarily based on clinical features, but molecular testing should be performed to confirm it in patients. Due to the high number of genes associated with NS and other RASopathy disorders, next-generation sequencing is the best choice for diagnostic testing. Patients with NS also have higher risk for leukemia and specific solid tumors. Age-specific guidelines for the management of NS are available. PMID:28144274

Pharmacogenomic knowledge representation, reasoning and genome-based clinical decision support based on OWL 2 DL ontologies.

PubMed

Samwald, Matthias; Miñarro Giménez, Jose Antonio; Boyce, Richard D; Freimuth, Robert R; Adlassnig, Klaus-Peter; Dumontier, Michel

2015-02-22

Every year, hundreds of thousands of patients experience treatment failure or adverse drug reactions (ADRs), many of which could be prevented by pharmacogenomic testing. However, the primary knowledge needed for clinical pharmacogenomics is currently dispersed over disparate data structures and captured in unstructured or semi-structured formalizations. This is a source of potential ambiguity and complexity, making it difficult to create reliable information technology systems for enabling clinical pharmacogenomics. We developed Web Ontology Language (OWL) ontologies and automated reasoning methodologies to meet the following goals: 1) provide a simple and concise formalism for representing pharmacogenomic knowledge, 2) finde errors and insufficient definitions in pharmacogenomic knowledge bases, 3) automatically assign alleles and phenotypes to patients, 4) match patients to clinically appropriate pharmacogenomic guidelines and clinical decision support messages and 5) facilitate the detection of inconsistencies and overlaps between pharmacogenomic treatment guidelines from different sources. We evaluated different reasoning systems and test our approach with a large collection of publicly available genetic profiles. Our methodology proved to be a novel and useful choice for representing, analyzing and using pharmacogenomic data. The Genomic Clinical Decision Support (Genomic CDS) ontology represents 336 SNPs with 707 variants; 665 haplotypes related to 43 genes; 22 rules related to drug-response phenotypes; and 308 clinical decision support rules. OWL reasoning identified CDS rules with overlapping target populations but differing treatment recommendations. Only a modest number of clinical decision support rules were triggered for a collection of 943 public genetic profiles. We found significant performance differences across available OWL reasoners. The ontology-based framework we developed can be used to represent, organize and reason over the growing wealth of pharmacogenomic knowledge, as well as to identify errors, inconsistencies and insufficient definitions in source data sets or individual patient data. Our study highlights both advantages and potential practical issues with such an ontology-based approach.

The Instrument for Measuring the Implementation Situation of Traditional Chinese Medicine Guideline: Evaluation and Application

PubMed Central

Wang, Yangyang; Chen, Yaolong; Wang, Xiaoyun; Deng, Jingwen

2017-01-01

Clinical practice guidelines play an important role in reducing the variations in clinical practices and improving the quality of care. To assess the real effect, measuring its implementation situation is needed. The implementation situation can be reflected by testing the consistency between the actual clinical practice and the guideline. We constructed an instrument to measure the implementation situation of Traditional Chinese Medicine (TCM) guideline through consistency testing. The main objectives of our study were to validate the instrument and evaluate the implementation situation of menopause syndrome guideline of TCM, using the data from the consistency test of comparing the medical records with the guideline. A total of 621 cases were included for data analysis. Cronbach's Alpha coefficient is 0.73. The model fit of 7 items in four dimensions was good (SRMR = 0.04; GFI = 0.97; NFI = 0.97; TLI = 0.96; CFI = 0.98; AGFI = 0.90). This instrument is of good reliability and validity. It can help the guideline developers to measure the implementation situation, find the reasons affecting the implementation, and revise the guideline. The method of using consistency test to measure the implementation situation may provide a sample for evaluating the guideline implementation in other fields. PMID:29234379

Woman's Pre-Conception Evaluation: Genetic and Fetal Risk Considerations for Counselling and Informed Choice.

PubMed

Wilson, R Douglas

2017-10-11

To inform reproductive and other health care providers about genetic and fetal risk information to consider during a woman/couples' pre-conception evaluation, including considerations for genetic risk assessment, genetic screening, or testing to allow for improved counselling and informed choice. This genetic information can be used for patient education, planning, and possible pre-conception and/or prenatal testing. This information may allow improved risk assessment for pre-conception counselling for individual patients and their families. PubMed or Medline and the Cochrane Database were searched in May 2017 using appropriate key words ("pre-conception," "genetic disease," "maternal," "family history," "genetic," "health risk," "genetic health surveillance," "prenatal screening," "prenatal diagnosis," "birth defects," and "teratogen"). Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, and national and international medical specialty societies. The benefits for the patient and her family include an increased understanding of relevant genetic risk pre-conception and in early pregnancy, and better pregnancy outcomes as a result of use of the information. The harm includes potential increased anxiety or psychological stress associated with the possibility of identifying genetic risks. The evidence obtained was peer-reviewed by the Genetics Committee of The Society of Obstetricians and Gynaecologists of Canada. Consideration for Care Statements For this review article, the Consideration for Care Statements use the GRADE strength and quality as it is comparable for the clinician and the patient/public user. [GRADE from the Canadian Task Force on Preventive Health Care (www.canadiantaskforce.ca). For clinicians, Strong = The recommendation would apply to most individuals. Formal discussion aids are not likely to be needed to help individuals make decisions consistent with their values and preferences. For patients/public, Strong = We believe most people in this situation would want the recommended course of actions and only a small number would not. Quality of evidence (High, Moderate, Low) based on the confidence that the true effect lies close to that of the estimate of the effect.] Conclusion Pre-conception planning is presently underutilized by both patients and providers. Pre-conception genetic assessment is only a part of the counselling, education, and health management change that can improve perinatal and maternal morbidity and mortality. A published literature review on pre-conception genetic counselling identified mainly clinical cohort studies, surveys, and expert opinion with no RCTs. There is strong support for pre-conception counselling and moderate quality based on the understanding that most individuals would support and use pre-conception counselling when choice, timing, and ease of access is considered. Copyright © 2017 Society of Obstetricians and Gynaecologists of Canada. Published by Elsevier Inc. All rights reserved.

Adaptation of the ToxRTool to Assess the Reliability of Toxicology Studies Conducted with Genetically Modified Crops and Implications for Future Safety Testing.

PubMed

Koch, Michael S; DeSesso, John M; Williams, Amy Lavin; Michalek, Suzanne; Hammond, Bruce

2016-01-01

To determine the reliability of food safety studies carried out in rodents with genetically modified (GM) crops, a Food Safety Study Reliability Tool (FSSRTool) was adapted from the European Centre for the Validation of Alternative Methods' (ECVAM) ToxRTool. Reliability was defined as the inherent quality of the study with regard to use of standardized testing methodology, full documentation of experimental procedures and results, and the plausibility of the findings. Codex guidelines for GM crop safety evaluations indicate toxicology studies are not needed when comparability of the GM crop to its conventional counterpart has been demonstrated. This guidance notwithstanding, animal feeding studies have routinely been conducted with GM crops, but their conclusions on safety are not always consistent. To accurately evaluate potential risks from GM crops, risk assessors need clearly interpretable results from reliable studies. The development of the FSSRTool, which provides the user with a means of assessing the reliability of a toxicology study to inform risk assessment, is discussed. Its application to the body of literature on GM crop food safety studies demonstrates that reliable studies report no toxicologically relevant differences between rodents fed GM crops or their non-GM comparators.

C-B3-03: Development and Pilot Testing of Guidelines to Monitor High-Risk Medications in the Ambulatory Setting

PubMed Central

Tjia, Jennifer; Field, Terry; Garber, Lawrence; Raebel, Marsha; Donovan, Jennifer; Kanaan, Abir; Fischer, Shira; Gagne, Shawn; Zhao, Yanfang; Fuller, Jackie; Gurwitz, Jerry

2010-01-01

Background: Inadequate laboratory monitoring of high-risk medications contributes to preventable adverse drug events. One barrier to appropriate monitoring is lack of standardized monitoring guidelines. The study aims were to develop guidelines to monitor high-risk medications and to assess the prevalence of laboratory testing for these medications in a multispecialty group practice. Methods: We developed guidelines for laboratory monitoring of high-risk medications as part of a patient safety intervention trial. An advisory committee of national experts and local leaders (clinicians, pharmacists, pharmacoepidemiologists, and patient safety experts) used a two-round, internet-based Delphi process to select guideline medications based on the importance of monitoring for efficacy, safety, and drug-drug interactions. Test frequency recommendations were developed by academic pharmacists based on literature review and local interdisciplinary consensus. To estimate the potential impact of the intervention, we determined the prevalence of high-risk drug dispensings and laboratory testing for guideline medications between January 1, 2008 and July 31, 2008. Results: Consensus on medications to include in the guidelines was achieved in two rounds. Final guidelines included 35 drugs/drug classes and 61 laboratory tests. The prevalence of monitoring ranged from <50% to >90%, with infrequently prescribed drugs having a lower prevalence of recommended testing. When more than one test was recommended for a selected medication, monitoring within a medication sometimes differed by > 50%. Conclusions: Even among drugs where there is general consensus that laboratory monitoring is important, prevalence of monitoring is highly variable. Further, infrequently prescribed medications are at higher risk for poor monitoring.

Standards for the Reporting of Genetic Counseling Interventions in Research and Other Studies (GCIRS): an NSGC Task Force Report.

PubMed

Hooker, Gillian W; Babu, D; Myers, M F; Zierhut, H; McAllister, M

2017-06-01

As the demand for evidence to support the value of genetic counseling increases, it is critical that reporting of genetic counseling interventions in research and other types of studies (e.g. process improvement or service evaluation studies) adopt greater rigor. As in other areas of healthcare, the appraisal, synthesis, and translation of research findings into genetic counseling practice are likely to be improved if clear specifications of genetic counseling interventions are reported when studies involving genetic counseling are published. To help improve reporting practices, the National Society of Genetic Counselors (NSGC) convened a task force in 2015 to develop consensus standards for the reporting of genetic counseling interventions. Following review by the NSGC Board of Directors, the NSGC Practice Guidelines Committee and the editorial board of the Journal of Genetic Counseling, 23 items across 8 domains were proposed as standards for the reporting of genetic counseling interventions in the published literature (GCIRS: Genetic Counseling Intervention Reporting Standards). The authors recommend adoption of these standards by authors and journals when reporting studies involving genetic counseling interventions.

Evidence-based guideline summary: evaluation, diagnosis, and management of congenital muscular dystrophy: Report of the Guideline Development Subcommittee of the American Academy of Neurology and the Practice Issues Review Panel of the American Association of Neuromuscular & Electrodiagnostic Medicine.

PubMed

Kang, Peter B; Morrison, Leslie; Iannaccone, Susan T; Graham, Robert J; Bönnemann, Carsten G; Rutkowski, Anne; Hornyak, Joseph; Wang, Ching H; North, Kathryn; Oskoui, Maryam; Getchius, Thomas S D; Cox, Julie A; Hagen, Erin E; Gronseth, Gary; Griggs, Robert C

2015-03-31

To delineate optimal diagnostic and therapeutic approaches to congenital muscular dystrophy (CMD) through a systematic review and analysis of the currently available literature. Relevant, peer-reviewed research articles were identified using a literature search of the MEDLINE, EMBASE, and Scopus databases. Diagnostic and therapeutic data from these articles were extracted and analyzed in accordance with the American Academy of Neurology classification of evidence schemes for diagnostic, prognostic, and therapeutic studies. Recommendations were linked to the strength of the evidence, other related literature, and general principles of care. The geographic and ethnic backgrounds, clinical features, brain imaging studies, muscle imaging studies, and muscle biopsies of children with suspected CMD help predict subtype-specific diagnoses. Genetic testing can confirm some subtype-specific diagnoses, but not all causative genes for CMD have been described. Seizures and respiratory complications occur in specific subtypes. There is insufficient evidence to determine the efficacy of various treatment interventions to optimize respiratory, orthopedic, and nutritional outcomes, and more data are needed regarding complications. Multidisciplinary care by experienced teams is important for diagnosing and promoting the health of children with CMD. Accurate assessment of clinical presentations and genetic data will help in identifying the correct subtype-specific diagnosis in many cases. Multiorgan system complications occur frequently; surveillance and prompt interventions are likely to be beneficial for affected children. More research is needed to fill gaps in knowledge regarding this category of muscular dystrophies. © 2015 American Academy of Neurology.

The clinical application of genome-wide sequencing for monogenic diseases in Canada: Position Statement of the Canadian College of Medical Geneticists

PubMed Central

Boycott, Kym; Hartley, Taila; Adam, Shelin; Bernier, Francois; Chong, Karen; Fernandez, Bridget A; Friedman, Jan M; Geraghty, Michael T; Hume, Stacey; Knoppers, Bartha M; Laberge, Anne-Marie; Majewski, Jacek; Mendoza-Londono, Roberto; Meyn, M Stephen; Michaud, Jacques L; Nelson, Tanya N; Richer, Julie; Sadikovic, Bekim; Skidmore, David L; Stockley, Tracy; Taylor, Sherry; van Karnebeek, Clara; Zawati, Ma'n H; Lauzon, Julie; Armour, Christine M

2015-01-01

Purpose and scope The aim of this Position Statement is to provide recommendations for Canadian medical geneticists, clinical laboratory geneticists, genetic counsellors and other physicians regarding the use of genome-wide sequencing of germline DNA in the context of clinical genetic diagnosis. This statement has been developed to facilitate the clinical translation and development of best practices for clinical genome-wide sequencing for genetic diagnosis of monogenic diseases in Canada; it does not address the clinical application of this technology in other fields such as molecular investigation of cancer or for population screening of healthy individuals. Methods of statement development Two multidisciplinary groups consisting of medical geneticists, clinical laboratory geneticists, genetic counsellors, ethicists, lawyers and genetic researchers were assembled to review existing literature and guidelines on genome-wide sequencing for clinical genetic diagnosis in the context of monogenic diseases, and to make recommendations relevant to the Canadian context. The statement was circulated for comment to the Canadian College of Medical Geneticists (CCMG) membership-at-large and, following incorporation of feedback, approved by the CCMG Board of Directors. The CCMG is a Canadian organisation responsible for certifying medical geneticists and clinical laboratory geneticists, and for establishing professional and ethical standards for clinical genetics services in Canada. Results and conclusions Recommendations include (1) clinical genome-wide sequencing is an appropriate approach in the diagnostic assessment of a patient for whom there is suspicion of a significant monogenic disease that is associated with a high degree of genetic heterogeneity, or where specific genetic tests have failed to provide a diagnosis; (2) until the benefits of reporting incidental findings are established, we do not endorse the intentional clinical analysis of disease-associated genes other than those linked to the primary indication; and (3) clinicians should provide genetic counselling and obtain informed consent prior to undertaking clinical genome-wide sequencing. Counselling should include discussion of the limitations of testing, likelihood and implications of diagnosis and incidental findings, and the potential need for further analysis to facilitate clinical interpretation, including studies performed in a research setting. These recommendations will be routinely re-evaluated as knowledge of diagnostic and clinical utility of clinical genome-wide sequencing improves. While the document was developed to direct practice in Canada, the applicability of the statement is broader and will be of interest to clinicians and health jurisdictions internationally. PMID:25951830

The clinical application of genome-wide sequencing for monogenic diseases in Canada: Position Statement of the Canadian College of Medical Geneticists.

PubMed

Boycott, Kym; Hartley, Taila; Adam, Shelin; Bernier, Francois; Chong, Karen; Fernandez, Bridget A; Friedman, Jan M; Geraghty, Michael T; Hume, Stacey; Knoppers, Bartha M; Laberge, Anne-Marie; Majewski, Jacek; Mendoza-Londono, Roberto; Meyn, M Stephen; Michaud, Jacques L; Nelson, Tanya N; Richer, Julie; Sadikovic, Bekim; Skidmore, David L; Stockley, Tracy; Taylor, Sherry; van Karnebeek, Clara; Zawati, Ma'n H; Lauzon, Julie; Armour, Christine M

2015-07-01

The aim of this Position Statement is to provide recommendations for Canadian medical geneticists, clinical laboratory geneticists, genetic counsellors and other physicians regarding the use of genome-wide sequencing of germline DNA in the context of clinical genetic diagnosis. This statement has been developed to facilitate the clinical translation and development of best practices for clinical genome-wide sequencing for genetic diagnosis of monogenic diseases in Canada; it does not address the clinical application of this technology in other fields such as molecular investigation of cancer or for population screening of healthy individuals. Two multidisciplinary groups consisting of medical geneticists, clinical laboratory geneticists, genetic counsellors, ethicists, lawyers and genetic researchers were assembled to review existing literature and guidelines on genome-wide sequencing for clinical genetic diagnosis in the context of monogenic diseases, and to make recommendations relevant to the Canadian context. The statement was circulated for comment to the Canadian College of Medical Geneticists (CCMG) membership-at-large and, following incorporation of feedback, approved by the CCMG Board of Directors. The CCMG is a Canadian organisation responsible for certifying medical geneticists and clinical laboratory geneticists, and for establishing professional and ethical standards for clinical genetics services in Canada. Recommendations include (1) clinical genome-wide sequencing is an appropriate approach in the diagnostic assessment of a patient for whom there is suspicion of a significant monogenic disease that is associated with a high degree of genetic heterogeneity, or where specific genetic tests have failed to provide a diagnosis; (2) until the benefits of reporting incidental findings are established, we do not endorse the intentional clinical analysis of disease-associated genes other than those linked to the primary indication; and (3) clinicians should provide genetic counselling and obtain informed consent prior to undertaking clinical genome-wide sequencing. Counselling should include discussion of the limitations of testing, likelihood and implications of diagnosis and incidental findings, and the potential need for further analysis to facilitate clinical interpretation, including studies performed in a research setting. These recommendations will be routinely re-evaluated as knowledge of diagnostic and clinical utility of clinical genome-wide sequencing improves. While the document was developed to direct practice in Canada, the applicability of the statement is broader and will be of interest to clinicians and health jurisdictions internationally. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Hearing Loss Associated with Retinitis Pigmentosa. Short Reports.

ERIC Educational Resources Information Center

Karp, Adrienne

1985-01-01

The article describes a variation of Usher's Syndrome, a genetic condition characterized by visual and auditory impairments, in which moderate, postlingual, and sometimes progressive hearing impairments may go undetected. Identification guidelines are offered. (Author/CL)

Privacy and policy for genetic research.

PubMed

DeCew, Judith Wagner

2004-01-01

I begin with a discussion of the value of privacy and what we lose without it. I then turn to the difficulties of preserving privacy for genetic information and other medical records in the face of advanced information technology. I suggest three alternative public policy approaches to the problem of protecting individual privacy and also preserving databases for genetic research: (1) governmental guidelines and centralized databases, (2) corporate self-regulation, and (3) my hybrid approach. None of these are unproblematic; I discuss strengths and drawbacks of each, emphasizing the importance of protecting the privacy of sensitive medical and genetic information as well as letting information technology flourish to aid patient care, public health and scientific research.

The importance of genetic diagnosis for Duchenne muscular dystrophy

PubMed Central

Aartsma-Rus, Annemieke; Ginjaar, Ieke B; Bushby, Kate

2016-01-01

Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy are caused by mutations in the dystrophin-encoding DMD gene. Large deletions and duplications are most common, but small mutations have been found as well. Having a correct diagnosis is important for family planning and providing proper care to patients according to published guidelines. With mutation-specific therapies under development for DMD, a correct diagnosis is now also important for assessing whether patients are eligible for treatments. This review discusses different mutations causing DMD, diagnostic techniques available for making a genetic diagnosis for children suspected of DMD and the importance of having a specific genetic diagnosis in the context of emerging genetic therapies for DMD. PMID:26754139

What Is Genetic Ancestry Testing?

MedlinePlus

... Testing What is genetic ancestry testing? What is genetic ancestry testing? Genetic ancestry testing, or genetic genealogy, ... mixed with other groups. For more information about genetic ancestry testing: The University of Utah provides video ...

Privacy and Biobanking in China: A Case of Policy in Transition.

PubMed

Chen, Haidan; Chan, Benny; Joly, Yann

2015-01-01

Disease-based biobanks have operated in hospitals and research institutes in China for decades, and China has recently embarked on a plan to establish further biobank networks with the aim of promoting data sharing among the existing biobanks. Although the Chinese Constitution has only recently begun to recognize individual privacy as a distinct and independent constitutional right, biobanking in China has been loosely regulated under a patchwork of sometimes overlapping laws (such as the Interim Measures for the Administration of Human Genetic Resources) and regulatory instruments, as well as and the policies of individual biobanks and networks of biobanks (such as the Shanghai Biobank Network Guidelines). A Draft Ordinance on Human Genetics Resources is currently being developed that will deal in more detail than previous laws with issues such as management measures, legal liability, and punishment for violations. International data sharing will be tightly regulated under this new law, and individual biobanks' policies such as the Shanghai Guidelines may choose to regulate such sharing even more. In contrast with national regulatory instruments, the Shanghai Guidelines also contain detailed de-identification policies, and explicitly endorse broad consent. © 2015 American Society of Law, Medicine & Ethics, Inc.

Monitoring ethical, legal, and social issues in developing population genetic databases.

PubMed

Austin, Melissa A; Harding, Sarah E; McElroy, Courtney E

2003-01-01

To characterize ethical, legal, and social issues unique to population genetic database research and to determine the relevance of international recommendations and guidelines for addressing these issues in the development of "genebank" projects globally. Building on our previous description of eight international genebanks, we conducted a comprehensive electronic search and literature review of relevant publications and consulted national and international documents applicable to genebank research. We identified and characterized five categories of ethical, legal, and social issues unique to genebank development: sponsorship and benefit-sharing, neutrality and regulatory power of ethics committees, public engagement, consent, and data protection. We illustrate these issues with examples from specific genebanks. Not all of the issues are addressed in current international guidelines, many of which are nonspecific and unenforceable. The trend of genebank development promises to provide new discoveries to the field of medical science and to greatly improve public health. However, there is a growing need for more explicit, enforceable, and coordinated international guidelines relevant to the development and implementation of genebanks. By comparing ethical, legal and social issues as they arise in genebanks, researchers can better evaluate how to best use these projects to improve public health while protecting participating populations.

DEVELOPMENTAL NEUROTOXICITY TESTING GUIDELINES: A QUALIFICATIVE RETROSPECTIVE ANALYSIS OF POSITIVE CONTROL DATA.

EPA Science Inventory

The USEPA Developmental Neurotoxicity (DNT) Study Test Guideline calls for both functional and neuropathological assessments in offspring during and following maternal exposure. This guideline also requires data from positive control (PC) agents. Submission of these data permit e...

Hypersensitivity reactions to HIV therapy

PubMed Central

Chaponda, Mas; Pirmohamed, Munir

2011-01-01

Many drugs used for the treatment of HIV disease (including the associated opportunistic infections) can cause drug hypersensitivity reactions, which vary in severity, clinical manifestations and frequency. These reactions are not only seen with the older compounds, but also with the newer more recently introduced drugs. The pathogenesis is unclear in most cases, but there is increasing evidence to support that many of these are mediated through a combination of immunologic and genetic factors through the major histocompatibility complex (MHC). Genetic predisposition to the occurrence of these allergic reactions has been shown for some of the drugs, notably abacavir hypersensitivity which is strongly associated with the class I MHC allele, HLA-B*5701. Testing before the prescription of abacavir has been shown to be of clinical utility, has resulted in a change in the drug label, is now recommended in clinical guidelines and is practiced in most Western countries. For most other drugs, however, there are no good methods of prevention, and clinical monitoring with appropriate (usually supportive and symptomatic) treatment is required. There is a need to undertake further research in this area to increase our understanding of the mechanisms, which may lead to better preventive strategies through the development of predictive genetic biomarkers or through guiding the design of drugs less likely to cause these types of adverse drug reactions. PMID:21480946

How Might the Genetics Profession Better Utilize Social Media.

PubMed

Moore, Rebekah A; Matthews, Anne L; Cohen, Leslie

2018-04-01

Social media is a common method of communication in people's personal lives and professional settings. Gallagher et al. (2016) recommended, "it is time for genetic counselors to embrace social media as a means of communicating with patients or other healthcare professionals." Full members of the National Society of Genetic Counselors (NSGC) in the USA and Canada and genetics patients in Cleveland, OH, were surveyed to determine interest in using social media for patient-provider interactions. Both cohorts indicated that patient privacy and confidentiality would be a concern; however, survey results indicated patients would be interested in using social media to receive general information about genetic counseling and to learn about genetics services. Genetic counselors indicated privacy issues were not concerning if social media were to be used in this capacity. The majority of genetic counselor participants (88.7%) indicated they would welcome national guidelines for patient-provider social media use. Data from this study demonstrated that sharing what to expect at a genetic counseling appointment, defining genetic counseling, and announcing community outreach events are possible ways genetic counselors could utilize social media to communicate with and educate patients.

Translational research in genomics of Alzheimer's disease: a review of current practice and future perspectives.

PubMed

Mihaescu, Raluca; Detmar, Symone B; Cornel, Martina C; van der Flier, Wiesje M; Heutink, Peter; Hol, Elly M; Rikkert, Marcel G M Olde; van Duijn, Cornelia M; Janssens, A Cecile J W

2010-01-01

Alzheimer's disease (AD) is the most prevalent form of dementia and the number of cases is expected to increase exponentially worldwide. Three highly penetrant genes (AbetaPP, PSEN1, and PSEN2) explain only a small number of AD cases with a Mendelian transmission pattern. Many genes have been analyzed for association with non-Mendelian AD, but the only consistently replicated finding is APOE. At present, possibilities for prevention, early detection, and treatment of the disease are limited. Predictive and diagnostic genetic testing is available only in Mendelian forms of AD. Currently, APOE genotyping is not considered clinically useful for screening, presymptomatic testing, or clinical diagnosis of non-Mendelian AD. However, clinical management of the disease is expected to benefit from the rapid pace of discoveries in the genomics of AD. Following a recently developed framework for the continuum of translation research that is needed to move genetic discoveries to health applications, this paper reviews recent genetic discoveries as well as translational research on genomic applications in the prevention, early detection, and treatment of AD. The four phases of translation research include: 1) translation of basic genomics research into a potential health care application; 2) evaluation of the application for the development of evidence-based guidelines; 3) evaluation of the implementation and use of the application in health care practice; and 4) evaluation of the achieved population health impact. Most research on genome-based applications in AD is still in the first phase of the translational research framework, which means that further research is still needed before their implementation can be considered.

ASVCP quality assurance guidelines: external quality assessment and comparative testing for reference and in-clinic laboratories.

PubMed

Camus, Melinda S; Flatland, Bente; Freeman, Kathleen P; Cruz Cardona, Janice A

2015-12-01

The purpose of this document is to educate providers of veterinary laboratory diagnostic testing in any setting about comparative testing. These guidelines will define, explain, and illustrate the importance of a multi-faceted laboratory quality management program which includes comparative testing. The guidelines will provide suggestions for implementation of such testing, including which samples should be tested, frequency of testing, and recommendations for result interpretation. Examples and a list of vendors and manufacturers supplying control materials and services to veterinary laboratories are also included. © 2015 American Society for Veterinary Clinical Pathology.

Towards a commercial process for the manufacture of genetically modified T cells for therapy

PubMed Central

Kaiser, A D; Assenmacher, M; Schröder, B; Meyer, M; Orentas, R; Bethke, U; Dropulic, B

2015-01-01

The recent successes of adoptive T-cell immunotherapy for the treatment of hematologic malignancies have highlighted the need for manufacturing processes that are robust and scalable for product commercialization. Here we review some of the more outstanding issues surrounding commercial scale manufacturing of personalized-adoptive T-cell medicinal products. These include closed system operations, improving process robustness and simplifying work flows, reducing labor intensity by implementing process automation, scalability and cost, as well as appropriate testing and tracking of products, all while maintaining strict adherence to Current Good Manufacturing Practices and regulatory guidelines. A decentralized manufacturing model is proposed, where in the future patients' cells could be processed at the point-of-care in the hospital. PMID:25613483

Direct-to-consumer genetic testing: an assessment of genetic counselors' knowledge and beliefs

PubMed Central

Hock, Kathryn T.; Christensen, Kurt D.; Yashar, Beverly M.; Roberts, J. Scott; Gollust, Sarah E.; Uhlmann, Wendy R.

2013-01-01

Purpose Direct-to-consumer genetic testing is a new means of obtaining genetic testing outside of a traditional clinical setting. This study assesses genetic counselors’ experience, knowledge, and beliefs regarding direct-to-consumer genetic testing for tests that would currently be offered in genetics clinics. Methods Members of the National Society of Genetic Counselors completed a web-administered survey in February 2008. Results Response rate was 36%; the final data analysis included 312 respondents. Eighty-three percent of respondents had two or fewer inquiries about direct-to-consumer genetic testing, and 14% had received requests for test interpretation or discussion. Respondents believed that genetic counselors have a professional obligation to be knowledgeable about direct-to-consumer genetic testing (55%) and interpret results (48%). Fifty-one percent of respondents thought genetic testing should be limited to a clinical setting; 56% agreed direct-to-consumer genetic testing is acceptable if genetic counseling is provided. More than 70% of respondents would definitely or possibly consider direct-to-consumer testing for patients who (1) have concerns about genetic discrimination, (2) want anonymous testing, or (3) have geographic constraints. Conclusions Results indicate that genetic counselors have limited patient experiences with direct-to-consumer genetic testing and are cautiously considering if and under what circumstances this approach should be used PMID:21233722

Noonan syndrome: clinical features, diagnosis, and management guidelines.

PubMed

Romano, Alicia A; Allanson, Judith E; Dahlgren, Jovanna; Gelb, Bruce D; Hall, Bryan; Pierpont, Mary Ella; Roberts, Amy E; Robinson, Wanda; Takemoto, Clifford M; Noonan, Jacqueline A

2010-10-01

Noonan syndrome (NS) is a common, clinically and genetically heterogeneous condition characterized by distinctive facial features, short stature, chest deformity, congenital heart disease, and other comorbidities. Gene mutations identified in individuals with the NS phenotype are involved in the Ras/MAPK (mitogen-activated protein kinase) signal transduction pathway and currently explain ∼61% of NS cases. Thus, NS frequently remains a clinical diagnosis. Because of the variability in presentation and the need for multidisciplinary care, it is essential that the condition be identified and managed comprehensively. The Noonan Syndrome Support Group (NSSG) is a nonprofit organization committed to providing support, current information, and understanding to those affected by NS. The NSSG convened a conference of health care providers, all involved in various aspects of NS, to develop these guidelines for use by pediatricians in the diagnosis and management of individuals with NS and to provide updated genetic findings.

Impact of genetic counseling and Connexin-26 and Connexin-30 testing on deaf identity and comprehension of genetic test results in a sample of deaf adults: a prospective, longitudinal study.

PubMed

Palmer, Christina G S; Boudreault, Patrick; Baldwin, Erin E; Sinsheimer, Janet S

2014-01-01

Using a prospective, longitudinal study design, this paper addresses the impact of genetic counseling and testing for deafness on deaf adults and the Deaf community. This study specifically evaluated the effect of genetic counseling and Connexin-26 and Connexin-30 genetic test results on participants' deaf identity and understanding of their genetic test results. Connexin-26 and Connexin-30 genetic testing was offered to participants in the context of linguistically and culturally appropriate genetic counseling. Questionnaire data collected from 209 deaf adults at four time points (baseline, immediately following pre-test genetic counseling, 1-month following genetic test result disclosure, and 6-months after result disclosure) were analyzed. Four deaf identity orientations (hearing, marginal, immersion, bicultural) were evaluated using subscales of the Deaf Identity Development Scale-Revised. We found evidence that participants understood their specific genetic test results following genetic counseling, but found no evidence of change in deaf identity based on genetic counseling or their genetic test results. This study demonstrated that culturally and linguistically appropriate genetic counseling can improve deaf clients' understanding of genetic test results, and the formation of deaf identity was not directly related to genetic counseling or Connexin-26 and Connexin-30 genetic test results.

Could accreditation bodies facilitate the implementation of medical guidelines in laboratories?

PubMed

Aakre, Kristin M; Oosterhuis, Wytze P; Misra, Shivani; Langlois, Michel R; Joseph, Watine; Twomey, Patrick J; Barth, Julian H

2017-05-01

Several studies have shown that recommendations related to how laboratory testing should be performed and results interpreted are limited in medical guidelines and that the uptake and implementation of the recommendations that are available need improvement. The EFLM/UEMS Working Group on Guidelines conducted a survey amongst the national societies for clinical chemistry in Europe regarding development of laboratory-related guidelines. The results showed that most countries have guidelines that are specifically related to laboratory testing; however, not all countries have a formal procedure for accepting such guidelines and few countries have guideline committees. Based on this, the EFLM/UEMS Working Group on Guidelines conclude that there is still room for improvement regarding these processes in Europe and raise the question if the accreditation bodies could be a facilitator for an improvement.

Multigene panels in Ashkenazi Jewish patients yield high rates of actionable mutations in multiple non-BRCA cancer-associated genes.

PubMed

Frey, Melissa K; Sandler, Gabriella; Sobolev, Rachel; Kim, Sarah H; Chambers, Rachelle; Bassett, Rebecca Y; Martineau, Jessica; Sapra, Katherine J; Boyd, Leslie; Curtin, John P; Pothuri, Bhavana; Blank, Stephanie V

2017-07-01

To evaluate the results of multigene panel testing among Ashkenazi Jewish compared with non-Ashkenazi Jewish patients. We reviewed the medical records for all patients who underwent multigene panel testing and targeted BRCA1/2 testing at a single institution between 6/2013-1/2015. Clinical actionability for identified pathogenic mutations was characterized based on the National Comprehensive Cancer Network (NCCN) guidelines and consensus statements and expert opinion for genes not addressed by these guidelines. Four hundred and fifty-four patients underwent multigene panel screening, including 138 Ashkenazi Jewish patients. The median patient age was fifty-two years. Three hundred and fifty-four patients (78%) had a personal history of cancer. Two hundred and fifty-one patients had breast cancer, 49, ovarian cancer, 26, uterine cancer and 20, colorectal cancer. We identified 62 mutations in 56 patients and 291 variants of uncertain significance in 196 patients. Among the 56 patients with mutations, 51 (91%) had actionable mutations. Twenty mutations were identified by multigene panels among Ashkenazi Jewish patients, 18 of which were in genes other than BRCA1/2. A review of targeted BRCA1/2 testing performed over the same study period included 103 patients and identified six mutations in BRCA1/2, all of which occurred in Ashkenazi Jewish patients. Among all Ashkenazi Jewish patients undergoing genetic testing, 25/183 (14%) had a mutation, 24/25 of which were actionable (96%) and 17/25 patients (68%) had mutations in non BRCA1/2 genes. With the rapid acceptance of multigene panels there is a pressing need to understand how this testing will affect patient management. While traditionally many Ashkenazi Jewish patients have undergone targeted BRCA1/2 testing, our data suggest consideration of multigene panels in this population as the majority of the results are clinically actionable and often in genes other than BRCA1/2. Copyright © 2017 Elsevier Inc. All rights reserved.

Knowledge of Genetics and Attitudes toward Genetic Testing among College Students in Saudi Arabia.

PubMed

Olwi, Duaa; Merdad, Leena; Ramadan, Eman

2016-01-01

Genetic testing has been gradually permeating the practice of medicine. Health-care providers may be confronted with new genetic approaches that require genetically informed decisions which will be influenced by patients' knowledge of genetics and their attitudes toward genetic testing. This study assesses the knowledge of genetics and attitudes toward genetic testing among college students. A cross-sectional study was conducted using a multistage stratified sample of 920 senior college students enrolled at King Abdulaziz University, Saudi Arabia. Information regarding knowledge of genetics, attitudes toward genetic testing, and sociodemographic data were collected using a self-administered questionnaire. In general, students had a good knowledge of genetics but lacked some fundamentals of genetics. The majority of students showed positive attitudes toward genetic testing, but some students showed negative attitudes toward certain aspects of genetic testing such as resorting to abortion in the case of an untreatable major genetic defect in an unborn fetus. The main significant predictors of knowledge were faculty, gender, academic year, and some prior awareness of 'genetic testing'. The main significant predictors of attitudes were gender, academic year, grade point average, and some prior awareness of 'genetic testing'. The knowledge of genetics among college students was higher than has been reported in other studies, and the attitudes toward genetic testing were fairly positive. Genetics educational programs that target youths may improve knowledge of genetics and create a public perception that further supports genetic testing. © 2016 S. Karger AG, Basel.

The use of forensic DNA analysis in humanitarian forensic action: The development of a set of international standards.

PubMed

Goodwin, William H

2017-09-01

DNA analysis was first applied to the identification of victims of armed conflicts and other situations of violence (ACOSV) in the mid-1990s, starting in South America and the Balkans. Argentina was the first country to establish a genetic database specifically developed to identify disappeared children. Following on from these programs the early 2000s marked major programs, using a largely DNA-led approach, identifying missing persons in the Balkans and following the attack on the World Trade Center in New York. These two identification programs significantly expanded the magnitude of events to which DNA analysis was used to help provide the identity of missing persons. Guidelines developed by Interpol (2014) [1] related to best practice for identification of human remains following DVI type scenarios have been widely disseminated around the forensic community; in numerous cases these guidelines have been adopted or incorporated into national guidelines/standards/practice. However, given the complexity of many humanitarian contexts in which forensic science is employed there is a lack of internationally accepted guidelines, related to these contexts, for authorities to reference. In response the Argentine government's Human Rights Division in the Ministry of Foreign Affairs and Worship (MREC) proposed that the United Nations (UN) should promote best practice in the use of forensic genetics in humanitarian forensic action: this was adopted by the UN in Resolutions A/HRC/RES/10/26 and A/HRC/RES/15/5. Following on from the adoption of the resolutions MREC has coordinated, with the support of the International Committee of the Red Cross (ICRC), the drafting of a set of guidelines (MREC, ICRC, 2014) [2], with input from national and international agencies. To date the guidelines have been presented to South America's MERCOSUR and the UN and have been disseminated to interested parties. Copyright © 2017 Elsevier B.V. All rights reserved.

Species delimitation, genetic diversity and population historical dynamics of Cycas diannanensis (Cycadaceae) occurring sympatrically in the Red River region of China

PubMed Central

Liu, Jian; Zhou, Wei; Gong, Xun

2015-01-01

Delimitating species boundaries could be of critical importance when evaluating the species' evolving process and providing guidelines for conservation genetics. Here, species delimitation was carried out on three endemic and endangered Cycas species with resembling morphology and overlapped distribution range along the Red River (Yuanjiang) in China: Cycas diananensis Z. T. Guan et G. D. Tao, Cycas parvula S. L. Yang and Cycas multiovula D. Y. Wang. A total of 137 individuals from 15 populations were genotyped by using three chloroplastic (psbA-trnH, atpI-atpH, and trnL-rps4) and two single copy nuclear (RPB1 and SmHP) DNA sequences. Basing on the carefully morphological comparison and cladistic haplotype aggregation (CHA) analysis, we propose all the populations as one species, with the rest two incorporated into C. diannanensis. Genetic diversity and structure analysis of the conflated C. diannanensis revealed this species possessed a relative lower genetic diversity than estimates of other Cycas species. The higher genetic diversity among populations and relative lower genetic diversity within populations, as well as obvious genetic differentiation among populations inferred from chloroplastic DNA (cpDNA) suggested a recent genetic loss within this protected species. Additionally, a clear genetic structure of C. diannanensis corresponding with geography was detected based on cpDNA, dividing its population ranges into “Yuanjiang-Nanhun” basin and “Ejia-Jiepai” basin groups. Demographical history analyses based on combined cpDNA and one nuclear DNA (nDNA) SmHP both showed the population size of C. diannanensis began to decrease in Quaternary glaciation with no subsequent expansion, while another nDNA RPB1 revealed a more recent sudden expansion after long-term population size contraction, suggesting its probable bottleneck events in history. Our findings offer grounded views for clarifying species boundaries of C. diannanensis when determining the conservation objectives. For operational guidelines, the downstream populations which occupy high and peculiar haplotypes should be given prior in-situ conservation. In addition, ex-situ conservation and reintroduction measures for decades of generations are supplemented for improving the population size and genetic diversity of the endemic and endangered species. PMID:26442013

Species delimitation, genetic diversity and population historical dynamics of Cycas diannanensis (Cycadaceae) occurring sympatrically in the Red River region of China.

PubMed

Liu, Jian; Zhou, Wei; Gong, Xun

2015-01-01

Delimitating species boundaries could be of critical importance when evaluating the species' evolving process and providing guidelines for conservation genetics. Here, species delimitation was carried out on three endemic and endangered Cycas species with resembling morphology and overlapped distribution range along the Red River (Yuanjiang) in China: Cycas diananensis Z. T. Guan et G. D. Tao, Cycas parvula S. L. Yang and Cycas multiovula D. Y. Wang. A total of 137 individuals from 15 populations were genotyped by using three chloroplastic (psbA-trnH, atpI-atpH, and trnL-rps4) and two single copy nuclear (RPB1 and SmHP) DNA sequences. Basing on the carefully morphological comparison and cladistic haplotype aggregation (CHA) analysis, we propose all the populations as one species, with the rest two incorporated into C. diannanensis. Genetic diversity and structure analysis of the conflated C. diannanensis revealed this species possessed a relative lower genetic diversity than estimates of other Cycas species. The higher genetic diversity among populations and relative lower genetic diversity within populations, as well as obvious genetic differentiation among populations inferred from chloroplastic DNA (cpDNA) suggested a recent genetic loss within this protected species. Additionally, a clear genetic structure of C. diannanensis corresponding with geography was detected based on cpDNA, dividing its population ranges into "Yuanjiang-Nanhun" basin and "Ejia-Jiepai" basin groups. Demographical history analyses based on combined cpDNA and one nuclear DNA (nDNA) SmHP both showed the population size of C. diannanensis began to decrease in Quaternary glaciation with no subsequent expansion, while another nDNA RPB1 revealed a more recent sudden expansion after long-term population size contraction, suggesting its probable bottleneck events in history. Our findings offer grounded views for clarifying species boundaries of C. diannanensis when determining the conservation objectives. For operational guidelines, the downstream populations which occupy high and peculiar haplotypes should be given prior in-situ conservation. In addition, ex-situ conservation and reintroduction measures for decades of generations are supplemented for improving the population size and genetic diversity of the endemic and endangered species.

EHR based Genetic Testing Knowledge Base (iGTKB) Development

PubMed Central

2015-01-01

Background The gap between a large growing number of genetic tests and a suboptimal clinical workflow of incorporating these tests into regular clinical practice poses barriers to effective reliance on advanced genetic technologies to improve quality of healthcare. A promising solution to fill this gap is to develop an intelligent genetic test recommendation system that not only can provide a comprehensive view of genetic tests as education resources, but also can recommend the most appropriate genetic tests to patients based on clinical evidence. In this study, we developed an EHR based Genetic Testing Knowledge Base for Individualized Medicine (iGTKB). Methods We extracted genetic testing information and patient medical records from EHR systems at Mayo Clinic. Clinical features have been semi-automatically annotated from the clinical notes by applying a Natural Language Processing (NLP) tool, MedTagger suite. To prioritize clinical features for each genetic test, we compared odds ratio across four population groups. Genetic tests, genetic disorders and clinical features with their odds ratios have been applied to establish iGTKB, which is to be integrated into the Genetic Testing Ontology (GTO). Results Overall, there are five genetic tests operated with sample size greater than 100 in 2013 at Mayo Clinic. A total of 1,450 patients who was tested by one of the five genetic tests have been selected. We assembled 243 clinical features from the Human Phenotype Ontology (HPO) for these five genetic tests. There are 60 clinical features with at least one mention in clinical notes of patients taking the test. Twenty-eight clinical features with high odds ratio (greater than 1) have been selected as dominant features and deposited into iGTKB with their associated information about genetic tests and genetic disorders. Conclusions In this study, we developed an EHR based genetic testing knowledge base, iGTKB. iGTKB will be integrated into the GTO by providing relevant clinical evidence, and ultimately to support development of genetic testing recommendation system, iGenetics. PMID:26606281

EHR based Genetic Testing Knowledge Base (iGTKB) Development.

PubMed

Zhu, Qian; Liu, Hongfang; Chute, Christopher G; Ferber, Matthew

2015-01-01

The gap between a large growing number of genetic tests and a suboptimal clinical workflow of incorporating these tests into regular clinical practice poses barriers to effective reliance on advanced genetic technologies to improve quality of healthcare. A promising solution to fill this gap is to develop an intelligent genetic test recommendation system that not only can provide a comprehensive view of genetic tests as education resources, but also can recommend the most appropriate genetic tests to patients based on clinical evidence. In this study, we developed an EHR based Genetic Testing Knowledge Base for Individualized Medicine (iGTKB). We extracted genetic testing information and patient medical records from EHR systems at Mayo Clinic. Clinical features have been semi-automatically annotated from the clinical notes by applying a Natural Language Processing (NLP) tool, MedTagger suite. To prioritize clinical features for each genetic test, we compared odds ratio across four population groups. Genetic tests, genetic disorders and clinical features with their odds ratios have been applied to establish iGTKB, which is to be integrated into the Genetic Testing Ontology (GTO). Overall, there are five genetic tests operated with sample size greater than 100 in 2013 at Mayo Clinic. A total of 1,450 patients who was tested by one of the five genetic tests have been selected. We assembled 243 clinical features from the Human Phenotype Ontology (HPO) for these five genetic tests. There are 60 clinical features with at least one mention in clinical notes of patients taking the test. Twenty-eight clinical features with high odds ratio (greater than 1) have been selected as dominant features and deposited into iGTKB with their associated information about genetic tests and genetic disorders. In this study, we developed an EHR based genetic testing knowledge base, iGTKB. iGTKB will be integrated into the GTO by providing relevant clinical evidence, and ultimately to support development of genetic testing recommendation system, iGenetics.

Identification of a Novel BRCA1 Pathogenic Mutation in Korean Patients Following Reclassification of BRCA1 and BRCA2 Variants According to the ACMG Standards and Guidelines Using Relevant Ethnic Controls.

PubMed

Park, Ji Soo; Nam, Eun Ji; Park, Hyung Seok; Han, Jung Woo; Lee, Jung-Yun; Kim, Jieun; Kim, Tae Il; Lee, Seung-Tae

2017-10-01

Comparison of variant frequencies in the general population has become an essential part of the American College of Medical Genetics and Genomics (ACMG) standards and guidelines for interpreting sequence variants. We determined the optimal number of relevant ethnic controls that should be used to accurately calculate the odds ratio (OR) of genetic variants. Using the ACMG guidelines, we reclassified BRCA1 and BRCA2 mutations and variants of unknown significance in 745 Korean patients susceptible to hereditary breast and ovarian cancer compared with 1,314 Korean population controls. We observed that the ORs were falsely inflated when we analyzed several variants using non-Korean population data. Our simulation indicated that the number of controls needed for the lower limit of a 95% confidence interval to exceed 1.0 varied according to the frequency of the variant in each patient group, with more than 820 controls needed for a variant existing in 1% of cases. Using a sufficient number of relevant population data, we could efficiently classify variants and identified the BRCA1 p.Leu1780Pro mutation as a possible pathogenic founder mutation in Korean patients. Our study suggests that BRCA1 p.Leu1780Pro is a novel pathogenic mutation found in Korean patients. We also determined the optimal number of relevant ethnic controls needed for accurate variant classification according to the ACMG guidelines.

Recommendations for the inclusion of Fabry disease as a rare febrile condition in existing algorithms for fever of unknown origin.

PubMed

Manna, Raffaele; Cauda, Roberto; Feriozzi, Sandro; Gambaro, Giovanni; Gasbarrini, Antonio; Lacombe, Didier; Livneh, Avi; Martini, Alberto; Ozdogan, Huri; Pisani, Antonio; Riccio, Eleonora; Verrecchia, Elena; Dagna, Lorenzo

2017-10-01

Fever of unknown origin (FUO) is a rather rare clinical syndrome representing a major diagnostic challenge. The occurrence of more than three febrile attacks with fever-free intervals of variable duration during 6 months of observation has recently been proposed as a subcategory of FUO, Recurrent FUO (RFUO). A substantial number of patients with RFUO have auto-inflammatory genetic fevers, but many patients remain undiagnosed. We hypothesize that this undiagnosed subgroup may be comprised of, at least in part, a number of rare genetic febrile diseases such as Fabry disease. We aimed to identify key features or potential diagnostic clues for Fabry disease as a model of rare genetic febrile diseases causing RFUO, and to develop diagnostic guidelines for RFUO, using Fabry disease as an example of inserting other rare diseases in the existing FUO algorithms. An international panel of specialists in recurrent fevers and rare diseases, including internists, infectious disease specialists, rheumatologists, gastroenterologists, nephrologists, and medical geneticists convened to review the existing diagnostic algorithms, and to suggest recommendations for arriving at accurate diagnoses on the basis of available literature and clinical experience. By combining specific features of rare diseases with other diagnostic considerations, guidelines have been designed to raise awareness and identify rare diseases among other causes of FUO. The proposed guidelines may be useful for the inclusion of rare diseases in the diagnostic algorithms for FUO. A wide spectrum of patients will be needed to validate the algorithm in different clinical settings.

Electronic Risk Assessment System as an Appropriate Tool for the Prevention of Cancer: a Qualitative Study.

PubMed

Javan Amoli, Amir Hossein; Maserat, Elham; Safdari, Reza; Zali, Mohammad Reza

2015-01-01

Decision making modalities for screening for many cancer conditions and different stages have become increasingly complex. Computer-based risk assessment systems facilitate scheduling and decision making and support the delivery of cancer screening services. The aim of this article was to survey electronic risk assessment system as an appropriate tool for the prevention of cancer. A qualitative design was used involving 21 face-to-face interviews. Interviewing involved asking questions and getting answers from exclusive managers of cancer screening. Of the participants 6 were female and 15 were male, and ages ranged from 32 to 78 years. The study was based on a grounded theory approach and the tool was a semi- structured interview. Researchers studied 5 dimensions, comprising electronic guideline standards of colorectal cancer screening, work flow of clinical and genetic activities, pathways of colorectal cancer screening and functionality of computer based guidelines and barriers. Electronic guideline standards of colorectal cancer screening were described in the s3 categories of content standard, telecommunications and technical standards and nomenclature and classification standards. According to the participations' views, workflow and genetic pathways of colorectal cancer screening were identified. The study demonstrated an effective role of computer-guided consultation for screening management. Electronic based systems facilitate real-time decision making during a clinical interaction. Electronic pathways have been applied for clinical and genetic decision support, workflow management, update recommendation and resource estimates. A suitable technical and clinical infrastructure is an integral part of clinical practice guidline of screening. As a conclusion, it is recommended to consider the necessity of architecture assessment and also integration standards.

Impact of Genetic Counseling and Connexin-26 and Connexin-30 Testing on Deaf Identity and Comprehension of Genetic Test Results in a Sample of Deaf Adults: A Prospective, Longitudinal Study

PubMed Central

Palmer, Christina G. S.; Boudreault, Patrick; Baldwin, Erin E.; Sinsheimer, Janet S.

2014-01-01

Using a prospective, longitudinal study design, this paper addresses the impact of genetic counseling and testing for deafness on deaf adults and the Deaf community. This study specifically evaluated the effect of genetic counseling and Connexin-26 and Connexin-30 genetic test results on participants' deaf identity and understanding of their genetic test results. Connexin-26 and Connexin-30 genetic testing was offered to participants in the context of linguistically and culturally appropriate genetic counseling. Questionnaire data collected from 209 deaf adults at four time points (baseline, immediately following pre-test genetic counseling, 1-month following genetic test result disclosure, and 6-months after result disclosure) were analyzed. Four deaf identity orientations (hearing, marginal, immersion, bicultural) were evaluated using subscales of the Deaf Identity Development Scale-Revised. We found evidence that participants understood their specific genetic test results following genetic counseling, but found no evidence of change in deaf identity based on genetic counseling or their genetic test results. This study demonstrated that culturally and linguistically appropriate genetic counseling can improve deaf clients' understanding of genetic test results, and the formation of deaf identity was not directly related to genetic counseling or Connexin-26 and Connexin-30 genetic test results. PMID:25375116

Mouse models of neurodegenerative diseases: criteria and general methodology.

PubMed

Janus, Christopher; Welzl, Hans

2010-01-01

The major symptom of Alzheimer's disease is rapidly progressing dementia, coinciding with the formation of amyloid and tau deposits in the central nervous system, and neuronal death. At present familial cases of dementias provide the most promising foundation for modelling neurodegeneration. We describe the mnemonic and other major behavioral symptoms of tauopathies, briefly outline the genetics underlying familiar cases and discuss the arising implications for modelling the disease in mostly transgenic mouse lines. We then depict to what degree the most recent mouse models replicate pathological and cognitive characteristics observed in patients.There is no universally valid behavioral test battery to evaluate mouse models. The selection of individual tests depends on the behavioral and/or memory system in focus, the type of a model and how well it replicates the pathology of a disease and the amount of control over the genetic background of the mouse model. However it is possible to provide guidelines and criteria for modelling the neurodegeneration, setting up the experiments and choosing relevant tests. One should not adopt a "one (trans)gene, one disease" interpretation, but should try to understand how the mouse genome copes with the protein expression of the transgene in question. Further, it is not possible to recommend some mouse models over others since each model is valuable within its own constraints, and the way experiments are performed often reflects the idiosyncratic reality of specific laboratories. Our purpose is to improve bridging molecular and behavioural approaches in translational research.

What Is Direct-to-Consumer Genetic Testing?

MedlinePlus

... consumer genetic testing? What is direct-to-consumer genetic testing? Most of the time, genetic testing is ... testing. For more information about direct-to-consumer genetic testing: Centers for Disease Control and Prevention (CDC) ...

Catch-up validation study of an in vitro skin irritation test method based on an open source reconstructed epidermis (phase II).

PubMed

Groeber, F; Schober, L; Schmid, F F; Traube, A; Kolbus-Hernandez, S; Daton, K; Hoffmann, S; Petersohn, D; Schäfer-Korting, M; Walles, H; Mewes, K R

2016-10-01

To replace the Draize skin irritation assay (OECD guideline 404) several test methods based on reconstructed human epidermis (RHE) have been developed and were adopted in the OECD test guideline 439. However, all validated test methods in the guideline are linked to RHE provided by only three companies. Thus, the availability of these test models is dependent on the commercial interest of the producer. To overcome this limitation and thus to increase the accessibility of in vitro skin irritation testing, an open source reconstructed epidermis (OS-REp) was introduced. To demonstrate the capacity of the OS-REp in regulatory risk assessment, a catch-up validation study was performed. The participating laboratories used in-house generated OS-REp to assess the set of 20 reference substances according to the performance standards amending the OECD test guideline 439. Testing was performed under blinded conditions. The within-laboratory reproducibility of 87% and the inter-laboratory reproducibility of 85% prove a high reliability of irritancy testing using the OS-REp protocol. In addition, the prediction capacity was with an accuracy of 80% comparable to previous published RHE based test protocols. Taken together the results indicate that the OS-REp test method can be used as a standalone alternative skin irritation test replacing the OECD test guideline 404. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.