Genetic screening of Greek patients with Huntington’s disease phenocopies identifies an SCA8 expansion.

PubMed

Koutsis, G; Karadima, G; Pandraud, A; Sweeney, M G; Paudel, R; Houlden, H; Wood, N W; Panas, M

2012-09-01

Huntington’s disease (HD) is an autosomal dominant disorder characterized by a triad of chorea, psychiatric disturbance and cognitive decline. Around 1% of patients with HD-like symptoms lack the causative HD expansion and are considered HD phenocopies. Genetic diseases that can present as HD phenocopies include HD-like syndromes such as HDL1, HDL2 and HDL4 (SCA17), some spinocerebellar ataxias (SCAs) and dentatorubral-pallidoluysian atrophy (DRPLA). In this study we screened a cohort of 21 Greek patients with HD phenocopy syndromes formutations causing HDL2, SCA17, SCA1, SCA2, SCA3,SCA8, SCA12 and DRPLA. Fifteen patients (71%) had a positive family history. We identified one patient (4.8% of the total cohort) with an expansion of 81 combined CTA/CTG repeats at the SCA8 locus. This falls within what is believed to be the high-penetrance allele range. In addition to the classic HD triad, the patient had features of dystonia and oculomotor apraxia. There were no cases of HDL2, SCA17, SCA1, SCA2, SCA3, SCA12 or DRPLA. Given the controversy surrounding the SCA8 expansion, the present finding may be incidental. However, if pathogenic, it broadens the phenotype that may be associated with SCA8 expansions. The absence of any other mutations in our cohort is not surprising, given the low probability of reaching a genetic diagnosis in HD phenocopy patients.

Preimplantation genetic diagnosis and screening by array comparative genomic hybridisation: experience of more than 100 cases in a single centre.

PubMed

Chow, J Fc; Yeung, W Sb; Lee, V Cy; Lau, E Yl; Ho, P C; Ng, E Hy

2017-04-01

Preimplantation genetic screening has been proposed to improve the in-vitro fertilisation outcome by screening for aneuploid embryos or blastocysts. This study aimed to report the outcome of 133 cycles of preimplantation genetic diagnosis and screening by array comparative genomic hybridisation. This study of case series was conducted in a tertiary assisted reproductive centre in Hong Kong. Patients who underwent preimplantation genetic diagnosis for chromosomal abnormalities or preimplantation genetic screening between 1 April 2012 and 30 June 2015 were included. They underwent in-vitro fertilisation and intracytoplasmic sperm injection. An embryo biopsy was performed on day-3 embryos and the blastomere was subject to array comparative genomic hybridisation. Embryos with normal copy numbers were replaced. The ongoing pregnancy rate, implantation rate, and miscarriage rate were studied. During the study period, 133 cycles of preimplantation genetic diagnosis for chromosomal abnormalities or preimplantation genetic screening were initiated in 94 patients. Overall, 112 cycles proceeded to embryo biopsy and 65 cycles had embryo transfer. The ongoing pregnancy rate per transfer cycle after preimplantation genetic screening was 50.0% and that after preimplantation genetic diagnosis was 34.9%. The implantation rates after preimplantation genetic screening and diagnosis were 45.7% and 41.1%, respectively and the miscarriage rates were 8.3% and 28.6%, respectively. There were 26 frozen-thawed embryo transfer cycles, in which vitrified and biopsied genetically transferrable embryos were replaced, resulting in an ongoing pregnancy rate of 36.4% in the screening group and 60.0% in the diagnosis group. The clinical outcomes of preimplantation genetic diagnosis and screening using comparative genomic hybridisation in our unit were comparable to those reported internationally. Genetically transferrable embryos replaced in a natural cycle may improve the ongoing pregnancy rate

Clinician-Stakeholders' Perspectives on Using Patient Portals to Return Lynch Syndrome Screening Results.

PubMed

Korngiebel, Diane M; West, Kathleen M; Burke, Wylie

2018-04-01

Test results for genetic conditions, such as Lynch Syndrome (LS), have traditionally been returned by genetic counselors or other providers who can explain results implications and provide psychosocial support. Returning genetic results through an Electronic Health Record's patient portal may increase the efficiency of returning results and could activate patient follow-up; however, stakeholder input is necessary to determine acceptability and appropriate implementation for LS. Twenty interviews were conducted with clinicians from six specialties involved in LS screening that represent a range of settings. Data were analyzed using directed content analysis and thematic analysis across content categories. Participants felt that patient portals could supplement personal calls, but the potential sensitive nature of LS screening results indicated the need for caution. Others felt that LS results could be returned through portals if there were clear explanations of the result, reputable additional information available within the portal, urging follow up confirmatory testing, and a referral to a genetics specialist. Patient portals were seen as helpful for prompting patient follow-up and providing resources to notify at-risk family members. There is potential for patient portals to return LS screening and other genetic results, however we raise several issues to resolve before implementation is warranted.

Impact of preimplantation genetic screening on donor oocyte-recipient cycles in the United States.

PubMed

Barad, David H; Darmon, Sarah K; Kushnir, Vitaly A; Albertini, David F; Gleicher, Norbert

2017-11-01

Our objective was to estimate the contribution of preimplantation genetic screening to in vitro fertilization pregnancy outcomes in donor oocyte-recipient cycles. This was a retrospective cross-sectional study of US national data from the Society for Assisted Reproductive Technology Clinic Outcome Reporting System between 2005 and 2013. Society for Assisted Reproductive Technology Clinic Outcome Reporting relies on voluntarily annual reports by more than 90% of US in vitro fertilization centers. We evaluated pregnancy and live birth rates in donor oocyte-recipient cycles after the first embryo transfer with day 5/6 embryos. Statistical models, adjusted for patient and donor ages, number of embryos transferred, race, infertility diagnosis, and cycle year were created to compare live birth rates in 392 preimplantation genetic screening and 20,616 control cycles. Overall, pregnancy and live birth rates were significantly lower in preimplantation genetic screening cycles than in control cycles. Adjusted odds of live birth for preimplantation genetic screening cycles were reduced by 35% (odds ratio, 0.65, 95% confidence interval, 0.53-0.80; P < .001). Preimplantation genetic screening, as practiced in donor oocyte-recipient cycles over the past 9 years, has not been associated with improved odds of live birth or reduction in miscarriage rates. Copyright © 2017 Elsevier Inc. All rights reserved.

Nationwide genetic analysis for molecularly unresolved cystic fibrosis patients in a multiethnic society: implications for preconception carrier screening.

PubMed

Behar, Doron M; Inbar, Ori; Shteinberg, Michal; Gur, Michal; Mussaffi, Huda; Shoseyov, David; Ashkenazi, Moshe; Alkrinawi, Soliman; Bormans, Concetta; Hakim, Fahed; Mei-Zahav, Meir; Cohen-Cymberknoh, Malena; Dagan, Adi; Prais, Dario; Sarouk, Ifat; Stafler, Patrick; Bar Aluma, Bat El; Akler, Gidon; Picard, Elie; Aviram, Micha; Efrati, Ori; Livnat, Galit; Rivlin, Joseph; Bentur, Lea; Blau, Hannah; Kerem, Eitan; Singer, Amihood

2017-05-01

Preconception carrier screening for cystic fibrosis (CF) is usually performed using ethnically targeted panels of selected mutations. This has been recently challenged by the use of expanded, ethnically indifferent, pan-population panels. Israel is characterized by genetically heterogeneous populations carrying a wide range of CFTR mutations. To assess the potential of expanding the current Israeli preconception screening program, we sought the subset of molecularly unresolved CF patients listed in the Israeli CF data registry comprising ~650 patients. An Israeli nationwide genotyping of 152 CF cases, representing 176 patients lacking molecular diagnosis, was conducted. Molecular analysis included Sanger sequencing for all exons and splice sites, multiplex ligation probe amplification (MLPA), and next-generation sequencing of the poly-T/TG tracts. We identified 54 different mutations, of which only 16 overlapped the 22 mutations included in the Israeli preconception screening program. A total of 29/54 (53.7%) mutations were already listed as CF causing by the CFTR2 database, and only 4/54 (7.4%) were novel. Molecular diagnosis was reached in 78/152 (51.3%) cases. Prenatal diagnosis of 24/78 (30.8%) cases could have been achieved by including all CFTR2-causing mutations in the Israeli panel. Our data reveal an overwhelming hidden abundance of CFTR gene mutations suggesting that expanded preconception carrier screening might achieve higher preconception detection rates.

Position statement on opportunistic genomic screening from the Association of Genetic Nurses and Counsellors (UK and Ireland).

PubMed

Middleton, Anna; Patch, Chris; Wiggins, Jennifer; Barnes, Kathy; Crawford, Gill; Benjamin, Caroline; Bruce, Anita

2014-08-01

The American College of Medical Genetics and Genomics released recommendations for reporting incidental findings (IFs) in clinical exome and genome sequencing. These suggest 'opportunistic genomic screening' should be available to both adults and children each time a sequence is done and would be undertaken without seeking preferences from the patient first. Should opportunistic genomic screening be implemented in the United Kingdom, the Association of Genetic Nurses and Counsellors (AGNC), which represents British and Irish genetic counsellors and nurses, feels strongly that the following must be considered (see article for complete list): (1) Following appropriate genetic counselling, patients should be allowed to consent to or opt out of opportunistic genomic screening. (2) If true IFs are discovered the AGNC are guided by the report from the Joint Committee on Medical Genetics about the sharing of genetic testing results. (3) Children should not be routinely tested for adult-onset conditions. (4) The formation of a list of variants should involve a representative from the AGNC as well as a patient support group. (5) The variants should be for serious or life-threatening conditions for which there are treatments or preventative strategies available. (6) There needs to be robust evidence that the benefits of opportunistic screening outweigh the potential harms. (7) The clinical validity and utility of variants should be known. (8) There must be a quality assurance framework that operates to International standards for laboratory testing. (9) Psychosocial research is urgently needed in this area to understand the impact on patients.

CRISPR genetic screens to discover host-virus interactions.

PubMed

McDougall, William M; Perreira, Jill M; Reynolds, Erin C; Brass, Abraham L

2018-04-01

Viruses impose an immense burden on human health. With the goal of treating and preventing viral infections, researchers have carried out genetic screens to improve our understanding of viral dependencies and identify potential anti-viral strategies. The emergence of CRISPR genetic screening tools has facilitated this effort by enabling host-virus screens to be undertaken in a more versatile and fidelitous manner than previously possible. Here we review the growing number of CRISPR screens which continue to increase our understanding of host-virus interactions. Copyright © 2018 Elsevier B.V. All rights reserved.

The genetics underlying acquired long QT syndrome: impact for genetic screening.

PubMed

Itoh, Hideki; Crotti, Lia; Aiba, Takeshi; Spazzolini, Carla; Denjoy, Isabelle; Fressart, Véronique; Hayashi, Kenshi; Nakajima, Tadashi; Ohno, Seiko; Makiyama, Takeru; Wu, Jie; Hasegawa, Kanae; Mastantuono, Elisa; Dagradi, Federica; Pedrazzini, Matteo; Yamagishi, Masakazu; Berthet, Myriam; Murakami, Yoshitaka; Shimizu, Wataru; Guicheney, Pascale; Schwartz, Peter J; Horie, Minoru

2016-05-07

Acquired long QT syndrome (aLQTS) exhibits QT prolongation and Torsades de Pointes ventricular tachycardia triggered by drugs, hypokalaemia, or bradycardia. Sometimes, QTc remains prolonged despite elimination of triggers, suggesting the presence of an underlying genetic substrate. In aLQTS subjects, we assessed the prevalence of mutations in major LQTS genes and their probability of being carriers of a disease-causing genetic variant based on clinical factors. We screened for the five major LQTS genes among 188 aLQTS probands (55 ± 20 years, 140 females) from Japan, France, and Italy. Based on control QTc (without triggers), subjects were designated 'true aLQTS' (QTc within normal limits) or 'unmasked cLQTS' (all others) and compared for QTc and genetics with 2379 members of 1010 genotyped congenital long QT syndrome (cLQTS) families. Cardiac symptoms were present in 86% of aLQTS subjects. Control QTc of aLQTS was 453 ± 39 ms, shorter than in cLQTS (478 ± 46 ms, P < 0.001) and longer than in non-carriers (406 ± 26 ms, P < 0.001). In 53 (28%) aLQTS subjects, 47 disease-causing mutations were identified. Compared with cLQTS, in 'true aLQTS', KCNQ1 mutations were much less frequent than KCNH2 (20% [95% CI 7-41%] vs. 64% [95% CI 43-82%], P < 0.01). A clinical score based on control QTc, age, and symptoms allowed identification of patients more likely to carry LQTS mutations. A third of aLQTS patients carry cLQTS mutations, those on KCNH2 being more common. The probability of being a carrier of cLQTS disease-causing mutations can be predicted by simple clinical parameters, thus allowing possibly cost-effective genetic testing leading to cascade screening for identification of additional at-risk family members. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.

Universal screening for Lynch syndrome among patients with colorectal cancer: Patient perspectives on screening and sharing results with at-risk relatives

PubMed Central

Hunter, Jessica Ezzell; Arnold, Kathleen A.; Cook, Jennifer E.; Zepp, Jamilyn; Gilmore, Marian J.; Rope, Alan F.; Davis, James V.; Bergen, Kellene M.; Esterberg, Elizabeth; Muessig, Kristin R.; Peterson, Susan K.; Syngal, Sapna; Acheson, Louise; Wiesner, Georgia; Reiss, Jacob; Goddard, Katrina A.B.

2018-01-01

Universal screening for Lynch syndrome (LS) among all cases of colorectal cancer (CRC) could increase the diagnosis of LS and reduce morbidity and mortality of LS-associated cancers. Given universal screening includes all patients, irrespective of high risk factors such early age at onset or family history of CRC, it is important to understand perspectives of all patients and not just those at high risk. As part of a study to assess the feasibility and implementation of universal screening, 189 patients newly diagnosed with CRC were surveyed about their interest in screening for LS and communication of results with at-risk family members. Overall, participants responded positively regarding screening for LS, with most wanting to know their genetic risks in general (86%) and risk of hereditary CRC (93%). Prior to receiving screening results, most participants stated they intended to share their screening results with parents (89%), siblings (96%), and children (96%). Of the 28 participants who received a positive LS screening result, 26 (93%) reported sharing their result with at least one first-degree family member. Interest in screening for LS and communication of screening results with family members was not associated with high risk factors. This study indicates that patients are interested in being screened for LS and that sharing information on the risk of LS with at-risk family members is not a significant barrier. These findings provide novel insight into patient perspectives about screening for LS and can guide successful implementation of universal screening programs. PMID:28176204

Studying circadian rhythm and sleep using genetic screens in Drosophila.

PubMed

Axelrod, Sofia; Saez, Lino; Young, Michael W

2015-01-01

The power of Drosophila melanogaster as a model organism lies in its ability to be used for large-scale genetic screens with the capacity to uncover the genetic basis of biological processes. In particular, genetic screens for circadian behavior, which have been performed since 1971, allowed researchers to make groundbreaking discoveries on multiple levels: they discovered that there is a genetic basis for circadian behavior, they identified the so-called core clock genes that govern this process, and they started to paint a detailed picture of the molecular functions of these clock genes and their encoded proteins. Since the discovery that fruit flies sleep in 2000, researchers have successfully been using genetic screening to elucidate the many questions surrounding this basic animal behavior. In this chapter, we briefly recall the history of circadian rhythm and sleep screens and then move on to describe techniques currently employed for mutagenesis and genetic screening in the field. The emphasis lies on comparing the newer approaches of transgenic RNA interference (RNAi) to classical forms of mutagenesis, in particular in their application to circadian behavior and sleep. We discuss the different screening approaches in light of the literature and published and unpublished sleep and rhythm screens utilizing ethyl methanesulfonate mutagenesis and transgenic RNAi from our lab. © 2015 Elsevier Inc. All rights reserved.

Screening Jews and genes: a consideration of the ethics of genetic screening within the Jewish community: challenges and responses.

PubMed

Levin, M

1999-01-01

Screening for genetic disorders, particularly Tay-Sachs Disease, has been traditionally welcome by the Jewish community. I review the history of genetic screening among Jews and the views from the Jewish tradition on the subject, and then discuss ethical challenges of screening and the impact of historical memories upon future acceptance of screening programs. Some rational principles to guide future design of genetic screening programs among Jews are proposed.

A genetic screen of the mutations in the Korean patients with early-onset Alzheimer’s disease

PubMed Central

An, Seong Soo; Park, Sun Ah; Bagyinszky, Eva; Bae, Sun Oh; Kim, Yoon-Jeong; Im, Ji Young; Park, Kyung Won; Park, Kee Hyung; Kim, Eun-Joo; Jeong, Jee Hyang; Kim, Jong Hun; Han, Hyun Jeong; Choi, Seong Hye; Kim, SangYun

2016-01-01

Early-onset Alzheimer’s disease (EOAD) has distinct clinical characteristics in comparison to late-onset Alzheimer’s disease (LOAD). The genetic contribution is suggested to be more potent in EOAD. However, the frequency of causative mutations in EOAD could be variable depending on studies. Moreover, no mutation screening study has been performed yet employing large population in Korea. Previously, we reported that the rate of family history of dementia in EOAD patients was 18.7% in a nationwide hospital-based cohort study, the Clinical Research Center for Dementia of South Korea (CREDOS) study. This rate is much lower than in other countries and is even comparable to the frequency of LOAD patients in our country. To understand the genetic characteristics of EOAD in Korea, we screened the common Alzheimer’s disease (AD) mutations in the consecutive EOAD subjects from the CREDOS study from April 2012 to February 2014. We checked the sequence of APP (exons 16–17), PSEN1 (exons 3–12), and PSEN2 (exons 3–12) genes. We identified different causative or probable pathogenic AD mutations, PSEN1 T116I, PSEN1 L226F, and PSEN2 V214L, employing 24 EOAD subjects with a family history and 80 without a family history of dementia. PSEN1 T116I case demonstrated autosomal dominant trait of inheritance, with at least 11 affected individuals over 2 generations. However, there was no family history of dementia within first-degree relation in PSEN1 L226F and PSEN2 V214L cases. Approximately, 55.7% of the EOAD subjects had APOE ε4 allele, while none of the mutation-carrying subjects had the allele. The frequency of genetic mutation in this study is lower compared to the studies from other countries. The study design that was based on nationwide cohort, which minimizes selection bias, is thought to be one of the contributors to the lower frequency of genetic mutation. However, the possibility of the greater likeliness of earlier onset of sporadic AD in Korea cannot be

Evaluation of two-year Jewish genetic disease screening program in Atlanta: insight into community genetic screening approaches.

PubMed

Shao, Yunru; Liu, Shuling; Grinzaid, Karen

2015-04-01

Improvements in genetic testing technologies have led to the development of expanded carrier screening panels for the Ashkenazi Jewish population; however, there are major inconsistencies in current screening practices. A 2-year pilot program was launched in Atlanta in 2010 to promote and facilitate screening for 19 Jewish genetic diseases. We analyzed data from this program, including participant demographics and outreach efforts. This retrospective analysis is based on a de-identified dataset of 724 screenees. Data were obtained through medical chart review and questionnaires and included demographic information, screening results, response to outreach efforts, and follow-up behavior and preferences. We applied descriptive analysis, chi-square tests, and logistic regression to analyze the data and compare findings with published literature. The majority of participants indicated that they were not pregnant or did not have a partner who was pregnant were affiliated with Jewish organizations and reported 100 % AJ ancestry. Overall, carrier frequency was 1 in 3.9. Friends, rabbis, and family members were the most common influencers of the decision to receive screening. People who were older, had a history of pregnancy, and had been previously screened were more likely to educate others (all p < 0.05). Analysis of this 2-year program indicated that people who are ready to have children or expand their families are more likely to get screened and encourage others to be screened. The most effective outreach efforts targeted influencers who then encouraged screening in the target population. Educating influencers and increasing overall awareness were the most effective outreach strategies.

Genetic screens for mutations affecting development of Xenopus tropicalis.

PubMed

Goda, Tadahiro; Abu-Daya, Anita; Carruthers, Samantha; Clark, Matthew D; Stemple, Derek L; Zimmerman, Lyle B

2006-06-01

We present here the results of forward and reverse genetic screens for chemically-induced mutations in Xenopus tropicalis. In our forward genetic screen, we have uncovered 77 candidate phenotypes in diverse organogenesis and differentiation processes. Using a gynogenetic screen design, which minimizes time and husbandry space expenditures, we find that if a phenotype is detected in the gynogenetic F2 of a given F1 female twice, it is highly likely to be a heritable abnormality (29/29 cases). We have also demonstrated the feasibility of reverse genetic approaches for obtaining carriers of mutations in specific genes, and have directly determined an induced mutation rate by sequencing specific exons from a mutagenized population. The Xenopus system, with its well-understood embryology, fate map, and gain-of-function approaches, can now be coupled with efficient loss-of-function genetic strategies for vertebrate functional genomics and developmental genetics.

Initiation of universal tumor screening for Lynch syndrome in colorectal cancer patients as a model for the implementation of genetic information into clinical oncology practice.

PubMed

Cohen, Stacey A; Laurino, Mercy; Bowen, Deborah J; Upton, Melissa P; Pritchard, Colin; Hisama, Fuki; Jarvik, Gail; Fichera, Alessandro; Sjoding, Britta; Bennett, Robin L; Naylor, Lorraine; Jacobson, Angela; Burke, Wylie; Grady, William M

2016-02-01

Lynch syndrome confers a hereditary predisposition to colorectal and other cancers. Universal tumor screening (UTS) for Lynch syndrome is recommended by several professional societies, but the implementation can be complex. This article describes the evaluation, process development, and initiation of Lynch syndrome UTS at a tertiary referral cancer center. A multidisciplinary team developed the new process design. Issues in 5 themes were noted: timing, funding, second-opinion patients, result processing, and the role of genetics providers. A committee approach was used to examine each issue for process-improvement development. The issues related to testing were addressed individually for the successful implementation of UTS at the institutional level. In the conventional-care period, 9 of 30 cases (30%) received Lynch syndrome screening, and 4 cases were referred to medical genetics. During the 6 months following the implementation of UTS, 32 of 44 patients (73%) received Lynch syndrome screening. The 13 unscreened patients all had identified reasons for nonscreening (eg, financial limitations). Ten patients were referred to medical genetics, which identified no new cases of Lynch syndrome, but a low-risk adenomatous polyposis coli (APC) variant was detected in 1 individual. The implementation of effective Lynch syndrome UTS can feasibly alter practice at the institutional level. This experience with the assessment and management of issues relevant to the successful implementation of a new clinical care paradigm based on emerging technology has implications for the uptake of advances across molecular oncology into clinical practice, and this is highly relevant in the current era of rapidly evolving genomic technology. © 2015 American Cancer Society.

Genetic screening in adolescents with steroid-resistant nephrotic syndrome.

PubMed

Lipska, Beata S; Iatropoulos, Paraskevas; Maranta, Ramona; Caridi, Gianluca; Ozaltin, Fatih; Anarat, Ali; Balat, Ayse; Gellermann, Jutta; Trautmann, Agnes; Erdogan, Ozlem; Saeed, Bassam; Emre, Sevinc; Bogdanovic, Radovan; Azocar, Marta; Balasz-Chmielewska, Irena; Benetti, Elisa; Caliskan, Salim; Mir, Sevgi; Melk, Anette; Ertan, Pelin; Baskin, Esra; Jardim, Helena; Davitaia, Tinatin; Wasilewska, Anna; Drozdz, Dorota; Szczepanska, Maria; Jankauskiene, Augustina; Higuita, Lina Maria Serna; Ardissino, Gianluigi; Ozkaya, Ozan; Kuzma-Mroczkowska, Elzbieta; Soylemezoglu, Oguz; Ranchin, Bruno; Medynska, Anna; Tkaczyk, Marcin; Peco-Antic, Amira; Akil, Ipek; Jarmolinski, Tomasz; Firszt-Adamczyk, Agnieszka; Dusek, Jiri; Simonetti, Giacomo D; Gok, Faysal; Gheissari, Alaleh; Emma, Francesco; Krmar, Rafael T; Fischbach, Michel; Printza, Nikoleta; Simkova, Eva; Mele, Caterina; Ghiggeri, Gian Marco; Schaefer, Franz

2013-07-01

Genetic screening paradigms for congenital and infantile nephrotic syndrome are well established; however, screening in adolescents has received only minor attention. To help rectify this, we analyzed an unselected adolescent cohort of the international PodoNet registry to develop a rational screening approach based on 227 patients with nonsyndromic steroid-resistant nephrotic syndrome aged 10-20 years. Of these, 21% had a positive family history. Autosomal dominant cases were screened for WT1, TRPC6, ACTN4, and INF2 mutations. All other patients had the NPHS2 gene screened, and WT1 was tested in sporadic cases. In addition, 40 sporadic cases had the entire coding region of INF2 tested. Of the autosomal recessive and the sporadic cases, 13 and 6%, respectively, were found to have podocin-associated nephrotic syndrome, and 56% of them were compound heterozygous for the nonneutral p.R229Q polymorphism. Four percent of the sporadic and 10% of the autosomal dominant cases had a mutation in WT1. Pathogenic INF2 mutations were found in 20% of the dominant but none of the sporadic cases. In a large cohort of adolescents including both familial and sporadic disease, NPHS2 mutations explained about 7% and WT1 4% of cases, whereas INF2 proved relevant only in autosomal dominant familial disease. Thus, screening of the entire coding sequence of NPHS2 and exons 8-9 of WT1 appears to be the most rational and cost-effective screening approach in sporadic juvenile steroid-resistant nephrotic syndrome.

Complex polarimetric and spectral techniques in diagnostics of blood plasma of patients with ovarian cancer as a preliminary stage molecular genetic screening

NASA Astrophysics Data System (ADS)

Grzegorzewski, B.; Peresunko, O. P.; Yermolenko, S. B.

2018-01-01

This work is devoted to the substantiation and selection of patients with ovarian cancer (OC) for the purpose of conducting expensive molecular genetic studies on genotyping. As diagnostic methods have been used ultraviolet spectrometry samples of blood plasma in the liquid state, infrared spectroscopy middle range (2,5 - 25 microns) dry residue of plasma polarization and laser diagnostic technique of thin histological sections of biological tissues. Obtained results showed that the use of spectrophotometry in the range of 1000-3000 cm-1 allowed to establish quantitative parameters of the plasma absorption rate of blood of patients in the third group in different ranges, which would allow in the future to conduct an express analysis of the patient's condition (procedure screening) for further molecular-genetic typing on BRCA I and II.

Assessment of Genetic Screening in the Military

DTIC Science & Technology

against the likelihood of saving lives of military recruits with undetected, potentially life- threatening genetic conditions. Largegenomic databases...The goal of this project was to undertake a cost-benefit analysis of genetic testing in military populations . We weighed the costs of genetictesting...of asymptomatic populations were used to analyze the effect that genetic screening for hypertrophic cardiomyopathy(HCM, the most common cause of sudden

An economic evaluation of a genetic screening program for Tay-Sachs disease.

PubMed Central

Nelson, W B; Swint, J M; Caskey, C T

1978-01-01

The resolution of policy questions relating to medical genetic screening programs will not be without considerable difficulty. Examples include such issues as the optimal degree of screening program expansion, the relative values of screening for different genetic diseases, the appropriate sources of program funding (public vs. private), and the relative value of funding expanded genetic screening programs vs. research directed toward elimination of genetic traits themselves. Information on the net impact of the relevant alternatives is greatly needed, and this need will increase if the National Genetics Act receives funding approval. We have provided what is hopefully a contribution toward this end. While our analysis pertains to a specific disease and a specific screening program for that disease, the methodology is readily generalizable to other genetic diseases, as well as programs of any size or structure. Hopefully, this will serve to stimulate further research efforts that we believe are needed for the objective consideration of resource allocation alternatives. PMID:418675

An economic evaluation of a genetic screening program for Tay-Sachs disease.

PubMed

Nelson, W B; Swint, J M; Caskey, C T

1978-03-01

The resolution of policy questions relating to medical genetic screening programs will not be without considerable difficulty. Examples include such issues as the optimal degree of screening program expansion, the relative values of screening for different genetic diseases, the appropriate sources of program funding (public vs. private), and the relative value of funding expanded genetic screening programs vs. research directed toward elimination of genetic traits themselves. Information on the net impact of the relevant alternatives is greatly needed, and this need will increase if the National Genetics Act receives funding approval. We have provided what is hopefully a contribution toward this end. While our analysis pertains to a specific disease and a specific screening program for that disease, the methodology is readily generalizable to other genetic diseases, as well as programs of any size or structure. Hopefully, this will serve to stimulate further research efforts that we believe are needed for the objective consideration of resource allocation alternatives.

Stigmatization of carrier status: social implications of heterozygote genetic screening programs.

PubMed Central

Kenen, R H; Schmidt, R M

1978-01-01

Possible latent psychological and social consequences ensuing from genetic screening programs need to be investigated during the planning phase of national genetic screening programs. The relatively few studies which have been performed to determine psychological, social, and economic consequences resulting from a genetic screening program are reviewed. Stigmatization of carrier-status, having major psychosocial implications in heterozygote genetic screening programs, is discussed and related to Erving Goffman's work in the area of stigmatization. Questions are raised regarding the relationship between such variables as religiosity and sex of the individual and acceptance of the status of newly identified carrier of a mutant gene. Severity of the deleterious gene and visibility of the carrier status are two important factors to consider in an estimation of potential stigma. Specific implications are discussed for four genetic diseases: Tay-Sachs, Sickle-Cell Anemia, Huntington's disease and Hemophilia. PMID:152585

High-throughput, image-based screening of pooled genetic variant libraries

PubMed Central

Emanuel, George; Moffitt, Jeffrey R.; Zhuang, Xiaowei

2018-01-01

Image-based, high-throughput screening of genetic perturbations will advance both biology and biotechnology. We report a high-throughput screening method that allows diverse genotypes and corresponding phenotypes to be imaged in numerous individual cells. We achieve genotyping by introducing barcoded genetic variants into cells and using massively multiplexed FISH to measure the barcodes. We demonstrated this method by screening mutants of the fluorescent protein YFAST, yielding brighter and more photostable YFAST variants. PMID:29083401

Potential of plant genetic systems for monitoring and screening mutagens

PubMed Central

Nilan, R. A.

1978-01-01

Plants have too long been ignored as useful screening and monitoring systems of environmental mutagens. However, there are about a dozen reliable, some even unique, plant genetic systems that can increase the scope and effectiveness of chemical and physical mutagen screening and monitoring procedures. Some of these should be included in the Tier II tests. Moreover, plants are the only systems now in use as monitors of genetic effects caused by polluted atmosphere and water and by pesticides. There are several major advantages of the plant test systems which relate to their reproductive nature, easy culture and growth habits that should be considered in mutagen screening and monitoring. In addition to these advantages, the major plant test systems exhibit numerous genetic and chromosome changes for determining the effects of mutagens. Some of these have not yet been detected in other nonmammalian and mammalian test systems, but probably occur in the human organism. Plants have played major roles in various aspects of mutagenesis research, primarily in mutagen screening (detection and verification of mutagenic activity), mutagen monitoring, and determining mutagen effects and mechanisms of mutagen action. They have played lesser roles in quantification of mutagenic activity and understanding the nature of induced mutations. Mutagen monitoring with plants, especially in situ on land or in water, will help determine potential genetic hazards of air and water pollutants and protect the genetic purity of crop plants and the purity of the food supply. The Tradescantia stamen-hair system is used in a mobile laboratory for determining the genetic effects of industrial and automobile pollution in a number of sites in the U.S.A. The fern is employed for monitoring genetic effects of water pollution in the Eastern states. The maize pollen system and certain weeds have monitored genetic effects of pesticides. Several other systems that have considerable value and should be

Genetic counseling for beta-thalassemia trait following health screening in a health maintenance organization: comparison of programmed and conventional counseling.

PubMed Central

Fisher, L; Rowley, P T; Lipkin, M

1981-01-01

Providing adequate counseling of patients identified in genetic screening programs is a major responsibility and expense. Adults in a health maintenance organization, unselected for interest, were screened for beta-thalassemia trait as part of preventive health care. Counseling was provided by either a trained physician (conventional counseling) or by a videotape containing the same information followed by an opportunity to question a trained physician (programmed counseling). Immediately before and after counseling, knowledge of thalassemia, knowledge of genetics, and mood change were assessed by questionnaire. Comparable mood changes and similar learning about thalassemia and genetics occurred with both counseling methods. Thus, as judged by immediate effects on knowledge and mood, videotaped instruction can greatly reduce professional time required for genetic counseling and facilitate the incorporation of genetic screening into primary health care. PMID:7325162

Design of a randomized controlled trial for genomic carrier screening in healthy patients seeking preconception genetic testing.

PubMed

Kauffman, Tia L; Wilfond, Benjamin S; Jarvik, Gail P; Leo, Michael C; Lynch, Frances L; Reiss, Jacob A; Richards, C Sue; McMullen, Carmit; Nickerson, Deborah; Dorschner, Michael O; Goddard, Katrina A B

2017-02-01

Population-based carrier screening is limited to well-studied or high-impact genetic conditions for which the benefits may outweigh the associated harms and costs. As the cost of genome sequencing declines and availability increases, the balance of risks and benefits may change for a much larger number of genetic conditions, including medically actionable additional findings. We designed an RCT to evaluate genomic clinical sequencing for women and partners considering a pregnancy. All results are placed into the medical record for use by healthcare providers. Through quantitative and qualitative measures, including baseline and post result disclosure surveys, post result disclosure interviews, 1-2year follow-up interviews, and team journaling, we are obtaining data about the clinical and personal utility of genomic carrier screening in this population. Key outcomes include the number of reportable carrier and additional findings, and the comparative cost, utilization, and psychosocial impacts of usual care vs. genomic carrier screening. As the study progresses, we will compare the costs of genome sequencing and usual care as well as the cost of screening, pattern of use of genetic or mental health counseling services, number of outpatient visits, and total healthcare costs. This project includes novel investigation into human reactions and responses from would-be parents who are learning information that could both affect a future pregnancy and their own health. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Measuring informed choice in population-based reproductive genetic screening: a systematic review

PubMed Central

Ames, Alice Grace; Metcalfe, Sylvia Ann; Archibald, Alison Dalton; Duncan, Rony Emily; Emery, Jon

2015-01-01

Genetic screening and health-care guidelines recommend that programmes should facilitate informed choice. It is therefore important that accurate measures of informed choice are available to evaluate such programmes. This review synthesises and appraises measures used to evaluate informed choice in population-based genetic screening programmes for reproductive risk. Databases were searched for studies offering genetic screening for the purpose of establishing reproductive risk to an adult population sample, in which aspects of informed choice were measured. Studies were included if, at a minimum, measures of uptake of screening and knowledge were used. Searches identified 1462 citations and 76 studies were reviewed in full text; 34 studies met the inclusion criteria. Over 20 different measures of informed choice were used. Many measures lacked adequate validity and reliability data. This systematic review will inform future evaluation of informed choice in population genetic screening programmes. PMID:24848746

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

PubMed

2012-04-06

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.

Miniaturizing 3D assay for high-throughput drug and genetic screens for small patient-derived tumor samples (Conference Presentation)

NASA Astrophysics Data System (ADS)

Rotem, Asaf; Garraway, Levi; Su, Mei-Ju; Basu, Anindita; Regev, Aviv; Struhl, Kevin

2017-02-01

Three-dimensional growth conditions reflect the natural environment of cancer cells and are crucial to be performed at drug screens. We developed a 3D assay for cellular transformation that involves growth in low attachment (GILA) conditions and is strongly correlated with the 50-year old benchmark assay-soft agar. Using GILA, we performed high-throughput screens for drugs and genes that selectively inhibit or increase transformation, but not proliferation. This phenotypic approach is complementary to our genetic approach that utilizes single-cell RNA-sequencing of a patient sample to identify putative oncogenes that confer sensitivity to drugs designed to specifically inhibit the identified oncoprotein. Currently, we are dealing with a big challenge in our field- the limited number of cells that might be extracted from a biopsy. Small patient-derived samples are hard to test in the traditional multiwell plate and it will be helpful to minimize the culture area and the experimental system. We managed to design a suitable microfluidic device for limited number of cells and perform the assay using image analysis. We aim to test drugs on tumor cells, outside of the patient body- and recommend on the ideal treatment that is tailored to the individual. This device will help to minimize biopsy-sampling volumes and minimize interventions in the patient's tumor.

Cytokine Autoantibody Screening in the Swedish Addison Registry Identifies Patients With Undiagnosed APS1.

PubMed

Eriksson, Daniel; Dalin, Frida; Eriksson, Gabriel Nordling; Landegren, Nils; Bianchi, Matteo; Hallgren, Åsa; Dahlqvist, Per; Wahlberg, Jeanette; Ekwall, Olov; Winqvist, Ola; Catrina, Sergiu-Bogdan; Rönnelid, Johan; Hulting, Anna-Lena; Lindblad-Toh, Kerstin; Alimohammadi, Mohammad; Husebye, Eystein S; Knappskog, Per Morten; Rosengren Pielberg, Gerli; Bensing, Sophie; Kämpe, Olle

2018-01-01

Autoimmune polyendocrine syndrome type 1 (APS1) is a monogenic disorder that features autoimmune Addison disease as a major component. Although APS1 accounts for only a small fraction of all patients with Addison disease, early identification of these individuals is vital to prevent the potentially lethal complications of APS1. To determine whether available serological and genetic markers are valuable screening tools for the identification of APS1 among patients diagnosed with Addison disease. We systematically screened 677 patients with Addison disease enrolled in the Swedish Addison Registry for autoantibodies against interleukin-22 and interferon-α4. Autoantibody-positive patients were investigated for clinical manifestations of APS1, additional APS1-specific autoantibodies, and DNA sequence and copy number variations of AIRE. In total, 17 patients (2.5%) displayed autoantibodies against interleukin-22 and/or interferon-α4, of which nine were known APS1 cases. Four patients previously undiagnosed with APS1 fulfilled clinical, genetic, and serological criteria. Hence, we identified four patients with undiagnosed APS1 with this screening procedure. We propose that patients with Addison disease should be routinely screened for cytokine autoantibodies. Clinical or serological support for APS1 should warrant DNA sequencing and copy number analysis of AIRE to enable early diagnosis and prevention of lethal complications. Copyright © 2017 Endocrine Society

Impact of the increased adoption of prenatal cfDNA screening on non-profit patient advocacy organizations in the United States.

PubMed

Meredith, Stephanie; Kaposy, Christopher; Miller, Victoria J; Allyse, Megan; Chandrasekharan, Subhashini; Michie, Marsha

2016-08-01

The 'Stakeholder Perspectives on Noninvasive Prenatal Genetic Screening' Symposium was held in conjunction with the 2015 annual meeting of the International Society for Prenatal Diagnosis. During the day-long meeting, a panel of patient advocacy group (PAG) representatives discussed concerns and challenges raised by prenatal cell-free DNA (cfDNA) screening, which has resulted in larger demands upon PAGs from concerned patients receiving prenatal cfDNA screening results. Prominent concerns included confusion about the accuracy of cfDNA screening and a lack of patient education resources about genetic conditions included in cfDNA screens. Some of the challenges faced by PAGs included funding limitations, lack of consistently implemented standards of care and oversight, diverse perspectives among PAGs and questions about neutrality, and lack of access to training and genetic counselors. PAG representatives also put forward suggestions for addressing these challenges, including improving educational and PAG funding and increasing collaboration between PAGs and the medical community. © 2016 John Wiley & Sons, Ltd. © 2016 John Wiley & Sons, Ltd.

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.

Carrier screening in the era of expanding genetic technology.

PubMed

Arjunan, Aishwarya; Litwack, Karen; Collins, Nick; Charrow, Joel

2016-12-01

The Center for Jewish Genetics provides genetic education and carrier screening to individuals of Jewish descent. Carrier screening has traditionally been performed by targeted mutation analysis for founder mutations with an enzyme assay for Tay-Sachs carrier detection. The development of next-generation sequencing (NGS) allows for higher detection rates regardless of ethnicity. Here, we explore differences in carrier detection rates between genotyping and NGS in a primarily Jewish population. Peripheral blood samples or saliva samples were obtained from 506 individuals. All samples were analyzed by sequencing, targeted genotyping, triplet-repeat detection, and copy-number analysis; the analyses were carried out at Counsyl. Of 506 individuals screened, 288 were identified as carriers of at least 1 condition and 8 couples were carriers for the same disorder. A total of 434 pathogenic variants were identified. Three hundred twelve variants would have been detected via genotyping alone. Although no additional mutations were detected by NGS in diseases routinely screened for in the Ashkenazi Jewish population, 26.5% of carrier results and 2 carrier couples would have been missed without NGS in the larger panel. In a primarily Jewish population, NGS reveals a larger number of pathogenic variants and provides individuals with valuable information for family planning.Genet Med 18 12, 1214-1217.

Functional genomics platform for pooled screening and mammalian genetic interaction maps

PubMed Central

Kampmann, Martin; Bassik, Michael C.; Weissman, Jonathan S.

2014-01-01

Systematic genetic interaction maps in microorganisms are powerful tools for identifying functional relationships between genes and defining the function of uncharacterized genes. We have recently implemented this strategy in mammalian cells as a two-stage approach. First, genes of interest are robustly identified in a pooled genome-wide screen using complex shRNA libraries. Second, phenotypes for all pairwise combinations of hit genes are measured in a double-shRNA screen and used to construct a genetic interaction map. Our protocol allows for rapid pooled screening under various conditions without a requirement for robotics, in contrast to arrayed approaches. Each stage of the protocol can be implemented in ~2 weeks, with additional time for analysis and generation of reagents. We discuss considerations for screen design, and present complete experimental procedures as well as a full computational analysis suite for identification of hits in pooled screens and generation of genetic interaction maps. While the protocols outlined here were developed for our original shRNA-based approach, they can be applied more generally, including to CRISPR-based approaches. PMID:24992097

Genetic screening of Wnt signaling factors in advanced retinopathy of prematurity

PubMed Central

Takahashi, Hiroshi; Orimo, Hideo; Hiraoka, Miina; Ogata, Tsutomu; Azuma, Noriyuki

2010-01-01

Purpose To evaluate the possibility of genetic involvement in retinopathy of prematurity (ROP). Although ROP is most often associated with low birthweight and low gestational age, these factors do not necessarily predict the severity of ROP. The possible involvement of other factors, including genetic variants, has been considered. Familial exudative vitreoretinopathy (FEVR) is a hereditary vitreoretinal disorder with clinical manifestations similar to those of ROP. Three genes involving the wingless/int1 (Wnt) receptor signaling pathway—FZD4 for frizzled 4, LRP5 for low-density lipoprotein receptor-related protein 5, and ND for Norrie disease protein—are associated with the development of FEVR. Methods In the present study, 17 Japanese patients with advanced ROP were screened for these three candidate genes of FEVR. Genomic DNA from each patient was subjected to PCR and direct sequencing of the ND, FZD4, and LRP5 genes. Results One patient had a heterozygous mutation in the 5′ untranslated region of the ND gene. Another had a leucine insertion in the signal peptide of LRP5. None showed any mutation in FZD4. Conclusions These findings suggest that genetic changes in the Wnt receptor signaling pathway associate to the development of advanced ROP. PMID:21151595

Ethical issues in pediatric genetic testing and screening.

PubMed

Botkin, Jeffrey R

2016-12-01

Developments in genetic test technologies enable a detailed analysis of the genomes of individuals across the range of human development from embryos to adults with increased precision and lower cost. These powerful technologies raise a number of ethical issues in pediatrics, primarily because of the frequent lack of clinical utility of genetic information, the generation of secondary results and questions over the proper scope of parental authority for testing. Several professional organizations in the fields of genetics and pediatrics have published new guidance on the ethical, legal, and policy issues relevant to genetic testing in children. The roles of predictive testing for adult-onset conditions, the management of secondary findings and the role of informed consent for newborn screening remain controversial. However, research and experience are not demonstrating serious adverse psychosocial impacts from genetic testing and screening in children. The use of these technologies is expanding with the notion that the personal utility of test results, rather than clinical utility, may be sufficient to justify testing. The use of microarray and genome sequencing technologies is expanding in the care of children. More deference to parental decision-making is evolving in contexts wherein information and counseling can be made readily available.

Randomized comparison of next-generation sequencing and array comparative genomic hybridization for preimplantation genetic screening: a pilot study.

PubMed

Yang, Zhihong; Lin, James; Zhang, John; Fong, Wai Ieng; Li, Pei; Zhao, Rong; Liu, Xiaohong; Podevin, William; Kuang, Yanping; Liu, Jiaen

2015-06-23

Recent advances in next-generation sequencing (NGS) have provided new methods for preimplantation genetic screening (PGS) of human embryos from in vitro fertilization (IVF) cycles. However, there is still limited information about clinical applications of NGS in IVF and PGS (IVF-PGS) treatments. The present study aimed to investigate the effects of NGS screening on clinical pregnancy and implantation outcomes for PGS patients in comparison to array comparative genomic hybridization (aCGH) screening. This study was performed in two phases. Phase I study evaluated the accuracy of NGS for aneuploidy screening in comparison to aCGH. Whole-genome amplification (WGA) products (n = 164) derived from previous IVF-PGS cycles (n = 38) were retrospectively analyzed with NGS. The NGS results were then compared with those of aCGH. Phase II study further compared clinical pregnancy and implantation outcomes between NGS and aCGH for IVF-PGS patients. A total of 172 patients at mean age 35.2 ± 3.5 years were randomized into two groups: 1) NGS (Group A): patients (n = 86) had embryos screened with NGS and 2) aCGH (Group B): patients (n = 86) had embryos screened with aCGH. For both groups, blastocysts were vitrified after trophectoderm biopsy. One to two euploid blastocysts were thawed and transferred to individual patients primarily based on the PGS results. Ongoing pregnancy and implantation rates were compared between the two study groups. NGS detected all types of aneuploidies of human blastocysts accurately and provided a 100 % 24-chromosome diagnosis consistency with the highly validated aCGH method. Moreover, NGS screening identified euploid blastocysts for transfer and resulted in similarly high ongoing pregnancy rates for PGS patients compared to aCGH screening (74.7 % vs. 69.2 %, respectively, p >0.05). The observed implantation rates were also comparable between the NGS and aCGH groups (70.5 % vs. 66.2 %, respectively, p >0.05). While NGS screening

Targeted Genetic Screen in Amyotrophic Lateral Sclerosis Reveals Novel Genetic Variants with Synergistic Effect on Clinical Phenotype.

PubMed

Cooper-Knock, Johnathan; Robins, Henry; Niedermoser, Isabell; Wyles, Matthew; Heath, Paul R; Higginbottom, Adrian; Walsh, Theresa; Kazoka, Mbombe; Ince, Paul G; Hautbergue, Guillaume M; McDermott, Christopher J; Kirby, Janine; Shaw, Pamela J

2017-01-01

Amyotrophic lateral sclerosis (ALS) is underpinned by an oligogenic rare variant architecture. Identified genetic variants of ALS include RNA-binding proteins containing prion-like domains (PrLDs). We hypothesized that screening genes encoding additional similar proteins will yield novel genetic causes of ALS. The most common genetic variant of ALS patients is a G4C2-repeat expansion within C9ORF72 . We have shown that G4C2-repeat RNA sequesters RNA-binding proteins. A logical consequence of this is that loss-of-function mutations in G4C2-binding partners might contribute to ALS pathogenesis independently of and/or synergistically with C9ORF72 expansions. Targeted sequencing of genomic DNA encoding either RNA-binding proteins or known ALS genes ( n = 274 genes) was performed in ALS patients to identify rare deleterious genetic variants and explore genotype-phenotype relationships. Genomic DNA was extracted from 103 ALS patients including 42 familial ALS patients and 61 young-onset (average age of onset 41 years) sporadic ALS patients; patients were chosen to maximize the probability of identifying genetic causes of ALS. Thirteen patients carried a G4C2-repeat expansion of C9ORF72 . We identified 42 patients with rare deleterious variants; 6 patients carried more than one variant. Twelve mutations were discovered in known ALS genes which served as a validation of our strategy. Rare deleterious variants in RNA-binding proteins were significantly enriched in ALS patients compared to control frequencies ( p = 5.31E-18). Nineteen patients featured at least one variant in a RNA-binding protein containing a PrLD. The number of variants per patient correlated with rate of disease progression ( t -test, p = 0.033). We identified eighteen patients with a single variant in a G4C2-repeat binding protein. Patients with a G4C2-binding protein variant in combination with a C9ORF72 expansion had a significantly faster disease course ( t -test, p = 0.025). Our data are consistent

Genetic highthroughput screening in retinitis pigmentosa based on high resolution melting (HRM) analysis.

PubMed

Anasagasti, Ander; Barandika, Olatz; Irigoyen, Cristina; Benitez, Bruno A; Cooper, Breanna; Cruchaga, Carlos; López de Munain, Adolfo; Ruiz-Ederra, Javier

2013-10-24

Retinitis Pigmentosa (RP) involves a group of genetically determined retinal diseases caused by a large number of mutations that result in rod photoreceptor cell death followed by gradual death of cone cells. Most cases of RP are monogenic, with more than 80 associated genes identified so far. The high number of genes and variants involved in RP, among other factors, is making the molecular characterization of RP a real challenge for many patients. Although HRM has been used for the analysis of isolated variants or single RP genes, as far as we are concerned, this is the first study that uses HRM analysis for a high-throughput screening of several RP genes. Our main goal was to test the suitability of HRM analysis as a genetic screening technique in RP, and to compare its performance with two of the most widely used NGS platforms, Illumina and PGM-Ion Torrent technologies. RP patients (n=96) were clinically diagnosed at the Ophthalmology Department of Donostia University Hospital, Spain. We analyzed a total of 16 RP genes that meet the following inclusion criteria: 1) size: genes with transcripts of less than 4 kb; 2) number of exons: genes with up to 22 exons; and 3) prevalence: genes reported to account for, at least, 0.4 % of total RP cases worldwide. For comparison purposes, RHO gene was also sequenced with Illumina (GAII; Illumina), Ion semiconductor technologies (PGM; Life Technologies) and Sanger sequencing (ABI 3130xl platform; Applied Biosystems). Detected variants were confirmed in all cases by Sanger sequencing and tested for co-segregation in the family of affected probands. We identified a total of 65 genetic variants, 15 of which (23%) were novel, in 49 out of 96 patients. Among them, 14 (4 novel) are probable disease-causing genetic variants in 7 RP genes, affecting 15 patients. Our HRM analysis-based study, proved to be a cost-effective and rapid method that provides an accurate identification of genetic RP variants. This approach is effective for

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

What Is Carrier Screening?

MedlinePlus

... Financial Planning Who Should I Tell? Genetic Testing & Counseling Compensation for Genetic Testing Whole Genome Sequencing Screening vs. Testing What Is Genetic Counseling? Participating in Research Disease Research Patient Privacy Clinical ...

Molecular Genetic Analysis of Pakistani Families With Autosomal Recessive Congenital Cataracts by Homozygosity Screening

PubMed Central

Chen, Jianjun; Wang, Qiwei; Cabrera, Patricia E.; Zhong, Zilin; Sun, Wenmin; Jiao, Xiaodong; Chen, Yabin; Govindarajan, Gowthaman; Naeem, Muhammad Asif; Khan, Shaheen N.; Ali, Muhammad Hassaan; Assir, Muhammad Zaman; Rahman, Fawad Ur; Qazi, Zaheeruddin A.; Riazuddin, Sheikh; Akram, Javed; Riazuddin, S. Amer; Hejtmancik, J. Fielding

2017-01-01

Purpose To identify the genetic origins of autosomal recessive congenital cataracts (arCC) in the Pakistani population. Methods Based on the hypothesis that most arCC patients in consanguineous families in the Punjab areas of Pakistan should be homozygous for causative mutations, affected individuals were screened for homozygosity of nearby highly informative microsatellite markers and then screened for pathogenic mutations by DNA sequencing. A total of 83 unmapped consanguineous families were screened for mutations in 33 known candidate genes. Results Patients in 32 arCC families were homozygous for markers near at least 1 of the 33 known CC genes. Sequencing the included genes revealed homozygous cosegregating sequence changes in 10 families, 2 of which had the same variation. These included five missense, one nonsense, two frame shift, and one splice site mutations, eight of which were novel, in EPHA2, FOXE3, FYCO1, TDRD7, MIP, GALK1, and CRYBA4. Conclusions The above results confirm the usefulness of homozygosity mapping for identifying genetic defects underlying autosomal recessive disorders in consanguineous families. In our ongoing study of arCC in Pakistan, including 83 arCC families that underwent homozygosity mapping, 3 mapped using genome-wide linkage analysis in unpublished data, and 30 previously reported families, mutations were detected in approximately 37.1% (43/116) of all families studied, suggesting that additional genes might be responsible in the remaining families. The most commonly mutated gene was FYCO1 (14%), followed by CRYBB3 (5.2%), GALK1 (3.5%), and EPHA2 (2.6%). This provides the first comprehensive description of the genetic architecture of arCC in the Pakistani population. PMID:28418495

“This Lifetime Commitment”: Public Conceptions of Disability and Noninvasive Prenatal Genetic Screening

PubMed Central

Steinbach, Rosemary J.; Allyse, Megan; Michie, Marsha; Liu, Emily Y.; Cho, Mildred K.

2016-01-01

Recently, new noninvasive prenatal genetic screening technologies for Down syndrome and other genetic conditions have become commercially available. Unique characteristics of these screening tests have reignited long-standing concerns about prenatal testing for intellectual and developmental disabilities. We conducted a web-based survey of a sample of the US public to examine how attitudes towards disability inform views of prenatal testing in the context of these rapidly advancing prenatal genetic screening technologies. Regardless of opinion toward disability, the majority of respondents supported both the availability of screening and the decision to continue a pregnancy positive for aneuploidy. Individuals rationalized their support with various conceptions of disability; complications of the expressivist argument and other concerns from the disability literature were manifested in many responses analyzed. PMID:26566970

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.

Carrier screening for single gene disorders.

PubMed

Rose, Nancy C; Wick, Myra

2018-04-01

Screening for genetic disorders began in 1963 with the initiation of newborn screening for phenylketonuria. Advances in molecular technology have made both newborn screening for newborns affected with serious disorders, and carrier screening of individuals at risk for offspring with genetic disorders, more complex and more widely available. Carrier screening today can be performed secondary to family history-based screening, ethnic-based screening, and expanded carrier screening (ECS). ECS is panel-based screening, which analyzes carrier status for hundreds of genetic disorders irrespective of patient race or ethnicity. In this article, we review the historical and current aspects of carrier screening for single gene disorders, including future research directions. Copyright © 2017 Elsevier Ltd. All rights reserved.

Genetic screens in human cells using the CRISPR-Cas9 system.

PubMed

Wang, Tim; Wei, Jenny J; Sabatini, David M; Lander, Eric S

2014-01-03

The bacterial clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 system for genome editing has greatly expanded the toolbox for mammalian genetics, enabling the rapid generation of isogenic cell lines and mice with modified alleles. Here, we describe a pooled, loss-of-function genetic screening approach suitable for both positive and negative selection that uses a genome-scale lentiviral single-guide RNA (sgRNA) library. sgRNA expression cassettes were stably integrated into the genome, which enabled a complex mutant pool to be tracked by massively parallel sequencing. We used a library containing 73,000 sgRNAs to generate knockout collections and performed screens in two human cell lines. A screen for resistance to the nucleotide analog 6-thioguanine identified all expected members of the DNA mismatch repair pathway, whereas another for the DNA topoisomerase II (TOP2A) poison etoposide identified TOP2A, as expected, and also cyclin-dependent kinase 6, CDK6. A negative selection screen for essential genes identified numerous gene sets corresponding to fundamental processes. Last, we show that sgRNA efficiency is associated with specific sequence motifs, enabling the prediction of more effective sgRNAs. Collectively, these results establish Cas9/sgRNA screens as a powerful tool for systematic genetic analysis in mammalian cells.

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.

The role of genetic factors in patients with hepatocellular carcinoma and iron overload - a prospective series of 234 patients.

PubMed

Funakoshi, Natalie; Chaze, Iphigénie; Alary, Anne-Sophie; Tachon, Gaëlle; Cunat, Séverine; Giansily-Blaizot, Muriel; Bismuth, Michael; Larrey, Dominique; Pageaux, Georges-Philippe; Schved, Jean-François; Donnadieu-Rigole, Hélène; Blanc, Pierre; Aguilar-Martinez, Patricia

2016-05-01

Iron overload (IO) in HFE-related hereditary haemochromatosis is associated with increased risk of liver cancer. This study aimed to investigate the role of other genes involved in hereditary IO among patients with hepatocellular carcinoma (HCC). Patients with HCC diagnosed in our institution were included in this prospective study. Those with ferritin levels ≥300 μg/L (males) or ≥200 μg/L (females) and/or transferrin saturation ≥50% (males) or ≥45% (females) had liver iron concentration (LIC) evaluated by MRI. HFE C282Y and H63D mutations were screened. Genetic analyses of genes involved in hereditary IO (HFE, HJV/HFE2, HAMP, TFR2, SLC40A1, GNPAT) were performed in patients with increased LIC. A total of 234 patients were included; 215 (92%) had common acquired risk factors of HCC (mainly alcoholism or chronic viral hepatitis). 119 patients had abnormal iron parameters. Twelve (5.1%) were C282Y homozygotes, three were compound C282Y/H63D heterozygotes. LIC was measured by MRI in 100 patients. Thirteen patients with a LIC>70 μmol/g were enrolled in further genetic analyses: two unrelated patients bore the HAMP:c.-153C>T mutation at the heterozygous state, which is associated with increased risk of IO and severe haemochromatosis. Specific haplotypes of SLC40A1 were also studied. Additional genetic risk factors of IO were found in 18 patients (7.7%) among a large series of 234 HCC patients. Screening for IO and the associated at-risk genotypes in patients who have developed HCC, is useful for both determining etiologic diagnosis and enabling family screening and possibly primary prevention in relatives. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Emergency preparedness for genetics centers, laboratories, and patients: the Southeast Region Genetics Collaborative strategic plan.

PubMed

Andersson, Hans C; Perry, William; Bowdish, Bruce; Floyd-Browning, Phaidra

2011-10-01

Emergencies occur unpredictably and interrupt routine genetic care. The events after hurricanes Katrina and Rita have led to the recognition that a coherent plan is necessary to ensure continuity of operations for genetic centers and laboratories, including newborn screening. No geographic region is protected from the effects of a variety of potential emergencies. Regional and national efforts have begun to address the need for such preparedness, but a plan for ensuring continuity of operations by creating an emergency preparedness plan must be developed for each genetic center and laboratory, with attention to the interests of patients. This article describes the first steps in development of an emergency preparedness plan for individual centers.

Detecting familial hypercholesterolemia by serum lipid profile screening in a hospital setting: Clinical, genetic and atherosclerotic burden profile.

PubMed

Scicali, R; Di Pino, A; Platania, R; Purrazzo, G; Ferrara, V; Giannone, A; Urbano, F; Filippello, A; Rapisarda, V; Farruggia, E; Piro, S; Rabuazzo, A M; Purrello, F

2018-01-01

Familial hypercholesterolemia (FH) is underdiagnosed and public cholesterol screening may be useful to find new subjects. In this study, we aim to investigate the prevalence of FH patients in a hospital screening program and evaluate their atherosclerotic burden using intima-media thickness (IMT). We screened 1575 lipid profiles and included for genetic analysis adults with a low-density lipoprotein (LDL) cholesterol >190 mg/dL and triglycerides <200 mg/dL and first-degree child relatives with LDL cholesterol >160 mg/dL and triglycerides <200 mg/dL. The diagnosis of FH was presumed by Dutch Lipid Clinic Network (DLCN) criteria and confirmed by the presence of the genetic variant. Mean common carotid intima-media thickness (IMT) was assessed using consensus criteria. After confirming LDL cholesterol value and excluding secondary hypercholesterolemia, 56 subjects with a DLCN ≥4 performed genetic analysis. Of these, 26 had an FH genetic variant. The proportion of patients with a mutation having a DLCN score of 6-8 was 75%; in individuals with a DLCN score >8 it was 100%. Mean IMT was higher in FH patients compared to non FH (0.73 [0.61-0.83] vs 0.71 [0.60-0.75] mm, p < 0.01). Moreover, we detected two mutations not previously described. Finally, simple regression analysis showed a correlation of IMT with LDL cholesterol >190 mg/dL and corneal arcus (p < 0.01 and p < 0.001, respectively). A hospital screening was useful to detect FH subjects with increased atherosclerosis. Also, next-generation sequencing was able to detect new FH mutations. Copyright © 2017 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.

Genetic high throughput screening in Retinitis Pigmentosa based on high resolution melting (HRM) analysis.

PubMed

Anasagasti, Ander; Barandika, Olatz; Irigoyen, Cristina; Benitez, Bruno A; Cooper, Breanna; Cruchaga, Carlos; López de Munain, Adolfo; Ruiz-Ederra, Javier

2013-11-01

Retinitis Pigmentosa (RP) involves a group of genetically determined retinal diseases caused by a large number of mutations that result in rod photoreceptor cell death followed by gradual death of cone cells. Most cases of RP are monogenic, with more than 80 associated genes identified so far. The high number of genes and variants involved in RP, among other factors, is making the molecular characterization of RP a real challenge for many patients. Although HRM has been used for the analysis of isolated variants or single RP genes, as far as we are concerned, this is the first study that uses HRM analysis for a high-throughput screening of several RP genes. Our main goal was to test the suitability of HRM analysis as a genetic screening technique in RP, and to compare its performance with two of the most widely used NGS platforms, Illumina and PGM-Ion Torrent technologies. RP patients (n = 96) were clinically diagnosed at the Ophthalmology Department of Donostia University Hospital, Spain. We analyzed a total of 16 RP genes that meet the following inclusion criteria: 1) size: genes with transcripts of less than 4 kb; 2) number of exons: genes with up to 22 exons; and 3) prevalence: genes reported to account for, at least, 0.4% of total RP cases worldwide. For comparison purposes, RHO gene was also sequenced with Illumina (GAII; Illumina), Ion semiconductor technologies (PGM; Life Technologies) and Sanger sequencing (ABI 3130xl platform; Applied Biosystems). Detected variants were confirmed in all cases by Sanger sequencing and tested for co-segregation in the family of affected probands. We identified a total of 65 genetic variants, 15 of which (23%) were novel, in 49 out of 96 patients. Among them, 14 (4 novel) are probable disease-causing genetic variants in 7 RP genes, affecting 15 patients. Our HRM analysis-based study, proved to be a cost-effective and rapid method that provides an accurate identification of genetic RP variants. This approach is effective for

A methodological overview on molecular preimplantation genetic diagnosis and screening: a genomic future?

PubMed

Vendrell, Xavier; Bautista-Llácer, Rosa

2012-12-01

The genetic diagnosis and screening of preimplantation embryos generated by assisted reproduction technology has been consolidated in the prenatal care framework. The rapid evolution of DNA technologies is tending to molecular approaches. Our intention is to present a detailed methodological view, showing different diagnostic strategies based on molecular techniques that are currently applied in preimplantation genetic diagnosis. The amount of DNA from one single, or a few cells, obtained by embryo biopsy is a limiting factor for the molecular analysis. In this sense, genetic laboratories have developed molecular protocols considering this restrictive condition. Nevertheless, the development of whole-genome amplification methods has allowed preimplantation genetic diagnosis for two or more indications simultaneously, like the selection of histocompatible embryos plus detection of monogenic diseases or aneuploidies. Moreover, molecular techniques have permitted preimplantation genetic screening to progress, by implementing microarray-based comparative genome hybridization. Finally, a future view of the embryo-genetics field based on molecular advances is proposed. The normalization, cost-effectiveness analysis, and new technological tools are the next topics for preimplantation genetic diagnosis and screening. Concomitantly, these additions to assisted reproduction technologies could have a positive effect on the schedules of preimplantation studies.

Familial Hypercholesterolemia: A Systematic Review of Guidelines on Genetic Testing and Patient Management.

PubMed

Migliara, Giuseppe; Baccolini, Valentina; Rosso, Annalisa; D'Andrea, Elvira; Massimi, Azzurra; Villari, Paolo; De Vito, Corrado

2017-01-01

Familial hypercholesterolemia (FH) is an autosomal-dominant hereditary disorder of lipid metabolism that causes lifelong exposure to increased LDL levels resulting in premature coronary heart disease and, if untreated, death. Recent studies have shown its prevalence to be higher than previously considered, which has important implications for the mortality and morbidity of associated cardiovascular disease (CVD). Several clinical tools are used worldwide to help physicians diagnose FH, but nevertheless most patients remain undetected. This systematic review of guidelines aims to assess the role of genetic testing in the screening, diagnosis, and management of patients affected by heterozygous or homozygous FH and to identify related health-care pathways. We performed a systematic review of the literature; inclusion criteria were English or Italian guidelines focusing on genetic testing. The guidelines were included and evaluated for their content and development process using the Appraisal of Guidelines for Research and Evaluation II instrument. Ten guidelines were considered eligible, and all were judged to be of good quality, with slight differences among them. The most common indications for performing genetic tests were high levels of cholesterol, or physical findings consistent with lipid disorder, in the subject or in the family history. Subsequent screening of family members was indicated when a mutation had been identified in the index patient. Regarding patient management, the various guidelines agreed that intensive treatment with lipid-lowering medications should begin as quickly as possible and that lifestyle modifications should be an integral part of the therapy. Since the early detection of affected patients is beneficial for effective prevention of CVD, genetic testing is particularly useful for identifying family members via cascade screening and for distinguishing between heterozygous and homozygous individuals, the latter of which require more

[Molecular genetic diagnostics and screening of hereditary hemochromatosis].

PubMed

Zlocha, J; Kovács, L; Pozgayová, S; Kupcová, V; Durínová, S

2006-06-01

282Y heterozygotes (p < 0.001), C282Y/H63D compound heterozygotes (p < 0.001) and wild type subjects (p < 0.001) respectively. Our observations confirm that DNA analysis significantly contributes to differential diagnostics of this severe, but in early recognition curable disease. Early detection and phlebotomy treatment prior to the onset of cirrhosis can reduce morbidity and normalize life expectancy. It is readily identified through biochemical testing for iron overload using serum transferrin saturation and genetic testing for C282Y homozygosity. DNA analysis is recommended in patients whose transferrin saturation is 45% or more on a repeated test. General population screening has been waived in preference to targeting high-risk groups such as first-degree relatives of affected individuals and those with secondary iron overload, especially patients with chronic liver disorders and chronic anemia. This screening strategy is likely to continue until uncertainties regarding the natural history of the disease, age-related penetrance, and management of asymptomatic individuals are clarified.

Online Module for Carrier Screening in Ashkenazi Jewish Individuals Compared with In-Person Genetics Education: A Randomized Controlled Trial.

PubMed

Fan, Chia Wei; Castonguay, Lysanne; Rummell, Sonja; Lévesque, Sébastien; Mitchell, John J; Sillon, Guillaume

2018-04-01

To increase accessibility to genetics services for low-urgency patients seeking Ashkenazi Jewish (AJ) carrier screening, we designed an interactive computer (IC) module that provides pre-test genetics education and allows genetics professionals to order the test without meeting the patients beforehand. We compared this module with in-person genetic counseling (GC) using a randomized trial. AJ individuals were randomized to undergo genetics education via the IC module (n = 26) or GC (n = 28). We compared post-interventional genetics knowledge, perceived genetic risk, and anxiety between the two groups, after accounting for pre-interventional scores, using ANCOVA. Wilcoxon Rank-Sum test was used to compare post-interventional satisfaction. Post-interventional genetics knowledge, risk perception, or anxiety were not significantly different between the two groups after accounting for baseline scores (p = 0.50-0.54), although the data are inconclusive regarding the module's non-inferiority at a 5% margin. Post-intervention satisfaction scores were generally higher in the GC group than the IC module group. Our IC module has the potential to improve access to clinical genetics services for patients and staff, but it is not suitable for all AJ patients and cannot completely replace the benefits of in-person consultations.

A Systematic Genetic Screen to Dissect the MicroRNA Pathway in Drosophila.

PubMed

Pressman, Sigal; Reinke, Catherine A; Wang, Xiaohong; Carthew, Richard W

2012-04-01

A central goal of microRNA biology is to elucidate the genetic program of miRNA function and regulation. However, relatively few of the effectors that execute miRNA repression have been identified. Because such genes may function in many developmental processes, mutations in them are expected to be pleiotropic and thus are discarded in most standard genetic screens. Here, we describe a systematic screen designed to identify all Drosophila genes in ∼40% of the genome that function in the miRNA pathway. To identify potentially pleiotropic genes, the screen analyzed clones of homozygous mutant cells in heterozygous animals. We identified 45 mutations representing 24 genes, and we molecularly characterized 9 genes. These include 4 previously known genes that encode core components of the miRNA pathway, including Drosha, Pasha, Dicer-1, and Ago1. The rest are new genes that function through chromatin remodeling, signaling, and mRNA decapping. The results suggest genetic screens that use clonal analysis can elucidate the miRNA program and that ∼100 genes are required to execute the miRNA program.

A model of genetic guidance for hemoglobinopathy patients and laboratory diagnosis of family members as educational and preventive measures

PubMed Central

Ferreira, Tatiana Dela-Sávia; Freire, Adriana Sousa; Silveira-Lacerda, Elisângela de Paula; García-Zapata, Marco Túlio Antônio

2012-01-01

Background: The high frequency of hemoglobinopathies in Brazil constitutes a public health problem and thus educational and preventive measures are necessary to reduce the incidence. Genetic guidance, a modality of genetic counseling, and family screening are measures that can assist in reproductive decisions and mitigate clinical, psychological and social problems of families with these disorders. Objetive: The objective of the current study was to evaluate the effectiveness of educational and preventive measures for hemoglobinopathies using genetic guidance and laboratory screening of families. Methods: The diagnoses of patients with hemoglobinopathies were confirmed and then the level of knowledge about their disease was evaluated and genetic guidance was provided. Three months later, the level of assimilated information of these patients was evaluated. In addition, laboratory diagnosis of family members was carried out. Results: Diagnosis of sickle cell anemia was confirmed for most patients. Moreover, the majority of the patients who had a low level of knowledge before genetic guidance (68.8%) demonstrated a higher level of assimilated information after the process (81.8%). Almost 70% of the family members had hemoglobin changes and some had hemoglobinopathies(2.6%). They were duly informed about the results of the examinations, which made it possible to investigate further. Conclusion: Genetic guidance and family screening were effective preventive and educational measures that improved the quality of life of patients, preventing complications and sequels and allowed the referral of those who may transmit altered genes for clinical diagnosis and to genetic counseling services. PMID:23125541

Prioritizing Genetic Testing in Patients With Kallmann Syndrome Using Clinical Phenotypes

PubMed Central

Costa-Barbosa, Flavia Amanda; Balasubramanian, Ravikumar; Keefe, Kimberly W.; Shaw, Natalie D.; Al-Tassan, Nada; Plummer, Lacey; Dwyer, Andrew A.; Buck, Cassandra L.; Choi, Jin-Ho; Seminara, Stephanie B.; Quinton, Richard; Monies, Dorota; Meyer, Brian; Hall, Janet E.; Pitteloud, Nelly

2013-01-01

Context: The complexity of genetic testing in Kallmann syndrome (KS) is growing and costly. Thus, it is important to leverage the clinical evaluations of KS patients to prioritize genetic screening. Objective: The objective of the study was to determine which reproductive and nonreproductive phenotypes of KS subjects have implications for specific gene mutations. Subjects: Two hundred nineteen KS patients were studied: 151 with identified rare sequence variants (RSVs) in 8 genes known to cause KS (KAL1, NELF, CHD7, HS6ST1, FGF8/FGFR1, or PROK2/PROKR2) and 68 KS subjects who remain RSV negative for all 8 genes. Main Outcome Measures: Reproductive and nonreproductive phenotypes within each genetic group were measured. Results: Male KS subjects with KAL1 RSVs displayed the most severe reproductive phenotype with testicular volumes (TVs) at presentation of 1.5 ± 0.1 mL vs 3.7 ± 0.3 mL, P < .05 vs all non-KAL1 probands. In both sexes, synkinesia was enriched but not unique to patients with KAL1 RSVs compared with KAL1-negative probands (43% vs 12%; P < .05). Similarly, dental agenesis and digital bone abnormalities were enriched in patients with RSVs in the FGF8/FGFR1 signaling pathway compared with all other gene groups combined (39% vs 4% and 23% vs 0%; P < .05, respectively). Hearing loss marked the probands with CHD7 RSVs (40% vs 13% in non-CHD7 probands; P < .05). Renal agenesis and cleft lip/palate did not emerge as statistically significant phenotypic predictors. Conclusions: Certain clinical features in men and women are highly associated with genetic causes of KS. Synkinesia (KAL1), dental agenesis (FGF8/FGFR1), digital bony abnormalities (FGF8/FGFR1), and hearing loss (CHD7) can be useful for prioritizing genetic screening. PMID:23533228

Patient actions and reactions after receiving negative results from expanded carrier screening

PubMed Central

Kraft, Stephanie A.; Schneider, Jennifer L.; Leo, Michael C.; Kauffman, Tia L.; Davis, James V.; Porter, Kathryn M.; McMullen, Carmit K.; Wilfond, Benjamin S.; Goddard, Katrina A.B.

2018-01-01

With the expansion of carrier screening to general preconception and prenatal patient populations, most patients will receive negative results, which we define as indicating <25% risk of having a child with a genetic condition. Because there is limited experience with expanded carrier screening, it is important to understand how receiving negative results affects patients, especially as providers, payers, and policymakers consider whether to offer it. In this mixed-methods study, we asked preconception patients enrolled in the NextGen study about their expectations and experiences receiving negative expanded carrier screening results. Participants completed surveys at study enrollment (n=110 women, 51 male partners), after receiving carrier results (n=100 women, 38 male partners), after receiving secondary findings (n=98 women, 36 male partners), and 6 months after receiving results (n=95 women, 28 male partners). We also interviewed a subset of participants 12–24 months after receiving results (n=24 women, 12 male partners). We found minimal negative emotional impact and privacy concerns, increased confidence in reproductive plans, and few changes to health behaviors, although some patients made health decisions based on misunderstandings of their results. These findings suggest that expanded carrier screening causes minimal psychosocial harms, but systems are needed to reduce the risk of misinterpreting results. PMID:29293279

Population-Based Assessment of a Biomarker-Based Screening Pathway to Aid Diagnosis of Monogenic Diabetes in Young-Onset Patients.

PubMed

Shields, Beverley M; Shepherd, Maggie; Hudson, Michelle; McDonald, Timothy J; Colclough, Kevin; Peters, Jaime; Knight, Bridget; Hyde, Chris; Ellard, Sian; Pearson, Ewan R; Hattersley, Andrew T

2017-08-01

Monogenic diabetes, a young-onset form of diabetes, is often misdiagnosed as type 1 diabetes, resulting in unnecessary treatment with insulin. A screening approach for monogenic diabetes is needed to accurately select suitable patients for expensive diagnostic genetic testing. We used C-peptide and islet autoantibodies, highly sensitive and specific biomarkers for discriminating type 1 from non-type 1 diabetes, in a biomarker screening pathway for monogenic diabetes. We studied patients diagnosed at age 30 years or younger, currently younger than 50 years, in two U.K. regions with existing high detection of monogenic diabetes. The biomarker screening pathway comprised three stages: 1 ) assessment of endogenous insulin secretion using urinary C-peptide/creatinine ratio (UCPCR); 2 ) if UCPCR was ≥0.2 nmol/mmol, measurement of GAD and IA2 islet autoantibodies; and 3 ) if negative for both autoantibodies, molecular genetic diagnostic testing for 35 monogenic diabetes subtypes. A total of 1,407 patients participated (1,365 with no known genetic cause, 34 with monogenic diabetes, and 8 with cystic fibrosis-related diabetes). A total of 386 out of 1,365 (28%) patients had a UCPCR ≥0.2 nmol/mmol, and 216 out of 386 (56%) were negative for GAD and IA2 and underwent molecular genetic testing. Seventeen new cases of monogenic diabetes were diagnosed (8 common Maturity Onset Diabetes of the Young [Sanger sequencing] and 9 rarer causes [next-generation sequencing]) in addition to the 34 known cases (estimated prevalence of 3.6% [51/1,407] [95% CI 2.7-4.7%]). The positive predictive value was 20%, suggesting a 1-in-5 detection rate for the pathway. The negative predictive value was 99.9%. The biomarker screening pathway for monogenic diabetes is an effective, cheap, and easily implemented approach to systematically screening all young-onset patients. The minimum prevalence of monogenic diabetes is 3.6% of patients diagnosed at age 30 years or younger. © 2017 by the American

Genetic and epigenetic markers in colorectal cancer screening: recent advances.

PubMed

Singh, Manish Pratap; Rai, Sandhya; Suyal, Shradha; Singh, Sunil Kumar; Singh, Nand Kumar; Agarwal, Akash; Srivastava, Sameer

2017-07-01

Colorectal cancer (CRC) is a heterogenous disease which develops from benign intraepithelial lesions known as adenomas to malignant carcinomas. Acquired alterations in Wnt signaling, TGFβ, MAPK pathway genes and clonal propagation of altered cells are responsible for this transformation. Detection of adenomas or early stage cancer in asymptomatic patients and better prognostic and predictive markers is important for improving the clinical management of CRC. Area covered: In this review, the authors have evaluated the potential of genetic and epigenetic alterations as markers for early detection, prognosis and therapeutic predictive potential in the context of CRC. We have discussed molecular heterogeneity present in CRC and its correlation to prognosis and response to therapy. Expert commentary: Molecular marker based CRC screening methods still fail to gain trust of clinicians. Invasive screening methods, molecular heterogeneity, chemoresistance and low quality test samples are some key challenges which need to be addressed in the present context. New sequencing technologies and integrated omics data analysis of individual or population cohort results in GWAS. MPE studies following a GWAS could be future line of research to establish accurate correlations between CRC and its risk factors. This strategy would identify most reliable biomarkers for CRC screening and management.

Delineating the genetic heterogeneity of OCA in Hungarian patients.

PubMed

Fábos, Beáta; Farkas, Katalin; Tóth, Lola; Sulák, Adrienn; Tripolszki, Kornélia; Tihanyi, Mariann; Németh, Réka; Vas, Krisztina; Csoma, Zsanett; Kemény, Lajos; Széll, Márta; Nagy, Nikoletta

2017-06-19

Oculocutaneous albinism (OCA) is a clinically and genetically heterogenic group of pigmentation abnormalities characterized by variable hair, skin, and ocular hypopigmentation. Six known genes and a locus on human chromosome 4q24 have been implicated in the etiology of isolated OCA forms (OCA 1-7). The most frequent OCA types among Caucasians are OCA1, OCA2, and OCA4. We aimed to investigate genes responsible for the development of these OCA forms in Hungarian OCA patients (n = 13). Mutation screening and polymorphism analysis were performed by direct sequencing on TYR, OCA2, SLC45A2 genes. Although the clinical features of the investigated Hungarian OCA patients were identical, the molecular genetic data suggested OCA1 subtype in eight cases and OCA4 subtype in two cases. The molecular diagnosis was not clearly identifiable in three cases. In four patients, two different heterozygous known pathogenic or predicted to be pathogenic mutations were present. Seven patients had only one pathogenic mutation, which was associated with non-pathogenic variants in six cases. In two patients no pathogenic mutation was identified. Our results suggest that the concomitant screening of the non-pathogenic variants-which alone do not cause the development of OCA, but might have clinical significance in association with a pathogenic variant-is important. Our results also show significant variation in the disease spectrum compared to other populations. These data also confirm that the concomitant analysis of OCA genes is critical, providing new insights to the phenotypic diversity of OCA and expanding the mutation spectrum of OCA genes in Hungarian patients.

Multiplicity of experimental approaches to therapy for genetic muscle diseases and necessity for population screening.

PubMed

Laing, Nigel G

2008-01-01

Currently a multiplicity of experimental approaches to therapy for genetic muscle diseases is being investigated. These include replacement of the missing gene, manipulation of the gene message, repair of the mutation, upregulation of an alternative gene and pharmacological interventions targeting a number of systems. A number of these approaches are in current clinical trials. There is considerable anticipation that perhaps more than one of the approaches will finally prove of clinical benefit, but there are many voices of caution. No matter which approaches might ultimately prove effective, there is a consensus that for most benefit to the patients it will be necessary to start treatment as early as possible. A consensus is also developing that the only way to do this is to implement population-based newborn screening to identify affected children shortly after birth. Population-based newborn screening is currently practised in very few places in the world and it brings with it implications for prevention rather than cure of genetic muscle diseases.

Comparing Universal Lynch Syndrome Tumor Screening Programs to Evaluate Associations Between Implementation Strategies and Patient Follow-through

PubMed Central

Cragun, Deborah; DeBate, Rita D.; Vadaparampil, Susan T.; Baldwin, Julie; Hampel, Heather; Pal, Tuya

2014-01-01

Purpose Universal tumor screening (UTS) for all colorectal cancer (CRC) patients can improve the identification of Lynch syndrome, the most common cause of hereditary CRC. This multiple-case study explored how variability in UTS procedures influence patient follow-through (PF) with germline testing after a screen-positive result. Methods Data were obtained through web-based surveys and telephone interviews with institutional informants. Institutions were categorized as Low-PF (≤10% underwent germline testing), Medium-PF (11–40%), or High-PF (>40%). To identify implementation procedures (i.e., conditions) unique High-PF institutions, qualitative comparative analysis was performed. Results Twenty-one informants from fifteen institutions completed surveys and/or interviews. Conditions present among all five High-PF institutions included: 1) disclosure of screen-positive results to patients by genetic counselors (GCs); and 2) GCs either facilitate physician referrals to genetics or eliminated the need for referrals. Although both of these High-PF conditions were present among two Medium-PF institutions, automatic reflex testing was lacking and difficulty contacting screen-positive patients was a barrier. The three remaining Medium-PF and five Low-PF institutions lacked High-PF conditions. Conclusion Methods for streamlining UTS procedures, incorporating a high level of involvement of GCs in results tracking and communication, and reducing barriers to patient contact are reviewed within a broader discussion on maximizing the effectiveness and public health impact of UTS. PMID:24651603

[The significance of pedigree genetic screening and rapid immunological parameters in the diagnosis of primary hemophagocytic lymphohistiocytosis].

PubMed

Zhang, J; Wang, Y N; Wang, J S; Wu, L; Wei, N; Fu, L; Gao, Z; Chen, J H; Pei, R J; Wang, Z

2016-07-01

To investigate the significance of pedigree genetic screening and rapid immunological parameters in the diagnosis of primary hemophagocytic lymphohistiocytosis (HLH). Four cases of primary HLH patients with PRF1, UNC13D and SH2D1A gene mutations were conducted pedigree investigation, including family genetic screening and detections of immunological parameters (NK cell activity, CD107a degranulation and expression of HLH related defective protein), to evaluate the significance of these different indicators in the diagnosis of primary HLH and explore their correlations. The DNA mutations of the four families included missense mutation c.T172C (p.S58P) and non- frameshift deletions c.1083_1094del (p.361_365del), missense mutation c.C1349T (p.T450M) and frameshift mutation c.1090_1091delCT (p.T364fsX93) in PRF1 gene, missense mutation c.G2588A (p.G863D) in UNC13D gene and hemizygous mutation c.32T>G (p.I11S) in SH2D1A gene. The patients and their family members presented decreased NK cell activities. Individuals who carried mutations of PRF1 gene and SH2D1A gene showed low expression of perforin (PRF1) and signaling lymphocytic activation molecule associated protein (SAP). And the patient with UNC13D gene mutation and his family member with identical mutation showed significant reducing cytotoxic degranulation function (expression of CD107a). Pedigree genetic screening and rapid detection of immunological parameters might play an important role in the diagnosis of primary HLH, and both of them had good consistency. As an efficient detection means, the rapid immunological detection indicators would provide reliable basis for the early diagnosis of the primary HLH.

Patient actions and reactions after receiving negative results from expanded carrier screening.

PubMed

Kraft, S A; Schneider, J L; Leo, M C; Kauffman, T L; Davis, J V; Porter, K M; McMullen, C K; Wilfond, B S; Goddard, K A B

2018-05-01

With the expansion of carrier screening to general preconception and prenatal patient populations, most patients will receive negative results, which we define as indicating <25% risk of having a child with a genetic condition. Because there is limited experience with expanded carrier screening, it is important to understand how receiving negative results affects patients, especially as providers, payers, and policymakers consider whether to offer it. In this mixed-methods study, we asked preconception patients enrolled in the NextGen study about their expectations and experiences receiving negative expanded carrier screening results. Participants completed surveys at study enrollment (n = 110 women, 51 male partners), after receiving carrier results (n = 100 women, 38 male partners), after receiving secondary findings (n = 98 women, 36 male partners), and 6 months after receiving results (n = 95 women, 28 male partners). We also interviewed a subset of participants 12 to 24 months after receiving results (n = 24 women, 12 male partners). We found minimal negative emotional impact and privacy concerns, increased confidence in reproductive plans, and few changes to health behaviors, although some patients made health decisions based on misunderstandings of their results. These findings suggest that expanded carrier screening causes minimal psychosocial harms, but systems are needed to reduce the risk of misinterpreting results. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Validation of a Nutrition Screening Tool for Pediatric Patients with Cystic Fibrosis.

PubMed

Souza Dos Santos Simon, Miriam Isabel; Forte, Gabriele Carra; da Silva Pereira, Juliane; da Fonseca Andrade Procianoy, Elenara; Drehmer, Michele

2016-05-01

In cystic fibrosis (CF), nutrition diagnosis is of critical relevance because the early identification of nutrition-related compromise enables early, adequate intervention and, consequently, influences patient prognosis. Up to now, there has not been a validated nutrition screening tool that takes into consideration clinical variables. To validate a specific nutritional risk screening tool for patients with CF based on clinical variables, anthropometric parameters, and dietary intake. Cross-sectional study. The nutrition screening tool was compared with a risk screening tool proposed by McDonald and the Cystic Fibrosis Foundation criteria. Patients aged 6 to 18 years, with a diagnosis of CF confirmed by two determinations of elevated chloride level in sweat (sweat test) and/or by identification of two CF-associated genetic mutations who were receiving follow-up care through the outpatient clinic of a Cystic Fibrosis Treatment Center. Earlier identification of nutritional risk in CF patients aged 6 to 18 years when a new screening tool was applied. Agreement among the tested methods was assessed by means of the kappa coefficient for categorical variables. Sensitivity, specificity, and accuracy values were calculated. The significance level was set at 5% (P<0.05). Statistical analyses were carried out in PASW Statistics for Windows version 18.0 (2009, SPSS Inc). Eighty-two patients (49% men, aged 6 to 18 years) were enrolled in the study. The agreement between the proposed screening tool and the tool for screening nutritional risk for CF by the McDonald method was good (κ=0.804; P<0.001) and the sensitivity and specificity was 85% and 95%, respectively. Agreement with the Cystic Fibrosis Foundation criteria was lower (κ=0.418; P<0.001), and the sensitivity and specificity were both 72%. The proposed screening tool with defined clinical variables promotes earlier identification of nutritional risk in pediatric patients with CF. Copyright © 2016 Academy of Nutrition

Validation of a clinical screening instrument for tumour predisposition syndromes in patients with childhood cancer (TuPS): protocol for a prospective, observational, multicentre study

PubMed Central

Postema, Floor A M; Hopman, Saskia M J; de Borgie, Corianne A J M; Hammond, Peter; Hennekam, Raoul C; Merks, Johannes H M; Aalfs, Cora M; Anninga, Jakob K; Berger, Lieke PV; Bleeker, Fonnet E; de Bont, Eveline SJM; de Borgie, Corianne AJM; Dommering, Charlotte J; van Eijkelenburg, Natasha KA; Hammond, Peter; Hennekam, Raoul C; van den Heuvel-Eibrink, Marry M; Hopman, Saskia MJ; Jongmans, Marjolijn CJ; Kors, Wijnanda A; Letteboer, Tom GW; Loeffen, Jan LCM; Merks, Johannes HM; Olderode-Berends, Maran JW; Postema, Floor AM; Wagner, Anja

2017-01-01

Introduction Recognising a tumour predisposition syndrome (TPS) in patients with childhood cancer is of significant clinical relevance, as it affects treatment, prognosis and facilitates genetic counselling. Previous studies revealed that only half of the known TPSs are recognised during standard paediatric cancer care. In current medical practice it is impossible to refer every patient with childhood cancer to a clinical geneticist, due to limited capacity for routine genetic consultation. Therefore, we have developed a screening instrument to identify patients with childhood cancer with a high probability of having a TPS. The aim of this study is to validate the clinical screening instrument for TPS in patients with childhood cancer. Methods and analysis This study is a prospective nationwide cohort study including all newly diagnosed patients with childhood cancer in the Netherlands. The screening instrument consists of a checklist, two- and three-dimensional photographic series of the patient. 2 independent clinical geneticists will assess the content of the screening instrument. If a TPS is suspected based on the instrument data and thus further evaluation is indicated, the patient will be invited for full genetic consultation. A negative control group consists of 20% of the patients in whom a TPS is not suspected based on the instrument; they will be randomly invited for full genetic consultation. Primary outcome measurement will be sensitivity of the instrument. Ethics and dissemination The Medical Ethical Committee of the Academic Medical Centre stated that the Medical Research Involving Human Subjects Act does not apply to this study and that official approval of this study by the Committee was not required. The results will be offered for publication in peer-reviewed journals and presented at International Conferences on Oncology and Clinical Genetics. The clinical data gathered in this study will be available for all participating centres. Trial

Moderating Effects of Autism on Parent Views of Genetic Screening for Aggression

ERIC Educational Resources Information Center

May, Michael E.; Brandt, Rachel C.; Bohannan, Joseph K.

2012-01-01

Advances in gene-environment interaction research have revealed genes that are associated with aggression. However, little is known about parent perceptions of genetic screening for behavioral symptoms like aggression as opposed to diagnosing disabilities. These perceptions may influence future research endeavors involving genetic linkage studies…

Moderating effects of autism on parent views of genetic screening for aggression.

PubMed

May, Michael E; Brandt, Rachel C; Bohannan, Joseph K

2012-10-01

Advances in gene-environment interaction research have revealed genes that are associated with aggression. However, little is known about parent perceptions of genetic screening for behavioral symptoms like aggression as opposed to diagnosing disabilities. These perceptions may influence future research endeavors involving genetic linkage studies to behavior, including proactive approaches for parents to avoid events leading to aggression. The purpose of this study was to solicit the perspectives of parents who have children with autism about screening for genes associated with aggression, compared to responses from those who have children without disabilities and those planning to have children. Parents of children with autism were more likely to support screening and the use of the results to seek treatment if necessary. Results are discussed in the context of surveillance screening and systematic early intervention for behavioral symptoms related to autism. The results may provide insight for clincians, researchers, policymakers, and advocacy groups related to diagnosing and treating aggression in people with autism.

Routine Screening for CYP2C19 Polymorphisms for Patients being Treated with Clopidogrel is not Recommended

PubMed Central

Hong, Robert A; Khan, Zia R; Valentin, Mona R; Badawi, Ramy A

2015-01-01

Recent efforts directed at potential litigation in Hawai‘i have resulted in a renewed interest for genetic screening for cytochrome P450 2C19 (CYP2C19) polymorphisms in patients treated with clopidogrel. Clopidogrel is an antiplatelet agent, frequently used in combination with aspirin, for the prevention of thrombotic complications with acute coronary syndrome and in patients undergoing percutaneous coronary interventions. Cytochrome P-450 (CYP) 2C19 is an enzyme involved in the bioactivation of clopidogrel from a pro-drug to an active inhibitor of platelet action. Patients of Asian and Pacific Island background have been reported to have an increase in CYP2C19 polymorphisms associated with loss-of-function of this enzyme when compared to other ethnicities. This has created an interest in genetic testing for CYP2C19 polymorphisms in Hawai‘i. Based upon our review of the current literature, we do not feel that there is support for the routine screening for CYP2C19 polymorphisms in patients being treated with clopidogrel; furthermore, the results of genetic testing may not be helpful in guiding therapeutic decisions. We recommend that decisions on the type of antiplatelet treatment be made based upon clinical evidence of potential differential outcomes associated with the use of these agents rather than on the basis of genetic testing. PMID:25628978

Employment discrimination implications of genetic screening in the workplace under Title VII and the Rehabilitation Act.

PubMed

Canter, E F

1984-01-01

The emergence of genetic screening techniques will permit employers to exclude hypersusceptible individuals from potentially hazardous workplace environments. The denial of employment opportunities to these individuals, however, may constitute discrimination. This Note analyzes genetic screening cases with respect to currently available remedies contained in Title VII of the Civil Rights Act of 1964 and the Rehabilitation Act of 1973. The Note concludes that Title VII claims may succeed but only in limited circumstances and that Rehabilitation Act claims will encounter numerous obstacles to relief. Additionally, the Note discusses some of the implications of the use of genetic screening in the workplace.

Alternative to the soft-agar assay that permits high-throughput drug and genetic screens for cellular transformation

PubMed Central

Rotem, Asaf; Janzer, Andreas; Izar, Benjamin; Ji, Zhe; Doench, John G.; Garraway, Levi A.; Struhl, Kevin

2015-01-01

Colony formation in soft agar is the gold-standard assay for cellular transformation in vitro, but it is unsuited for high-throughput screening. Here, we describe an assay for cellular transformation that involves growth in low attachment (GILA) conditions and is strongly correlated with the soft-agar assay. Using GILA, we describe high-throughput screens for drugs and genes that selectively inhibit or increase transformation, but not proliferation. Such molecules are unlikely to be found through conventional drug screening, and they include kinase inhibitors and drugs for noncancer diseases. In addition to known oncogenes, the genetic screen identifies genes that contribute to cellular transformation. Lastly, we demonstrate the ability of Food and Drug Administration-approved noncancer drugs to selectively kill ovarian cancer cells derived from patients with chemotherapy-resistant disease, suggesting this approach may provide useful information for personalized cancer treatment. PMID:25902495

Alternative to the soft-agar assay that permits high-throughput drug and genetic screens for cellular transformation.

PubMed

Rotem, Asaf; Janzer, Andreas; Izar, Benjamin; Ji, Zhe; Doench, John G; Garraway, Levi A; Struhl, Kevin

2015-05-05

Colony formation in soft agar is the gold-standard assay for cellular transformation in vitro, but it is unsuited for high-throughput screening. Here, we describe an assay for cellular transformation that involves growth in low attachment (GILA) conditions and is strongly correlated with the soft-agar assay. Using GILA, we describe high-throughput screens for drugs and genes that selectively inhibit or increase transformation, but not proliferation. Such molecules are unlikely to be found through conventional drug screening, and they include kinase inhibitors and drugs for noncancer diseases. In addition to known oncogenes, the genetic screen identifies genes that contribute to cellular transformation. Lastly, we demonstrate the ability of Food and Drug Administration-approved noncancer drugs to selectively kill ovarian cancer cells derived from patients with chemotherapy-resistant disease, suggesting this approach may provide useful information for personalized cancer treatment.

Clinical and genetic analysis of Indian patients with NDP-related retinopathies.

PubMed

Sudha, Dhandayuthapani; Ganapathy, Aparna; Mohan, Puja; Mannan, Ashraf U; Krishna, Shuba; Neriyanuri, Srividya; Swaminathan, Meenakshi; Rishi, Pukhraj; Chidambaram, Subbulakshmi; Arunachalam, Jayamuruga Pandian

2017-06-10

NDP-related retinopathies are a group of X-linked disorders characterized by degenerative and proliferative changes of the neuroretina, occasionally accompanied with varying degrees of mental retardation and sensorineural hearing loss. NDP is the predominant gene associated with NDP-related retinopathies. The purpose of this study was to report the clinical and genetic findings in three unrelated patients diagnosed with NDP-related retinopathies. The patients underwent complete ophthalmic examination followed by genetic analyses. NDP gene was screened by direct sequencing approach. Targeted resequencing of several other ocular genes was carried out in patient samples that either indicated NDP gene deletion or tested negative for NDP mutation. Gene quantitation analysis was performed using real-time PCR. The whole NDP gene was deleted in patient I, while a missense NDP mutation, c.205T>C, was identified in patient II, and both had classical Norrie disease ocular phenotype (with no other systemic defects). Patient III who was diagnosed with familial exudative vitreoretinopathy did not show any mutation in the known candidate genes as well as in other ocular genes tested. The patient with whole NDP gene deletion did not exhibit any apparent extraocular defects (like mental retardation or sensorineural hearing loss) during his first decade of life, and this is considered to be a notable finding. Our study also provides evidence emphasizing the need for genetic testing which could eliminate ambiguities in clinical diagnosis and detect carrier status, thereby aiding the patient and family members during genetic counseling.

Physician counseling on colorectal cancer screening and receipt of screening among Latino patients.

PubMed

Nápoles, Anna M; Santoyo-Olsson, Jasmine; Stewart, Anita L; Olmstead, Jill; Gregorich, Steven E; Farren, Georgianna; Cabral, Ruben; Freudman, Andrew; Pérez-Stable, Eliseo J

2015-04-01

Latinos have lower rates of colorectal cancer (CRC) screening and later stage diagnosis than Whites, which may be partially explained by physician communication factors. We assessed associations between patient-reported physician counseling regarding CRC screening and receipt of CRC screening among Latino primary care patients. This was a cross-sectional telephone survey. The participants of this study were Latino primary care patients 50 years of age or older, with one or more visits during the preceding year. We developed patient-reported measures to assess whether physicians provided explanations of CRC risks and tests, elicited patients' barriers to CRC screening, were responsive to patients' concerns about screening, and encouraged patients to be screened. Outcomes were patient reports of receipt of endoscopy (sigmoidoscopy or colonoscopy) and fecal occult blood test (FOBT) within recommended guidelines. Of 817 eligible patients contacted, 505 (62 %) completed the survey; mean age was 61 years (SD 8.4), 69 % were women, and 53 % had less than high school education. Forty-six percent reported obtaining endoscopy (with or without FOBT), 13 % reported FOBT only, and 41 % reported no CRC screening. In bivariate analyses, physician explanations, elicitation of barriers, responsiveness to concerns, and greater encouragement for screening were associated with receipt of endoscopy (p < 0.001), and explanations (p < 0.05) and encouragement (p < 0.001) were associated with FOBT. Adjusting for covariates, physician explanations (OR = 1.27; 95 % CI 1.03, 1.58) and greater physician encouragement (OR = 6.74; 95 % CI 3.57, 12.72) were associated with endoscopy; patients reporting quite a bit/a lot of physician encouragement had six times higher odds of obtaining the FOBT as those reporting none/a little encouragement (OR = 6.54; 95 % CI 2.76, 15.48). Among primarily lower-socioeconomic status Latino patients, the degree to which patients perceived that physicians encouraged

Should patients with ocular genetic disorders have genetic testing?

PubMed

Zanolli, Mario T; Khetan, Vikas; Dotan, Gad; Pizzi, Laura; Levin, Alex V

2014-09-01

To discuss the risks, benefits and value of genetic testing for ocular genetic disease. Testing for ocular genetics diseases is becoming more available and successful gene therapy is being reported. Clinicians must prepare for this trend by considering diagnostic genetic testing for their patients. As advances continually occur in genetic testing for ocular genetic disorders, clinicians must develop an understanding of the potential risks and benefits for their patients.

Cost-effectiveness analysis of preimplantation genetic screening and in vitro fertilization versus expectant management in patients with unexplained recurrent pregnancy loss.

PubMed

Murugappan, Gayathree; Ohno, Mika S; Lathi, Ruth B

2015-05-01

To determine whether in vitro fertilization with preimplantation genetic screening (IVF/PGS) is cost effective compared with expectant management in achieving live birth for patients with unexplained recurrent pregnancy loss (RPL). Decision analytic model comparing costs and clinical outcomes. Academic recurrent pregnancy loss programs. Women with unexplained RPL. IVF/PGS with 24-chromosome screening and expectant management. Cost per live birth. The IVF/PGS strategy had a live-birth rate of 53% and a clinical miscarriage rate of 7%. Expectant management had a live-birth rate of 67% and clinical miscarriage rate of 24%. The IVF/PGS strategy was 100-fold more expensive, costing $45,300 per live birth compared with $418 per live birth with expectant management. In this model, IVF/PGS was not a cost-effective strategy for increasing live birth. Furthermore, the live-birth rate with IVF/PGS needs to be 91% to be cost effective compared with expectant management. Copyright © 2015 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

A practical approach to screen for authorised and unauthorised genetically modified plants.

PubMed

Waiblinger, Hans-Ulrich; Grohmann, Lutz; Mankertz, Joachim; Engelbert, Dirk; Pietsch, Klaus

2010-03-01

In routine analysis, screening methods based on real-time PCR are most commonly used for the detection of genetically modified (GM) plant material in food and feed. In this paper, it is shown that the combination of five DNA target sequences can be used as a universal screening approach for at least 81 GM plant events authorised or unauthorised for placing on the market and described in publicly available databases. Except for maize event LY038, soybean events DP-305423 and BPS-CV127-9 and cotton event 281-24-236 x 3006-210-23, at least one of the five genetic elements has been inserted in these GM plants and is targeted by this screening approach. For the detection of these sequences, fully validated real-time PCR methods have been selected. A screening table is presented that describes the presence or absence of the target sequences for most of the listed GM plants. These data have been verified either theoretically according to available databases or experimentally using available reference materials. The screening table will be updated regularly by a network of German enforcement laboratories.

Patient Beliefs About Colon Cancer Screening.

PubMed

Ely, John W; Levy, Barcey T; Daly, Jeanette; Xu, Yinghui

2016-03-01

Only about half of eligible individuals undergo colon cancer screening. We have limited knowledge about the patient beliefs that adversely affect screening decisions and about which beliefs might be amenable to change through education. As part of a clinical trial, 641 rural Iowans, aged 52 to 79 years, reported their beliefs about colon cancer screening in response to a mailed questionnaire. Consenting subjects were randomized into four groups, which were distinguished by four levels of increasingly intensive efforts to promote screening. Two of the groups received mailed educational materials and completed a follow-up questionnaire, which allowed us to determine whether their beliefs about screening changed following the education. We also completed a factor analysis to identify underlying (latent) factors that might explain the responses to 33 questions about readiness, attitudes, and perceived barriers related to colon cancer screening. The strongest predictors of a patient's stated readiness to be screened were a physician's recommendation to be screened (1 point difference on 10-point Likert scale, 95 % confidence interval [CI], 0.5 to 1.6 point difference), a family history of colon cancer (0.85-point Likert scale difference, 95 % CI, 0.1 to 1.6), and a belief that health-care decisions should be mostly left to physicians rather than patients (Spearman correlation coefficient 0.21, P < .001). Of the 33 questionnaire items about screening beliefs, 11 (33 %) changed favorably following the educational intervention. In the factor analysis, the 33 items were reduced to 8 underlying factors, such as being too busy to undergo screening and worries about screening procedures. We found a limited number of underlying factors that may help explain patient resistance to colon cancer screening.

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.

Does patient time spent viewing computer-tailored colorectal cancer screening materials predict patient-reported discussion of screening with providers?

PubMed

Sanders, Mechelle; Fiscella, Kevin; Veazie, Peter; Dolan, James G; Jerant, Anthony

2016-08-01

The main aim is to examine whether patients' viewing time on information about colorectal cancer (CRC) screening before a primary care physician (PCP) visit is associated with discussion of screening options during the visit. We analyzed data from a multi-center randomized controlled trial of a tailored interactive multimedia computer program (IMCP) to activate patients to undergo CRC screening, deployed in primary care offices immediately before a visit. We employed usage time information stored in the IMCP to examine the association of patient time spent using the program with patient-reported discussion of screening during the visit, adjusting for previous CRC screening recommendation and reading speed.On average, patients spent 33 minutes on the program. In adjusted analyses, 30 minutes spent using the program was associated with a 41% increase in the odds of the patient having a discussion with their PCP (1.04, 1.59, 95% CI). In a separate analysis of the tailoring modules; the modules encouraging adherence to the tailored screening recommendation and discussion with the patient's PCP yielded significant results. Other predictors of screening discussion included better self-reported physical health and increased patient activation. Time spent on the program predicted greater patient-physician discussion of screening during a linked visit.Usage time information gathered automatically by IMCPs offers promise for objectively assessing patient engagement around a topic and predicting likelihood of discussion between patients and their clinician. © The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.

[Ethical aspects of prenatal screening for Down's syndrome].

PubMed

Tóth, A; Szabó, J

2000-10-15

Trisomy 21, the chromosomal base of Down's syndrome, results in severe mental and physical handicap. Owing to the development of medical genetics reliable screening and diagnostic procedures for the detection of the disorder are available in Hungary. To achieve the goals of prenatal screening it is important to address the main ethical issues arising through the application of technical-professional skills. The core objective of prenatal screening for Down's syndrome is to give information about the genetic condition of the fetus in order to enhance the autonomy of the parents in family planning. Screening programs should respect the ethical requirements of the principles of "do no harm", beneficence and autonomy of the patients, which are the most important ethical norms of doctor-patient relationship. Regarding the social aspects of screening it is essential to claim that voluntary participation and nondirective genetic counselling can exclude eugenic purposes. Though introduction of prenatal tests does not imply the discrimination of the disabled, anxiety of handicapped people deserves more attention. Abortion of affected fetuses isn't among the objectives of prenatal genetic screening but patient's autonomy is supported in decisions concerning the future of the pregnancy. Social justice can be taken into consideration by providing the test to all women without respect to their social position, educational level or their age. An open debate about the issues of prenatal screening for Down's syndrome could promote the formation of a consensus between professionals and the public.

A fast boosting-based screening method for large-scale association study in complex traits with genetic heterogeneity.

PubMed

Wang, Lu-Yong; Fasulo, D

2006-01-01

Genome-wide association study for complex diseases will generate massive amount of single nucleotide polymorphisms (SNPs) data. Univariate statistical test (i.e. Fisher exact test) was used to single out non-associated SNPs. However, the disease-susceptible SNPs may have little marginal effects in population and are unlikely to retain after the univariate tests. Also, model-based methods are impractical for large-scale dataset. Moreover, genetic heterogeneity makes the traditional methods harder to identify the genetic causes of diseases. A more recent random forest method provides a more robust method for screening the SNPs in thousands scale. However, for more large-scale data, i.e., Affymetrix Human Mapping 100K GeneChip data, a faster screening method is required to screening SNPs in whole-genome large scale association analysis with genetic heterogeneity. We propose a boosting-based method for rapid screening in large-scale analysis of complex traits in the presence of genetic heterogeneity. It provides a relatively fast and fairly good tool for screening and limiting the candidate SNPs for further more complex computational modeling task.

Implementing a screening tool for identifying patients at risk for hereditary breast and ovarian cancer: a statewide initiative.

PubMed

Brannon Traxler, L; Martin, Monique L; Kerber, Alice S; Bellcross, Cecelia A; Crane, Barbara E; Green, Victoria; Matthews, Roland; Paris, Nancy M; Gabram, Sheryl G A

2014-10-01

The Georgia Breast Cancer Genomic Health Consortium is a partnership created with funding from the Centers for Disease Control and Prevention (CDC) to the Georgia Department of Public Health to reduce cancer disparities among high-risk minority women. The project addresses young women at increased risk for hereditary breast and ovarian cancer (HBOC) syndrome through outreach efforts. The consortium provides education and collects surveillance data using the breast cancer genetics referral screening tool (B-RST) available at www.BreastCancerGeneScreen.org . The HBOC educational protocol was presented to 73 staff in 6 public health centers. Staff used the tool during the collection of medical history. Further family history assessments and testing for mutations in the BRCA1/2 genes were facilitated if appropriate. Data was collected from November 2012 through December 2013, including 2,159 screened women. The majority of patients identified as black/African American and were 18-49 years old. Also, 6.0 % (n = 130) had positive screens, and 60.9 % (n = 67) of the 110 patients who agreed to be contacted provided a detailed family history. A total of 47 patients (42.7 %) met National Comprehensive Cancer Network guidelines when family history was clarified. Fourteen (12.7 %) underwent genetic testing; 1 patient was positive for a BRCA2 mutation, and 1 patient was found to carry a variant of uncertain significance. The introduction of genomics practice within public health departments has provided access to comprehensive cancer care for uninsured individuals. The successful implementation of the B-RST into public health centers demonstrates the opportunity for integration of HBOC screening into primary care practices.

Toward a generalized and high-throughput enzyme screening system based on artificial genetic circuits.

PubMed

Choi, Su-Lim; Rha, Eugene; Lee, Sang Jun; Kim, Haseong; Kwon, Kilkoang; Jeong, Young-Su; Rhee, Young Ha; Song, Jae Jun; Kim, Hak-Sung; Lee, Seung-Goo

2014-03-21

Large-scale screening of enzyme libraries is essential for the development of cost-effective biological processes, which will be indispensable for the production of sustainable biobased chemicals. Here, we introduce a genetic circuit termed the Genetic Enzyme Screening System that is highly useful for high-throughput enzyme screening from diverse microbial metagenomes. The circuit consists of two AND logics. The first AND logic, the two inputs of which are the target enzyme and its substrate, is responsible for the accumulation of a phenol compound in cell. Then, the phenol compound and its inducible transcription factor, whose activation turns on the expression of a reporter gene, interact in the other logic gate. We confirmed that an individual cell harboring this genetic circuit can present approximately a 100-fold higher cellular fluorescence than the negative control and can be easily quantified by flow cytometry depending on the amounts of phenolic derivatives. The high sensitivity of the genetic circuit enables the rapid discovery of novel enzymes from metagenomic libraries, even for genes that show marginal activities in a host system. The crucial feature of this approach is that this single system can be used to screen a variety of enzymes that produce a phenol compound from respective synthetic phenyl-substrates, including cellulase, lipase, alkaline phosphatase, tyrosine phenol-lyase, and methyl parathion hydrolase. Consequently, the highly sensitive and quantitative nature of this genetic circuit along with flow cytometry techniques could provide a widely applicable toolkit for discovering and engineering novel enzymes at a single cell level.

Genetic screening of prospective parents and of workers: some scientific and social issues.

PubMed

Hubbard, R; Henifin, M S

1985-01-01

Genetic screening programs are based on assumptions and values that reflect the history of racial and social eugenics in the United States and Europe. They stigmatize individuals by shifting the focus from social, economic, and political decisions that affect the health of prospective parents, newborns, and workers to "bad genes," that is, intrapersonal factors that are given the status of "causes" of disease. Prenatal screening, at best, can help the relatively few individuals who know that their future children are at risk for a particular inherited disease or disability; it has little positive value for the average person. Workplace genetic screening has not been shown to reduce occupational disease, but it has led to employment discrimination and has drawn attention away from controlling exposures to toxic chemicals in the workplace.

Carrier screening for cystic fibrosis.

PubMed

Dungan, Jeffrey S

2010-03-01

Cystic fibrosis is the first genetic disorder for which universal screening of preconceptional or prenatal patients became a component of standard prenatal care. The molecular genetics and mutation profile of the CFTR gene are complex, with a wide range of phenotypic consequences. Carrier screening can facilitate risk assessment for prospective parents to have an affected offspring, although there remains a small residual risk for carrying a mutation even with a negative screening result. There are ethnic differences with respect to disease incidence and effectiveness of carrier testing, which may complicate counseling. Copyright (c) 2010 Elsevier Inc. All rights reserved.

Pregnant Women's Perspectives on Expanded Carrier Screening.

PubMed

Propst, Lauren; Connor, Gwendolyn; Hinton, Megan; Poorvu, Tabitha; Dungan, Jeffrey

2018-02-23

Expanded carrier screening (ECS) is a relatively new carrier screening option that assesses many conditions simultaneously, as opposed to traditional ethnicity-based carrier screening for a limited number of conditions. This study aimed to explore pregnant women's perspectives on ECS, including reasons for electing or declining and anxiety associated with this decision-making. A total of 80 pregnant women were surveyed from Northwestern Medicine's Clinical Genetics Division after presenting for aneuploidy screening. Of the 80 participants, 40 elected and 40 declined ECS. Trends regarding reasons for electing or declining ECS include ethnicity, desire for genetic risk information, lack of family history, perceived likelihood of being a carrier, and perceived impact on reproductive decisions. Individuals who declined ECS seemed to prefer ethnicity-based carrier screening and believed that ECS would increase their anxiety, whereas individuals who elected ECS seemed to prefer more screening and tended to believe that ECS would reduce their anxiety. These findings provide insight on decision-making with regard to ECS and can help guide interactions that genetic counselors and other healthcare providers have with patients, including assisting patients in the decision-making process.

Noninvasive prenatal screening for fetal aneuploidy, 2016 update: a position statement of the American College of Medical Genetics and Genomics.

PubMed

Gregg, Anthony R; Skotko, Brian G; Benkendorf, Judith L; Monaghan, Kristin G; Bajaj, Komal; Best, Robert G; Klugman, Susan; Watson, Michael S

2016-10-01

This statement is designed primarily as an educational resource for clinicians to help them provide quality medical services. Adherence to this statement is completely voluntary and does not necessarily assure a successful medical outcome. This statement should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed toward obtaining the same results. In determining the propriety of any specific procedure or test, the clinician should apply his or her own professional judgment to the specific clinical circumstances presented by the individual patient or specimen. Clinicians are encouraged to document the reasons for the use of a particular procedure or test, whether or not it is in conformance with this statement. Clinicians also are advised to take notice of the date this statement was adopted and to consider other 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.Noninvasive prenatal screening using cell-free DNA (NIPS) has been rapidly integrated into prenatal care since the initial American College of Medical Genetics and Genomics (ACMG) statement in 2013. New evidence strongly suggests that NIPS can replace conventional screening for Patau, Edwards, and Down syndromes across the maternal age spectrum, for a continuum of gestational age beginning at 9-10 weeks, and for patients who are not significantly obese. This statement sets forth a new framework for NIPS that is supported by information from validation and clinical utility studies. Pretest counseling for NIPS remains crucial; however, it needs to go beyond discussions of Patau, Edwards, and Down syndromes. The use of NIPS to include sex chromosome aneuploidy screening and screening for selected copy-number variants (CNVs) is becoming commonplace because there are

Using a genetic, observational study as a strategy to estimate the potential cost-effectiveness of pharmacological CCR5 blockade in dialysis patients.

PubMed

Muntinghe, Friso L H; Vegter, Stefan; Verduijn, Marion; Boeschoten, Elisabeth W; Dekker, Friedo W; Navis, Gerjan; Postma, Maarten

2011-07-01

Randomized clinical trials are expensive and time consuming. Therefore, strategies are needed to prioritise tracks for drug development. Genetic association studies may provide such a strategy by considering the differences between genotypes as a proxy for a natural, lifelong, randomized at conception, clinical trial. Previously an association with better survival was found in dialysis patients with systemic inflammation carrying a deletion variant of the CC-chemokine receptor 5 (CCR5). We hypothesized that in an analogous manner, pharmacological CCR5 blockade could protect against inflammation-driven mortality and estimated if such a treatment would be cost-effective. A genetic screen and treat strategy was modelled using a decision-analytic Markov model, in which patients were screened for the CCR5 deletion 32 polymorphism and those with the wild type and systemic inflammation were treated with pharmacological CCR5 blockers. Kidney transplantation and mortality rates were calculated using patient level data. Extensive sensitivity analyses were performed. The cost-effectiveness of the genetic screen and treat strategy was &OV0556;18 557 per life year gained and &OV0556;21 896 per quality-adjusted life years gained. Concordance between the genetic association and pharmacological effectiveness was a main driver of cost-effectiveness. Sensitivity analyses showed that even a modest effectiveness of pharmacological CCR5 blockade would result in a treatment strategy that is good value for money. Pharmacological blockade of the CCR5 receptor in inflamed dialysis patients can be incorporated in a potentially cost-effective screen and treat programme. These findings provide formal rationale for clinical studies. This study illustrates the potential of genetic association studies for drug development, as a source of Mendelian randomized evidence from an observational setting.

The Development of a Clinical Screening Instrument For Tumour Predisposition Syndromes In Childhood Cancer Patients

PubMed Central

Hopman, Saskia M. J.; Merks, Johannes H. M.; de Borgie, Corianne A. J. M.; Aalfs, C. M.; Biesecker, Leslie G.; Cole, Trevor; Eng, Charis; Legius, Eric; Maher, Eamonn R.; van Noesel, Max M.; Verloes, Alain; Viskochil, David H.; Wagner, Anja; Weksberg, Rosanna; Caron, Huib N.; Hennekam, Raoul C. M.

2014-01-01

Background Identification of tumour predisposition syndromes in patients who have cancer in childhood is paramount for optimal care. A screening instrument that can help to identify such patients will facilitate physicians caring for children with cancer. The complete screening instrument should consist of a standardized series of pictures and a screening form for manifestations not visible in the pictures. Here we describe the development of such a screening form based on an international two-stage Delphi process and an initial validation of the complete instrument. Patients and Methods We identified manifestations that may contribute to the diagnosis of a tumour predisposition syndrome through the Winter-Baraitser Dysmorphology Database and the textbook “Gorlin's Syndromes of the Head and Neck”. In a two-round Delphi process, eight international content-experts scored the contribution of each of these manifestations. We performed a clinical validation of the instrument in a selected cohort of ten paediatric cancer patients from another centre. Results In total, 49 manifestations were found to contribute to the diagnosis of a tumour predisposition syndrome and were included in the screening form. The pilot validation study showed that patients suspect for having a tumour predisposition syndrome were recognized. Excellent correlation for indication for referral of a patient between the screening instrument and the reference standard (personal evaluation by an experienced clinical geneticist) was found.). Conclusions The Delphi process performed by international specialists with a function as opinion leaders in their field of expertise has led to a screening form and instrument with which those childhood cancer patients can be identified who may have a tumour predisposition syndrome and thus have an indication to be referred for further genetic analysis. PMID:23855994

Increasing importance of genetics in nursing.

PubMed

Camak, Deborah Jacks

2016-09-01

To examine the empirical literature related to the incorporation of genetic research and genetic competency needed by the nurse in practice. Literature review. This article will explore published research within the past seven years of 2008-2015 that address the need for the increased incorporation of genetic content in nursing practice in addition to the need for the nurse to effectively screen the patient at risk of a genetic disorder. This literature review specifically focuses on the inadequacy of nurses in addressing genomic health compromise and serving as advocates for patients and families facing genetic disorders. A review of the literature published from 2008 to 2015 related to the incorporation of genetics in nursing practice and the role of the nurse as a patient advocate for families facing genetic disorders with resulting genomic health compromise. The research exposes the lack of adequate preparation of nurses to incorporate and utilize the recent advances in genomic healthcare. Practicing nurses lack understating and skill in the application of genetics and genomic technologies to patient care. The nursing profession, including nursing academia, need to enhance the integration of genetic and genomic content into nursing curriculum and practice. Practicing nurses are inadequately prepared to apply genetic advancements in screening at risk patients and addressing the needs of the patient or family facing a genomic health compromise. Copyright © 2016 Elsevier Ltd. All rights reserved.

Rare genetic variants in Tunisian Jewish patients suffering from age-related macular degeneration.

PubMed

Pras, Eran; Kristal, Dana; Shoshany, Nadav; Volodarsky, Dina; Vulih, Inna; Celniker, Gershon; Isakov, Ofer; Shomron, Noam; Pras, Elon

2015-07-01

To explore the molecular basis of familial, early onset, age-related macular degeneration (AMD) with diverse phenotypes, using whole exome sequencing (WES). We performed WES on four patients (two sibs from two families) manifesting early-onset AMD and searched for disease-causing genetic variants in previously identified macular degeneration related genes. Validation studies of the variants included bioinformatics tools, segregation analysis of mutations within the families and mutation screening in an AMD cohort of patients. The index patients were in their 50s when diagnosed and displayed a wide variety of clinical AMD presentations: from limited drusen in the posterior pole to multiple basal-laminar drusen extending peripherally. Severe visual impairment due to extensive geographic atrophy and/or choroidal-neovascularisation was common by the age of 75 years. Approximately, 400 000 genomic variants for each DNA sample were included in the downstream bioinformatics analysis, which ended in the discovery of two novel variants; in one family a single bp deletion was identified in the Hemicentin (HMCN1) gene (c.4162delC), whereas in the other, a missense variant (p.V412M) in the Complement Factor-I (CFI) gene was found. Screening for these variants in a cohort of patients with AMD identified another family with the CFI variant. This report uses WES to uncover rare genetic variants in AMD. A null-variant in HMCN1 has been identified in one AMD family, and a missense variant in CFI was discovered in two other families. These variants confirm the genetic complexity and significance of rare genetic variants in the pathogenesis of AMD. 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.

Cancer screening in patients infected with HIV.

PubMed

Sigel, Keith; Dubrow, Robert; Silverberg, Michael; Crothers, Kristina; Braithwaite, Scott; Justice, Amy

2011-09-01

Non-AIDS-defining cancers are a rising health concern among HIV-infected patients. Cancer screening is now an important component of health maintenance in HIV clinical practice. The decision to screen an HIV-infected patient for cancer should include an assessment of individualized risk for the particular cancer, life expectancy, and the harms and benefits associated with the screening test and its potential outcome. HIV-infected patients are at enhanced risk of several cancers compared to the general population; anal cancer, hepatocellular carcinoma, Hodgkin's lymphoma, and lung cancer all have good evidence demonstrating an enhanced risk in HIV-infected persons. A number of cancer screening interventions have shown benefit for specific cancers in the general population, but data on the application of these tests to HIV-infected persons are limited. Here we review the epidemiology and background literature relating to cancer screening interventions in HIV-infected persons. We then use these data to inform a conceptual model for evaluating HIV-infected patients for cancer screening.

Women's Understanding and Attitudes towards Down Syndrome and Other Genetic Conditions in the Context of Prenatal Screening.

PubMed

Long, Sarah; O'Leary, Peter; Lobo, Roanna; Dickinson, Jan E

2018-06-01

In order to explore the impact of potential new technologies in the area of prenatal screening, we conducted a baseline study using qualitative interviews to explore women's attitudes and knowledge regarding current and future prenatal screening technology and methods. Three cohorts were interviewed, including healthy women without children, healthy women with healthy children, and healthy women with children who have de novo genetic disorders. This study aimed to assess the baseline understanding and attitudes of women in Western Australia. Women from each cohort demonstrated adequate knowledge of the differences between screening and diagnostic tests, but were mostly unaware of the conditions for which screening is currently available except Down syndrome. Women who had children with de novo genetic conditions were generally aware of more genetic conditions than women with or without healthy children. Most women recognised the genetic basis for the conditions mentioned. Two thirds of women understood that Down syndrome is a chromosomal condition; just one third recognised that the phenotype is variable. Most women expressed a positive attitude towards Down syndrome. Social acceptance of children with Down syndrome was commonly mentioned as a concern. While the majority of women with children supported screening for Down syndrome, they emphasised that it must be an autonomous choice. General knowledge of genetic conditions illustrated that women are exposed to diverse conditions from lived experience as well as the media.

ESHRE Task Force on Ethics and Law 21: genetic screening of gamete donors: ethical issues.

PubMed

Dondorp, W; De Wert, G; Pennings, G; Shenfield, F; Devroey, P; Tarlatzis, B; Barri, P; Diedrich, K; Eichenlaub-Ritter, U; Tüttelmann, F; Provoost, V

2014-07-01

This Task Force document explores the ethical issues involved in the debate about the scope of genetic screening of gamete donors. Calls for expanded donor screening arise against the background of both occasional findings of serious but rare genetic conditions in donors or donor offspring that were not detected through present screening procedures and the advent of new genomic technologies promising affordable testing of donors for a wide range of conditions. Ethical principles require that all stakeholders' interests are taken into account, including those of candidate donors. The message of the profession should be that avoiding all risks is impossible and that testing should remain proportional.

Healthcare and patient costs of a proactive chlamydia screening programme: the Chlamydia Screening Studies project.

PubMed

Robinson, Suzanne; Roberts, Tracy; Barton, Pelham; Bryan, Stirling; Macleod, John; McCarthy, Anne; Egger, Matthias; Sanford, Emma; Low, Nicola

2007-07-01

Most economic evaluations of chlamydia screening do not include costs incurred by patients. The objective of this study was to estimate both the health service and private costs of patients who participated in proactive chlamydia screening, using mailed home-collected specimens as part of the Chlamydia Screening Studies project. Data were collected on the administrative costs of the screening study, laboratory time and motion studies and patient-cost questionnaire surveys were conducted. The cost for each screening invitation and for each accepted offer was estimated. One-way sensitivity analysis was conducted to explore the effects of variations in patient costs and the number of patients accepting the screening offer. The time and costs of processing urine specimens and vulvo-vaginal swabs from women using two nucleic acid amplification tests were similar. The total cost per screening invitation was 20.37 pounds (95% CI 18.94 pounds to 24.83). This included the National Health Service cost per individual screening invitation 13.55 pounds (95% CI 13.15 pounds to 14.33) and average patient costs of 6.82 pounds (95% CI 5.48 pounds to 10.22). Administrative costs accounted for 50% of the overall cost. The cost of proactive chlamydia screening is comparable to those of opportunistic screening. Results from this study, which is the first to collect private patient costs associated with a chlamydia screening programme, could be used to inform future policy recommendations and provide unique primary cost data for economic evaluations.

Validation of Version 3.0 of the Breast Cancer Genetics Referral Screening Tool (B-RST™).

PubMed

Bellcross, Cecelia; Hermstad, April; Tallo, Christine; Stanislaw, Christine

2018-05-08

Despite increased awareness of hereditary breast and ovarian cancer among clinicians and the public, many BRCA1/2 mutation carriers remain unaware of their risk status. The Breast Cancer Genetics Referral Screening Tool (B-RST™) was created and validated to easily identify individuals at increased risk for hereditary breast and ovarian cancer for referral to cancer genetics services. The purpose of this study was to revise B-RST™ to maximize sensitivity against BRCA1/2 mutation status. We analyzed pedigrees of 277 individuals who had undergone BRCA1/2 testing to determine modifications to the B-RST™ 2.0 algorithm that would maximize sensitivity for mutations, while maintaining simplicity. We used McNemar's chi-square test to compare validation measures between the revised version (3.0) and the 2.0 version. Algorithmic changes made to B-RST™ 2.0 increased the sensitivity against BRCA1/2 mutation analysis from 71.1 to 94.0% (P < 0.0001). While specificity decreased, all screen-positive individuals were appropriate for cancer genetics referral, the primary purpose of the tool. Despite calls for BRCA1/2 population screening, there remains a critical need to identify those most at risk who should receive cancer genetics services. B-RST™ version 3.0 demonstrates high sensitivity for BRCA1/2 mutations, yet remains a simple and quick screening tool for at-risk individuals.

Cancer screening behaviors and risk perceptions among family members of colorectal cancer patients with unexplained mismatch repair deficiency.

PubMed

Katz, Lior H; Advani, Shailesh; Burton-Chase, Allison M; Fellman, Bryan; Polivka, Katrina M; Yuan, Ying; Lynch, Patrick M; Peterson, Susan K

2017-04-01

Communication gaps in families with unexplained mismatch repair (MMR) deficiency (UMMRD) could negatively impact the screening behaviors of relatives of individual with UMMRD. We evaluated cancer risk perception, screening behaviors, and family communication among relatives of colorectal cancer (CRC) patients with UMMRD. Fifty-one family members of 17 probands with UMMRD completed a questionnaire about cancer risk perception, adherence to Lynch syndrome (LS) screening recommendations, and communication with relatives. Clinical data about the probands were obtained from medical records. Thirty-eight participants (78%) were worried from having cancer and twenty-one participants (42%) had undergone colonoscopy in the past 2 years, as recommended for LS families. In terms of screening for extracolonic cancers, only two eligible participants (3.9%) were screened for gastric, endometrial (10.0%), and ovarian (9.5%) cancers. Additionally, 5 participants (10%) underwent genetic counseling. Most participants were not told by anyone to be screened for extracolonic cancers (84, 85, and 95% for gastric, ovarian, and endometrial cancers, respectively). A minority of family members of CRC patients with UMMRD follow cancer screening as recommended for LS families. Health care providers should encourage patients with UMMRD to share information on LS-related cancers screening, especially extracolonic cancers, with their relatives.

Cancer screening behaviors and risk perceptions among family members of colorectal cancer patients with unexplained mismatch repair deficiency

PubMed Central

Advani, Shailesh; Burton-Chase, Allison M.; Fellman, Bryan; Polivka, Katrina M.; Yuan, Ying; Lynch, Patrick M.; Peterson, Susan K.

2018-01-01

Communication gaps in families with unexplained mismatch repair (MMR) deficiency (UMMRD) could negatively impact the screening behaviors of relatives of individual with UMMRD. We evaluated cancer risk perception, screening behaviors, and family communication among relatives of colorectal cancer (CRC) patients with UMMRD. Fifty-one family members of 17 probands with UMMRD completed a questionnaire about cancer risk perception, adherence to Lynch syndrome (LS) screening recommendations, and communication with relatives. Clinical data about the probands were obtained from medical records. Thirty-eight participants (78%) were worried from having cancer and twenty-one participants (42%) had undergone colonoscopy in the past 2 years, as recommended for LS families. In terms of screening for extracolonic cancers, only two eligible participants (3.9%) were screened for gastric, endometrial (10.0%), and ovarian (9.5%) cancers. Additionally, 5 participants (10%) underwent genetic counseling. Most participants were not told by anyone to be screened for extracolonic cancers (84, 85, and 95% for gastric, ovarian, and endometrial cancers, respectively). A minority of family members of CRC patients with UMMRD follow cancer screening as recommended for LS families. Health care providers should encourage patients with UMMRD to share information on LS-related cancers screening, especially extracolonic cancers, with their relatives. PMID:27832499

Pathways and barriers to genetic testing and screening: Molecular genetics meets the high-risk family. Final report

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

Duster, T.

The proliferation of genetic screening and testing is requiring increasing numbers of Americans to integrate genetic knowledge and interventions into their family life and personal experience. This study examines the social processes that occur as families at risk for two of the most common autosomal recessive diseases, sickle cell disease (SC) and cystic fibrosis (CF), encounter genetic testing. Each of these diseases is found primarily in a different ethnic/racial group (CF in Americans of North European descent and SC in Americans of West African descent). This has permitted them to have a certain additional lens on the role of culturemore » in integrating genetic testing into family life and reproductive planning. A third type of genetic disorder, the thalassemias was added to the sample in order to extent the comparative frame and to include other ethnic and racial groups.« less

Combined treatment with octreotide LAR and pegvisomant in patients with pituitary gigantism: clinical evaluation and genetic screening.

PubMed

Mangupli, Ruth; Rostomyan, Liliya; Castermans, Emilie; Caberg, Jean-Hubert; Camperos, Paul; Krivoy, Jaime; Cuauro, Elvia; Bours, Vincent; Daly, Adrian F; Beckers, Albert

2016-10-01

Pituitary gigantism is a rare condition caused by growth hormone secreting hypersecretion, usually by a pituitary tumor. Acromegaly and gigantism cases that have a genetic cause are challenging to treat, due to large tumor size and poor responses to some medical therapies (e.g. AIP mutation affected cases and those with X-linked acrogigantism syndrome). We performed a retrospective study to identify gigantism cases among 160 somatotropinoma patients treated between 1985 and 2015 at the University Hospital of Caracas, Venezuela. We studied clinical details at diagnosis, hormonal responses to therapy and undertook targeted genetic testing. Among the 160 cases, eight patients (six males; 75 %) were diagnosed with pituitary gigantism and underwent genetic analysis that included array comparative genome hybridization for Xq26.3 duplications. All patients had GH secreting pituitary macroadenomas that were difficult to control with conventional treatment options, such as surgery or primary somatostatin receptor ligand (SRL) therapy. Combined therapy (long-acting SRL and pegvisomant) as primary treatment or after pituitary surgery and radiotherapy permitted the normalization of IGF-1 levels and clinical improvement. Novel AIP mutations were the found in three patients. None of the patients had Xq26.3 microduplications. Treatment of pituitary gigantism is frequently challenging; delayed control increases the harmful effects of GH excess, such as, excessive stature and symptom burden, so early diagnosis and effective treatment are particularly important in these cases.

Genetic counselors' experience with cell-free fetal DNA testing as a prenatal screening option for aneuploidy.

PubMed

Horsting, Julie M H; Dlouhy, Stephen R; Hanson, Katelyn; Quaid, Kimberly; Bai, Shaochun; Hines, Karrie A

2014-06-01

First identified in 1997, cell-free fetal DNA (cffDNA) has just recently been used to detect fetal aneuploidy of chromosomes 13, 18, and 21, showing its potential to revolutionize prenatal genetic testing as a non-invasive screening tool. Although this technological advancement is exciting and has certain medical applications, it has been unclear how it will be implemented in a clinical setting. Genetic counselors will likely be instrumental in answering that question, but to date, there is no published research regarding prenatal counselors' implementation of and experiences with cffDNA testing. We developed a 67 question survey to gather descriptive information from counselors regarding their personal opinions, experiences, thoughts, and concerns regarding the validity, usefulness, and implementation of this new technology. A total of 236 individuals completed a portion of the survey; not all respondents answered all questions. Qualitative questions complemented quantitative survey items, allowing respondents to voice their thoughts directly. Results indicate that counselors value cffDNA testing as a screening option but are concerned regarding how some obstetricians and patients make use of this testing. Further results, discussion, and practice implications are presented.

Comprehensive Molecular Screening in Chinese Usher Syndrome Patients.

PubMed

Sun, Tengyang; Xu, Ke; Ren, Yanfan; Xie, Yue; Zhang, Xiaohui; Tian, Lu; Li, Yang

2018-03-01

Usher syndrome (USH) refers to a group of autosomal recessive disorders causing deafness and blindness. The objectives of this study were to determine the mutation spectrum in a cohort of Chinese patients with USH and to describe the clinical features of the patients with mutations. A total of 119 probands who were clinically diagnosed with USH were recruited for genetic analysis. All probands underwent ophthalmic examinations. A combination of molecular screening methods, including targeted next-generation sequencing, Sanger-DNA sequencing, and multiplex ligation probe amplification assay, was used to detect mutations. We found biallelic mutations in 92 probands (77.3%), monoallelic mutations in 5 patients (4.2%), and 1 hemizygous mutation in 1 patient (0.8%), resulting in an overall mutation detection rate of 78.2%. Overall, 132 distinct disease-causing mutations involving seven USH (ABHD12, CDH23, GPR98, MYO7A, PCDH15, USH1C, and USH2A) genes; 5 other retinal degeneration genes (CHM, CNGA1, EYS, PDE6B, and TULP1); and 1 nonsyndromic hearing loss gene (MYO15A) were identified, and 78 were novel. Mutations of MYOA7 were responsible for 60% of USH1 families, followed by PCDH15 (20%) and USH1C (10%). Mutations of USH2A accounted for 67.7% of USH2 families, and mutation c.8559-2A>G was the most frequent one, accounting for 19.1% of the identified USH2A alleles. Our results confirm that the mutation spectrum for each USH gene in Chinese patients differs from those of other populations. The formation of the mutation profile for the Chinese population will enable a precise genetic diagnosis for USH patients in the future.

Recent advances in the molecular genetics of epilepsy.

PubMed

Hildebrand, Michael S; Dahl, Hans-Henrik M; Damiano, John Anthony; Smith, Richard J H; Scheffer, Ingrid E; Berkovic, Samuel F

2013-05-01

Recent advances in molecular genetics have translated into the increasing utilisation of genetic testing in the routine clinical practice of neurologists. There has been a steady, incremental increase in understanding the genetic variation associated with epilepsies. Genetic testing in the epilepsies is not yet widely practiced, but the advent of new screening technologies promises to exponentially expand both knowledge and clinical utility. To maximise the value of this new genetic insight we need to rapidly extrapolate genetic findings to inform patients of their diagnosis, prognosis, recurrence risk and the clinical management options available for their specific genetic condition. Comprehensive, highly specific and sensitive genetic test results improve the management of patients by neurologists and clinical geneticists. Here we discuss the latest developments in clinical genetic testing for epilepsy and describe new molecular genetics platforms that will transform both genetic screening and novel gene discovery.

Spectrum of genetic variation at the ABCC6 locus in South Africans: Pseudoxanthoma elasticum patients and healthy individuals.

PubMed

Ramsay, Michèle; Greenberg, Tarryn; Lombard, Zane; Labrum, Robyn; Lubbe, Steven; Aron, Shaun; Marais, Anna-Susan; Terry, Sharon; Bercovitch, Lionel; Viljoen, Denis

2009-06-01

Pseudoxanthoma elasticum (PXE) is an autosomal recessive metabolic disorder with ectopic mineralization in the skin, eyes and cardiovascular system. PXE is caused by mutations in ABCC6. To examine 54 unrelated South African PXE patients for ABCC6 PXE causing mutations. Patients were screened for mutations in ABCC6 using two strategies. The first involved a comprehensive screening of all the ABCC6 exons and flanking regions by dHPLC or sequencing whereas the second involved screening patients only for the common PXE mutations. The ABCC6 gene was screened in ten white and ten black healthy unrelated South Africans in order to examine the level of common non-PXE associated variation. The Afrikaner founder mutation, R1339C, was present in 0.41 of white ABCC6 PXE alleles, confirming the founder effect and its presence in both Afrikaans- (34/63 PXE alleles) and English-speakers (4/28). Eleven mutations were detected in the white patients (of European origin), including two nonsense mutations, 6 missense mutations, two frameshift mutations and a large deletion mutation. The five "Coloured" patients (of mixed Khoisan, Malay, European and African origin) included three compound heterozygotes with R1339C as one of the mutations. The three black patients (sub-Saharan African origin) were all apparent homozygotes for the R1314W mutation. Blacks showed a trend towards a higher degree of neurtral variation (18 variants) when compared to whites (12 variants). Delineation of the ABCC6 mutation profile in South African PXE patients will be used as a guide for molecular genetic testing in a clinical setting and for genetic counselling.

HIV screening in commercially insured patients screened or diagnosed with sexually transmitted diseases or blood-borne pathogens.

PubMed

Chen, Judy Ying; Ma, Qiufei; Everhard, Francois; Yermilov, Irina; Tian, Haijun; Mayer, Kenneth Hugh

2011-06-01

The Centers for Disease Control strongly recommends HIV screening for all patients who present to health care settings with sexually transmitted diseases (STD) or blood-borne pathogens exposure. The objective of this study is to assess the rates and determinants of HIV screening in a national sample of commercially insured patients screened or diagnosed with an STD or hepatitis B or C. We used Poisson regression model with a robust error variance to assess the determinants of HIV screening using administrative claims data from health plans across 6 states (n = 270,423). The overall HIV screening rate of patients who were diagnosed or screened for STDs or hepatitis was low (32.7%); rates were lowest for patients presenting with epididymitis or granuloma inguinale (<10%). Patients aged 25 to 34 years were more likely to be screened than other age groups. Females were significantly less likely to be screened for HIV (prevalence ratio = 0.90; 95% CI = 0.89, 0.91) than males. Patients living in states where no written HIV informed consent was required were significantly more likely to be screened than those living in states where written HIV informed consent was specifically required. HIV screening rates were low and varied by STD categories. Females and younger and older patients were at increased risk of no HIV screening. Requiring specific written informed consent for HIV screening resulted in less HIV screening. Interventions are urgently needed to increase the HIV screening rate among this at-risk population.

Accelerating glioblastoma drug discovery: Convergence of patient-derived models, genome editing and phenotypic screening.

PubMed

O'Duibhir, Eoghan; Carragher, Neil O; Pollard, Steven M

2017-04-01

Patients diagnosed with glioblastoma (GBM) continue to face a bleak prognosis. It is critical that new effective therapeutic strategies are developed. GBM stem cells have molecular hallmarks of neural stem and progenitor cells and it is possible to propagate both non-transformed normal neural stem cells and GBM stem cells, in defined, feeder-free, adherent culture. These primary stem cell lines provide an experimental model that is ideally suited to cell-based drug discovery or genetic screens in order to identify tumour-specific vulnerabilities. For many solid tumours, including GBM, the genetic disruptions that drive tumour initiation and growth have now been catalogued. CRISPR/Cas-based genome editing technologies have recently emerged, transforming our ability to functionally annotate the human genome. Genome editing opens prospects for engineering precise genetic changes in normal and GBM-derived neural stem cells, which will provide more defined and reliable genetic models, with critical matched pairs of isogenic cell lines. Generation of more complex alleles such as knock in tags or fluorescent reporters is also now possible. These new cellular models can be deployed in cell-based phenotypic drug discovery (PDD). Here we discuss the convergence of these advanced technologies (iPS cells, neural stem cell culture, genome editing and high content phenotypic screening) and how they herald a new era in human cellular genetics that should have a major impact in accelerating glioblastoma drug discovery. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

A multimedia patient education program on colorectal cancer screening increases knowledge and willingness to consider screening among Hispanic/Latino patients.

PubMed

Makoul, Gregory; Cameron, Kenzie A; Baker, David W; Francis, Lee; Scholtens, Denise; Wolf, Michael S

2009-08-01

To test a multimedia patient education program on colorectal cancer (CRC) screening that was designed specifically for the Hispanic/Latino community, and developed with input from community members. A total of 270 Hispanic/Latino adults, age 50-80 years, participated in Spanish for all phases of this pretest-posttest design. Patients were randomly assigned to a version of the multimedia program that opened with either a positive or negative introductory appeal. Structured interviews assessed screening relevant knowledge (anatomy and key terms, screening options, and risk information), past screening behavior, willingness to consider screening options, intention to discuss CRC screening with the doctor, and reactions to the multimedia patient education program. The multimedia program significantly increased knowledge of anatomy and key terms (e.g., polyp), primary screening options (FOBT, flexible sigmoidoscopy, colonoscopy), and risk information as well as willingness to consider screening (p<.001 for all). No significant differences emerged between positive and negative introductory appeals on these measures, intention to discuss CRC screening with their doctor, or rating the multimedia program. Multimedia tools developed with community input that are designed to present important health messages using graphics and audio can reach Hispanic/Latino adults across literacy levels and ethnic backgrounds. Additional research is needed to determine effects on actual screening behavior. Despite promising results for engaging a difficult-to-reach audience, the multimedia program should not be considered a stand-alone intervention or a substitute for communication with physicians. Rather, it is a priming mechanism intended to prepare patients for productive discussions of CRC screening.

The utility of alpha-fetoprotein screening in Beckwith-Wiedemann syndrome.

PubMed

Duffy, Kelly A; Deardorff, Matthew A; Kalish, Jennifer M

2017-03-01

Beckwith-Wiedemann syndrome (BWS) is one of the most common cancer predisposition disorders. As a result, BWS patients receive tumor screening as part of their clinical management. Until recently, this screening has been employed uniformly across all genetic and epigenetic causes of BWS, including the utilization of ultrasonography to detect abdominal tumors and alpha-fetoprotein (AFP) to detect hepatoblastoma. The advancements in our understanding of the genetics and epigenetics leading to BWS has evolved over time, and has led to the development of genotype/phenotype correlations. As tumor risk appears to correlate with genetic and epigenetic causes of BWS, several groups have proposed alterations to tumor screening protocols based on the etiology of BWS, with the elimination of AFP as a screening measure and the elimination of all screening measures in BWS patients with loss of methylation at the KCNQ1OT1:TSS-DMR 2 (IC2). There are many challenges to this suggestion, as IC2 patients may have additional factors that contribute to risk of hepatoblastoma including fetal growth patterns, relationship with assisted reproductive technologies, and the regulation of the IC2 locus. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

A Comprehensive Study on the Etiology of Patients Receiving Cochlear Implantation With Special Emphasis on Genetic Epidemiology

PubMed Central

Miyagawa, Maiko; Nishio, Shin-Ya; Usami, Shin-Ichi

2016-01-01

Objective: Cochlear implantation is the most important treatment currently available for profound sensorineural hearing loss. The aim of this study was to investigate the etiology of hearing loss in patients with cochlear implantation, and to compare outcomes. Methods: Japanese hearing loss patients who received cochlear implants (CIs) or electric acoustic stimulation (EAS) in Shinshu University hospital (n = 173, prelingual onset: 92, postlingual onset: 81) participated in this study. Invader assay followed by the targeted exon-sequencing of 63 deafness genes using Massively parallel DNA sequencing (MPS) was applied. For prelingual patients, additional imaging examination, cCMV screening, and pediatric examination were performed for precise diagnosis. Results: Genetic screening successfully identified the causative mutation in 60% of patients with prelingual onset hearing loss and in 36% of those with postlingual hearing loss. Differences in the kinds of genes identified were observed between the two groups. Although there were marked variations in the outcome of cochlear implantation, patients with specific deafness gene mutations showed relatively good results. Conclusion: The present study showed genetic etiology is a major cause of hearing loss in CI/EAS patients. Patients possessing mutations in a number of deafness genes known to be expressed within inner ear have achieved satisfactory auditory performance, suggesting that the identification of the genetic background facilitates the prediction of post-CI performance. MPS is a powerful tool for the identification of causative deafness genes in patients receiving cochlear implantation. Therefore, determination of the involved region inside/outside of the cochlea by identification of the responsible gene is essential. PMID:26756145

Pathways to genetic screening: Patient knowledges, Patient practices. Technical report of research progress

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

Not Available

1994-08-29

This study is designed to clarify the integration of genetic knowledge into the lived experience of high-risk family members. A major focus is elucidation of the social and cultural barriers and bridges to the use of genetic information to increase reproductive options and improve the quality of family life. They study focuses on families at risk for cystic fibrosis and sickle cell disease. These two disease groups were selected because they are among the most common potentially lethal genetic diseases and because while each has a similar pattern of inheritance and raises similarly serious bio-medical challenges and issues of informationmore » management, they primarily affect different racial and ethno-cultural groups permitting a naturally occurring experiment. In the variable penetration and meaning of genetic medicine in two populations. We have conducted intensive interviews with more than 300 individuals in approximately 88 families. We have attempted to balance the effort equally between the two groups, but have found we are able to penetrate the family systems of the cystic fibrosis families more easily than the sickle cell families.« less

From what should we protect future generations: germ-line therapy or genetic screening?

PubMed

Mallia, Pierre; ten Have, Henk

2003-01-01

This paper discusses the issue of whether we have responsibilities to future generations with respect to genetic screening, including for purposes of selective abortion or discard. Future generations have been discussed at length among scholars. The concept of 'Guardian for Future Generations' is tackled and its main criticisms discussed. Whilst germ-line cures, it is argued, can only affect family trees, genetic screening and testing can have wider implications. If asking how this may affect future generations is a legitimate question and since we indeed make retrospective moral judgements, it would be wise to consider that future generations will make the same retrospective judgements on us. Moreover such technologies affect present embryos to which we indeed can be considered to have an obligation.

A genetic screen in Drosophila reveals novel cytoprotective functions of the autophagy-lysosome pathway.

PubMed

Arsham, Andrew M; Neufeld, Thomas P

2009-06-29

The highly conserved autophagy-lysosome pathway is the primary mechanism for breakdown and recycling of macromolecular and organellar cargo in the eukaryotic cell. Autophagy has recently been implicated in protection against cancer, neurodegeneration, and infection, and interest is increasing in additional roles of autophagy in human health, disease, and aging. To search for novel cytoprotective features of this pathway, we carried out a genetic mosaic screen for mutations causing increased lysosomal and/or autophagic activity in the Drosophila melanogaster larval fat body. By combining Drosophila genetics with live-cell imaging of the fluorescent dye LysoTracker Red and fixed-cell imaging of autophagy-specific fluorescent protein markers, the screen was designed to identify essential metazoan genes whose disruption causes increased flux through the autophagy-lysosome pathway. The screen identified a large number of genes associated with the protein synthesis and ER-secretory pathways (e.g. aminoacyl tRNA synthetases, Oligosaccharyl transferase, Sec61alpha), and with mitochondrial function and dynamics (e.g. Rieske iron-sulfur protein, Dynamin-related protein 1). We also observed that increased lysosomal and autophagic activity were consistently associated with decreased cell size. Our work demonstrates that disruption of the synthesis, transport, folding, or glycosylation of ER-targeted proteins at any of multiple steps leads to autophagy induction. In addition to illuminating cytoprotective features of autophagy in response to cellular damage, this screen establishes a genetic methodology for investigating cell biological phenotypes in live cells, in the context of viable wild type organisms.

CRISPR-Cas9 for medical genetic screens: applications and future perspectives.

PubMed

Xue, Hui-Ying; Ji, Li-Juan; Gao, Ai-Mei; Liu, Ping; He, Jing-Dong; Lu, Xiao-Jie

2016-02-01

CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats-CRISPR associated nuclease 9) systems have emerged as versatile and convenient (epi)genome editing tools and have become an important player in medical genetic research. CRISPR-Cas9 and its variants such as catalytically inactivated Cas9 (dead Cas9, dCas9) and scaffold-incorporating single guide sgRNA (scRNA) have been applied in various genomic screen studies. CRISPR screens enable high-throughput interrogation of gene functions in health and diseases. Compared with conventional RNAi screens, CRISPR screens incur less off-target effects and are more versatile in that they can be used in multiple formats such as knockout, knockdown and activation screens, and can target coding and non-coding regions throughout the genome. This powerful screen platform holds the potential of revolutionising functional genomic studies in the near future. Herein, we introduce the mechanisms of (epi)genome editing mediated by CRISPR-Cas9 and its variants, introduce the procedures and applications of CRISPR screen in functional genomics, compare it with conventional screen tools and at last discuss current challenges and opportunities and propose future directions. 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/

Quantifying the advantages and disadvantages of pre-placement genetic screening

PubMed Central

Palmer, K; Poole, J; Rawbone, R; Coggon, D

2004-01-01

Background: Tests of genotype may enable workers at unusual risk of future ill-health to be identified. Using them to select for employment, however, entails gains and losses to employers and employees. Ensuring a fair balance between the rights and obligations of each group requires a value judgement, but the advantages and disadvantages to interested parties must first be quantified in a meaningful way. Method and Results: The purposes of pre-employment screening are reviewed, and several simple measures relevant to the separate interests of employers and job applicants proposed—number screened to prevent a single adverse outcome; number excluded to prevent a case; expected incidence of the adverse outcome in those excluded; and preventable fraction. The derivation of these measures is illustrated, and the factors that influence them (the prevalence of the prognostic trait, the relative risk that it carries for an adverse outcome, and the overall incidence of disease) are related algebraically and graphically, to aid judgement on the utility of screening under different circumstances. Conclusions: In sensitive areas such as genetic testing the onus should be on the employer to justify plans for pre-placement screening. Several quantitative measures can be used to inform the ethical and economic debate about screening and to evaluate alternative strategies for prevention. PMID:15090667

Quantifying the advantages and disadvantages of pre-placement genetic screening.

PubMed

Palmer, K T; Poole, J; Rawbone, R G; Coggon, D

2004-05-01

Tests of genotype may enable workers at unusual risk of future ill-health to be identified. Using them to select for employment, however, entails gains and losses to employers and employees. Ensuring a fair balance between the rights and obligations of each group requires a value judgement, but the advantages and disadvantages to interested parties must first be quantified in a meaningful way. The purposes of pre-employment screening are reviewed, and several simple measures relevant to the separate interests of employers and job applicants proposed-number screened to prevent a single adverse outcome; number excluded to prevent a case; expected incidence of the adverse outcome in those excluded; and preventable fraction. The derivation of these measures is illustrated, and the factors that influence them (the prevalence of the prognostic trait, the relative risk that it carries for an adverse outcome, and the overall incidence of disease) are related algebraically and graphically, to aid judgement on the utility of screening under different circumstances. In sensitive areas such as genetic testing the onus should be on the employer to justify plans for pre-placement screening. Several quantitative measures can be used to inform the ethical and economic debate about screening and to evaluate alternative strategies for prevention.

[Ethical aspects of disclosing information on prenatal screening for Down's syndrome].

PubMed

Tóth, Adél; Szabó, János

2005-02-06

Giving detailed information on prenatal screening for Down's syndrome is considered as paramount since this medical procedure intends to enhance the patient's self-governance in reproductive issues. Not only the respect for autonomy, but also the increased maternal anxiety and the reproductive decisions following the positive test result demand from the genetic professional to offer the test through genetic counselling. The counsellor's awareness about the expectations of pregnant women and the clarification of her own attitude concerning the screening can contribute to the effectiveness of counselling. The content of information embraces the technical aspects of screening and its consequences, like the description of Down's syndrome, the method of screening, the way of risk assessment, the detection rate, the false positive and false negative test results, the diagnostic procedures, and the termination of pregnancy. Written information leaflets should be completed by personal communication as the combination of these two forms has proved to be the most useful. The process of consultation is influenced by the communication skill of the genetic professional and the information seeking activity of the patient, so doctors should be trained to communicate better and patients should be encouraged to get more information about the screening.

Low incidence of SCN1A genetic mutation in patients with hemiconvulsion-hemiplegia-epilepsy syndrome.

PubMed

Kim, Dong Wook; Lim, Byung Chan; Kim, Ki Joong; Chae, Jong Hee; Lee, Ran; Lee, Sang Kun

2013-10-01

Genetic mutations in SCN1A account for more than two-thirds of patients with classic Dravet syndrome. A role for SCN1A genetic mutations in the development of hemiconvulsion-hemiplegia-epilepsy (HHE) syndrome was recently suggested based on the observation that HHE syndrome and classic Dravet syndrome share many clinical features. We previously identified a 2 bp-deletion mutation in SCN1A in a Dravet patient, and we found out the patient also had HHE syndrome upon clinical re-evaluation. We subsequently screened 10 additional HHE patients for SCN1A. Among the 11 patients who were diagnosed with HHE syndrome, six patients had no other etiology with the exception of prolonged febrile illness, therefore classified as idiopathic HHE syndrome, whereas five patients were classified as symptomatic HHE syndrome. Direct sequencing of all coding exons and flanking intronic sequences of the SCN1A gene was performed, but we failed to identify additional mutations in 10 patients. The patient with SCN1A mutation had the earliest onset of febrile convulsion and hemiparesis. Our study suggests that SCN1A genetic mutation is only a rare predisposing cause of HHE syndrome. Copyright © 2013 Elsevier B.V. All rights reserved.

Impact of human genome initiative-derived technology on genetic testing, screening and counseling: Cultural, ethical and legal issues

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

Trottier, R.W.; Hodgin, F.C.; Imara, M.

Genetic medical services provided by the Georgia Division of Public Health in two northern and two central districts are compared to services provided in a district in which a tertiary care facility is located. Genetics outreach public health nurses play key roles in Georgia's system of Children's Health Services Genetics Program, including significant roles as counselors and information sources on special needs social services and support organizations. Unique features of individual health districts, (e.g., the changing face of some rural communities in ethnocultural diversity and socioeconomic character), present new challenges to current and future genetics services delivery. Preparedness as tomore » educational needs of both health professionals and the lay population is of foremost concern in light of the ever expanding knowledge and technology in medical genetics. Perspectives on genetics and an overview of services offered by a local private sector counselor are included for comparison to state supported services. The nature of the interactions which transpire between private and public genetic services resources in Georgia will be described. A special focus of this research includes issues associated with sickle cell disease newborn screening service delivery process in Georgia, with particular attention paid to patient follow-up and transition to primary care. Of particular interest to this focus is the problem of loss to follow-up in the current system. Critical factors in education and counseling of sickle cell patients and the expectations of expanding roles of primary care physicians are discussed. The Florida approach to the delivery of genetic services contrasts to the Georgia model by placing more emphasis on a consultant-specialist team approach.« less

Leaf phenomics: a systematic reverse genetic screen for Arabidopsis leaf mutants.

PubMed

Wilson-Sánchez, David; Rubio-Díaz, Silvia; Muñoz-Viana, Rafael; Pérez-Pérez, José Manuel; Jover-Gil, Sara; Ponce, María Rosa; Micol, José Luis

2014-09-01

The study and eventual manipulation of leaf development in plants requires a thorough understanding of the genetic basis of leaf organogenesis. Forward genetic screens have identified hundreds of Arabidopsis mutants with altered leaf development, but the genome has not yet been saturated. To identify genes required for leaf development we are screening the Arabidopsis Salk Unimutant collection. We have identified 608 lines that exhibit a leaf phenotype with full penetrance and almost constant expressivity and 98 additional lines with segregating mutant phenotypes. To allow indexing and integration with other mutants, the mutant phenotypes were described using a custom leaf phenotype ontology. We found that the indexed mutation is present in the annotated locus for 78% of the 553 mutants genotyped, and that in half of these the annotated T-DNA is responsible for the phenotype. To quickly map non-annotated T-DNA insertions, we developed a reliable, cost-effective and easy method based on whole-genome sequencing. To enable comprehensive access to our data, we implemented a public web application named PhenoLeaf (http://genetics.umh.es/phenoleaf) that allows researchers to query the results of our screen, including text and visual phenotype information. We demonstrated how this new resource can facilitate gene function discovery by identifying and characterizing At1g77600, which we found to be required for proximal-distal cell cycle-driven leaf growth, and At3g62870, which encodes a ribosomal protein needed for cell proliferation and chloroplast function. This collection provides a valuable tool for the study of leaf development, characterization of biomass feedstocks and examination of other traits in this fundamental photosynthetic organ. © 2014 The Authors The Plant Journal © 2014 John Wiley & Sons Ltd.

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

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

A Simultaneous Genetic Screen for Zygotic and Sterile Mutants in a Hermaphroditic Vertebrate (Kryptolebias marmoratus)

PubMed Central

Sucar, Sofia; Moore, Ginger L.; Ard, Melissa E.; Ring, Brian C.

2016-01-01

The mangrove killifish, Kryptolebias marmoratus, is unique among vertebrates due to its self-fertilizing mode of reproduction involving an ovotestis. As a result, it constitutes a simplistic and desirable vertebrate model for developmental genetics as it is easily maintained, reaches sexual maturity in about 100 days, and provides a manageable number of relatively clear embryos. After the establishment and characterization of an initial mutagenesis pilot screen using N-ethyl-N-nitrosourea, a three-generation genetic screen was performed to confirm zygotic mutant allele heritability and simultaneously score for homozygous recessive mutant sterile F2 fish. From a total of 307 F2 fish screened, 10 were found to be 1° males, 16 were sterile, 92 wild-type, and the remaining 189, carriers of zygotic recessive alleles. These carriers produced 25% progeny exhibiting several zygotic phenotypes similar to those previously described in zebrafish and in the aforementioned pilot screen, as expected. Interestingly, new phenotypes such as golden yolk, no trunk, and short tail were observed. The siblings of sterile F2 mutants were used to produce an F3 generation in order to confirm familial sterility. Out of the 284 F3 fish belonging to 10 previously identified sterile families, 12 were found to be 1° males, 69 were wild-type, 83 sterile, and 120 were classified as */+ (either wild-type or carriers) with undefined genotypes. This screen provides proof of principle that K. marmoratus is a powerful vertebrate model for developmental genetics and can be used to identify mutations affecting fertility. PMID:26801648

Combined CRISPRi/a-Based Chemical Genetic Screens Reveal that Rigosertib Is a Microtubule-Destabilizing Agent. | Office of Cancer Genomics

Cancer.gov

Chemical libraries paired with phenotypic screens can now readily identify compounds with therapeutic potential. A central limitation to exploiting these compounds, however, has been in identifying their relevant cellular targets. Here, we present a two-tiered CRISPR-mediated chemical-genetic strategy for target identification: combined genome-wide knockdown and overexpression screening as well as focused, comparative chemical-genetic profiling.

Combined zebrafish-yeast chemical-genetic screens reveal gene-copper-nutrition interactions that modulate melanocyte pigmentation.

PubMed

Ishizaki, Hironori; Spitzer, Michaela; Wildenhain, Jan; Anastasaki, Corina; Zeng, Zhiqiang; Dolma, Sonam; Shaw, Michael; Madsen, Erik; Gitlin, Jonathan; Marais, Richard; Tyers, Mike; Patton, E Elizabeth

2010-01-01

Hypopigmentation is a feature of copper deficiency in humans, as caused by mutation of the copper (Cu(2+)) transporter ATP7A in Menkes disease, or an inability to absorb copper after gastric surgery. However, many causes of copper deficiency are unknown, and genetic polymorphisms might underlie sensitivity to suboptimal environmental copper conditions. Here, we combined phenotypic screens in zebrafish for compounds that affect copper metabolism with yeast chemical-genetic profiles to identify pathways that are sensitive to copper depletion. Yeast chemical-genetic interactions revealed that defects in intracellular trafficking pathways cause sensitivity to low-copper conditions; partial knockdown of the analogous Ap3s1 and Ap1s1 trafficking components in zebrafish sensitized developing melanocytes to hypopigmentation in low-copper environmental conditions. Because trafficking pathways are essential for copper loading into cuproproteins, our results suggest that hypomorphic alleles of trafficking components might underlie sensitivity to reduced-copper nutrient conditions. In addition, we used zebrafish-yeast screening to identify a novel target pathway in copper metabolism for the small-molecule MEK kinase inhibitor U0126. The zebrafish-yeast screening method combines the power of zebrafish as a disease model with facile genome-scale identification of chemical-genetic interactions in yeast to enable the discovery and dissection of complex multigenic interactions in disease-gene networks.

Screening for Lynch syndrome and referral to clinical genetics by selective mismatch repair protein immunohistochemistry testing: an audit and cost analysis.

PubMed

Colling, Richard; Church, David N; Carmichael, Juliet; Murphy, Lucinda; East, James; Risby, Peter; Kerr, Rachel; Chetty, Runjan; Wang, Lai Mun

2015-12-01

Lynch syndrome (LS) accounts for around 3% of colorectal cancers (CRCs) and is caused by germline mutations in mismatch repair (MMR) genes. Recently, screening strategies to identify patients with LS have become popular. We audited CRCs screened with MMR immunohistochemistry (IHC) in 2013. 209 tumours had MMR IHC performed at a cost of £12 540. 47/209 (21%) cases showed IHC loss of expression in at least one MMR protein. 28/44 cases with loss of MLH1 had additional BRAF V600E testing, at a cost of £5040. MMR IHC reduced the number of potential clinical genetics referrals from 209 to 47. BRAF mutation testing, performed in a subset of cases with MLH1 loss, further reduced this to 21. At a cost of £1340 per referral, this model of LS screening for clinical genetics referral had significant potential savings (£234 340) and can be easily implemented in parallel with MMR IHC done for prognostication in CRCs. 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/

Genetic screens and functional genomics using CRISPR/Cas9 technology.

PubMed

Hartenian, Ella; Doench, John G

2015-04-01

Functional genomics attempts to understand the genome by perturbing the flow of information from DNA to RNA to protein, in order to learn how gene dysfunction leads to disease. CRISPR/Cas9 technology is the newest tool in the geneticist's toolbox, allowing researchers to edit DNA with unprecedented ease, speed and accuracy, and representing a novel means to perform genome-wide genetic screens to discover gene function. In this review, we first summarize the discovery and characterization of CRISPR/Cas9, and then compare it to other genome engineering technologies. We discuss its initial use in screening applications, with a focus on optimizing on-target activity and minimizing off-target effects. Finally, we comment on future challenges and opportunities afforded by this technology. © 2015 FEBS.

A Genetic Interaction Screen for Breast Cancer Progression Driver Genes

DTIC Science & Technology

2013-06-01

analysis of genetic alterations in human breast cancers has revealed that individual tumors accumulate mutations in approximately ninety different genes ...cancer. We performed a screen to test the roles of seventy breast cancer mutated genes in mouse mammary tumorigenesis using the MMTV-PyVT mouse breast...cancer model and piggyBac insertional mutation strains. We found that insertional mutations in 23 genes altered the onset of tumor formation and four

Genetics Home Reference: hyperprolinemia

MedlinePlus

... Hyperprolinemia type 1 Orphanet: Hyperprolinemia type 2 Screening, Technology and Research in Genetics Patient Support and Advocacy Resources (3 links) Children Living with Inherited Metabolic Diseases National Organization for ...

Genetics Home Reference: argininosuccinic aciduria

MedlinePlus

... Aciduria MalaCards: argininosuccinic aciduria Orphanet: Argininosuccinic aciduria Screening, Technology and Research in Genetics Vanderbilt Children's Hospital (PDF) Virginia Department of Health (PDF) Patient ...

Pooled-matrix protein interaction screens using Barcode Fusion Genetics.

PubMed

Yachie, Nozomu; Petsalaki, Evangelia; Mellor, Joseph C; Weile, Jochen; Jacob, Yves; Verby, Marta; Ozturk, Sedide B; Li, Siyang; Cote, Atina G; Mosca, Roberto; Knapp, Jennifer J; Ko, Minjeong; Yu, Analyn; Gebbia, Marinella; Sahni, Nidhi; Yi, Song; Tyagi, Tanya; Sheykhkarimli, Dayag; Roth, Jonathan F; Wong, Cassandra; Musa, Louai; Snider, Jamie; Liu, Yi-Chun; Yu, Haiyuan; Braun, Pascal; Stagljar, Igor; Hao, Tong; Calderwood, Michael A; Pelletier, Laurence; Aloy, Patrick; Hill, David E; Vidal, Marc; Roth, Frederick P

2016-04-22

High-throughput binary protein interaction mapping is continuing to extend our understanding of cellular function and disease mechanisms. However, we remain one or two orders of magnitude away from a complete interaction map for humans and other major model organisms. Completion will require screening at substantially larger scales with many complementary assays, requiring further efficiency gains in proteome-scale interaction mapping. Here, we report Barcode Fusion Genetics-Yeast Two-Hybrid (BFG-Y2H), by which a full matrix of protein pairs can be screened in a single multiplexed strain pool. BFG-Y2H uses Cre recombination to fuse DNA barcodes from distinct plasmids, generating chimeric protein-pair barcodes that can be quantified via next-generation sequencing. We applied BFG-Y2H to four different matrices ranging in scale from ~25 K to 2.5 M protein pairs. The results show that BFG-Y2H increases the efficiency of protein matrix screening, with quality that is on par with state-of-the-art Y2H methods. © 2016 The Authors. Published under the terms of the CC BY 4.0 license.

Genetics Home Reference: hypermethioninemia

MedlinePlus

... Psychomotor retardation due to S-adenosylhomocysteine hydrolase deficiency Screening, Technology and Research in Genetics Patient Support and Advocacy Resources (1 link) Children Living with Inherited Metabolic Diseases Scientific Articles on ...

Mutations in FUS are the most frequent genetic cause in juvenile sporadic ALS patients of Chinese origin.

PubMed

Zou, Zhang-Yu; Liu, Ming-Sheng; Li, Xiao-Guang; Cui, Li-Ying

2016-01-01

Juvenile onset ALS is a very rare form of motor neuron disease, with the first symptoms of motor neuron degeneration manifested before 25 years of age. Mutations in the alsin (ALS2), senataxin (SETX), and spatacsin (SPG11) genes have been associated with familial ALS with juvenile onset and slow progression, whereas the genetic architecture of sporadic juvenile ALS remains unclear. We screened mutations in C9orf72, SOD1, FUS, TARDBP, ANG, VCP and PFN1 in 16 juvenile sporadic ALS patients. Four cases (25%) carrying FUS mutations and one individual (6%) harbouring a SOD1 mutation were identified. All cases had an aggressive disease course. Our results suggest that FUS mutations are the most frequent genetic cause in early-onset sporadic ALS patients of Chinese origin. Genetic testing of FUS should be performed in early-onset ALS patients especially those with an aggressive disease course.

Noninvasive molecular screening for oral precancer in Fanconi anemia patients.

PubMed

Smetsers, Stephanie E; Velleuer, Eunike; Dietrich, Ralf; Wu, Thijs; Brink, Arjen; Buijze, Marijke; Deeg, Dorly J H; Soulier, Jean; Leemans, C René; Braakhuis, Boudewijn J M; Brakenhoff, Ruud H

2015-11-01

LOH at chromosome arms 3p, 9p, 11q, and 17p are well-established oncogenetic aberrations in oral precancerous lesions and promising biomarkers to monitor the development of oral cancer. Noninvasive LOH screening of brushed oral cells is a preferable method for precancer detection in patients at increased risk for head and neck squamous cell carcinoma (HNSCC), such as patients with Fanconi anemia. We determined the prevalence of LOH in brushed samples of the oral epithelium of 141 patients with Fanconi anemia and 144 aged subjects, and studied the association between LOH and HNSCC. LOH was present in 14 (9.9%) nontransplanted patients with Fanconi anemia, whereas LOH was not detected in a low-risk group (n = 50, >58 years, nonsmoking/nonalcohol history) and a group with somewhat increased HNSCC risk (n = 94, >58 years, heavy smoking/excessive alcohol use); Fisher exact test, P = 0.023 and P = 0.001, respectively. Most frequent genetic alteration was LOH at 9p. Age was a significant predictor of LOH (OR, 1.13, P = 0.001). Five patients with Fanconi anemia developed HNSCC during the study at a median age of 39.6 years (range, 24.8-53.7). LOH was significantly associated with HNSCC (Fisher exact test, P = 0.000). Unexpectedly, the LOH assay could not be used for transplanted patients with Fanconi anemia because donor DNA in brushed oral epithelium, most likely from donor leukocytes present in the oral cavity, disturbed the analysis. Noninvasive screening using a LOH assay on brushed samples of the oral epithelium has a promising outlook in patients with Fanconi anemia. However, assays need to be adapted in case of stem cell transplantation, because of contaminating donor DNA. ©2015 American Association for Cancer Research.

Adopted Individuals' Views on the Utility and Value of Expanded Carrier Screening.

PubMed

Spencer, Sara; Ewing, Sarah; Calcagno, Kathryn; O'Neill, Suzanne

2018-03-30

Adoptees may not have family medical history and ethnicity information. Carrier screening assesses reproductive risk. Expanded carrier screening (ECS) screens for many genetic conditions regardless of a patient's knowledge of family history and ethnicity. This study aimed to better understand the opinions and attitudes of adopted individuals on the use of ECS in determining a patient's reproductive genetic risks. Specifically, the study assessed how adopted individuals feel that results of ECS may be useful to them and whether adoptees feel that meeting with a genetics professional in the process of undergoing ECS would be useful. Adult adoptees (N = 124) were recruited online. Their opinions on ECS were explored. The majority reported they had never been offered carrier screening (92%). The majority of adoptees wanted ECS (76%). Neither the amount of contact with biological relatives nor having medical knowledge about biological relatives was significantly associated with adoptees' desire to pursue ECS. There was a significant positive correlation between adoptees of higher education levels and the amount they would pay for ECS (p = 0.004). The majority of participants (95%) indicated a genetics professional would be helpful when undergoing ECS. The findings suggest this population may want ECS and support from genetics healthcare professionals. Advocacy for genetic counseling and testing for adoptees appears justifiable.

The genetic spectrum and the evaluation of CADASIL screening scale in Chinese patients with NOTCH3 mutations.

PubMed

Liu, Xiao; Zuo, Yuehuan; Sun, Wei; Zhang, Wei; Lv, He; Huang, Yining; Xiao, Jiangxi; Yuan, Yun; Wang, Zhaoxia

2015-07-15

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited small artery disease caused by NOTCH3 gene mutation. Here we report clinical, pathological and genetic profiles of 29 newly-diagnosed CADASIL patients, evaluation of the CADASIL scale in Chinese CADASIL patients, and reanalysis of all reported mainland Chinese patients with identified NOTCH3 gene mutation. We found two novel mutations (p.C134G and p.C291Y) and 13 reported NOTCH3 mutations in the newly-diagnosed group. CADASIL scale score was less than the cutoff score in 19 of 53 Chinese patients with NOTCH3 mutation, generating only a sensitivity of 64.1%. At the time of study, the total number of genetically confirmed CADASIL cases reached 158 from 97 unrelated mainland Chinese families, with 9/97 (9.3%) sporadic patients. The NOTCH3 gene mutation profile showed 43 mutations, with hotspots in exon 4, followed by exon 3. The considerable variability in onset age and CADASIL scale score in patients carrying the same NOTCH3 missense mutation suggested no obvious phenotype-genotype correlation. In conclusion, we report two novel mutations which expand the NOTCH3 mutational spectrum. Exons 4 and 3 are hotspots in mainland Chinese patients with NOTCH3 mutation. The low sensitivity of CADASIL scale in our patients group indicated that the CADASIL scale should be refined according to the clinical characteristics of Chinese CADASIL patients when used in Chinese populations. Copyright © 2015. Published by Elsevier B.V.

GAPscreener: An automatic tool for screening human genetic association literature in PubMed using the support vector machine technique

PubMed Central

Yu, Wei; Clyne, Melinda; Dolan, Siobhan M; Yesupriya, Ajay; Wulf, Anja; Liu, Tiebin; Khoury, Muin J; Gwinn, Marta

2008-01-01

Background Synthesis of data from published human genetic association studies is a critical step in the translation of human genome discoveries into health applications. Although genetic association studies account for a substantial proportion of the abstracts in PubMed, identifying them with standard queries is not always accurate or efficient. Further automating the literature-screening process can reduce the burden of a labor-intensive and time-consuming traditional literature search. The Support Vector Machine (SVM), a well-established machine learning technique, has been successful in classifying text, including biomedical literature. The GAPscreener, a free SVM-based software tool, can be used to assist in screening PubMed abstracts for human genetic association studies. Results The data source for this research was the HuGE Navigator, formerly known as the HuGE Pub Lit database. Weighted SVM feature selection based on a keyword list obtained by the two-way z score method demonstrated the best screening performance, achieving 97.5% recall, 98.3% specificity and 31.9% precision in performance testing. Compared with the traditional screening process based on a complex PubMed query, the SVM tool reduced by about 90% the number of abstracts requiring individual review by the database curator. The tool also ascertained 47 articles that were missed by the traditional literature screening process during the 4-week test period. We examined the literature on genetic associations with preterm birth as an example. Compared with the traditional, manual process, the GAPscreener both reduced effort and improved accuracy. Conclusion GAPscreener is the first free SVM-based application available for screening the human genetic association literature in PubMed with high recall and specificity. The user-friendly graphical user interface makes this a practical, stand-alone application. The software can be downloaded at no charge. PMID:18430222

GAPscreener: an automatic tool for screening human genetic association literature in PubMed using the support vector machine technique.

PubMed

Yu, Wei; Clyne, Melinda; Dolan, Siobhan M; Yesupriya, Ajay; Wulf, Anja; Liu, Tiebin; Khoury, Muin J; Gwinn, Marta

2008-04-22

Synthesis of data from published human genetic association studies is a critical step in the translation of human genome discoveries into health applications. Although genetic association studies account for a substantial proportion of the abstracts in PubMed, identifying them with standard queries is not always accurate or efficient. Further automating the literature-screening process can reduce the burden of a labor-intensive and time-consuming traditional literature search. The Support Vector Machine (SVM), a well-established machine learning technique, has been successful in classifying text, including biomedical literature. The GAPscreener, a free SVM-based software tool, can be used to assist in screening PubMed abstracts for human genetic association studies. The data source for this research was the HuGE Navigator, formerly known as the HuGE Pub Lit database. Weighted SVM feature selection based on a keyword list obtained by the two-way z score method demonstrated the best screening performance, achieving 97.5% recall, 98.3% specificity and 31.9% precision in performance testing. Compared with the traditional screening process based on a complex PubMed query, the SVM tool reduced by about 90% the number of abstracts requiring individual review by the database curator. The tool also ascertained 47 articles that were missed by the traditional literature screening process during the 4-week test period. We examined the literature on genetic associations with preterm birth as an example. Compared with the traditional, manual process, the GAPscreener both reduced effort and improved accuracy. GAPscreener is the first free SVM-based application available for screening the human genetic association literature in PubMed with high recall and specificity. The user-friendly graphical user interface makes this a practical, stand-alone application. The software can be downloaded at no charge.

Cost-Effectiveness Analysis of Different Genetic Testing Strategies for Lynch Syndrome in Taiwan.

PubMed

Chen, Ying-Erh; Kao, Sung-Shuo; Chung, Ren-Hua

2016-01-01

Patients with Lynch syndrome (LS) have a significantly increased risk of developing colorectal cancer (CRC) and other cancers. Genetic screening for LS among patients with newly diagnosed CRC aims to identify mutations in the disease-causing genes (i.e., the DNA mismatch repair genes) in the patients, to offer genetic testing for relatives of the patients with the mutations, and then to provide early prevention for the relatives with the mutations. Several genetic tests are available for LS, such as DNA sequencing for MMR genes and tumor testing using microsatellite instability and immunohistochemical analyses. Cost-effectiveness analyses of different genetic testing strategies for LS have been performed in several studies from different countries such as the US and Germany. However, a cost-effectiveness analysis for the testing has not yet been performed in Taiwan. In this study, we evaluated the cost-effectiveness of four genetic testing strategies for LS described in previous studies, while population-specific parameters, such as the mutation rates of the DNA mismatch repair genes and treatment costs for CRC in Taiwan, were used. The incremental cost-effectiveness ratios based on discounted life years gained due to genetic screening were calculated for the strategies relative to no screening and to the previous strategy. Using the World Health Organization standard, which was defined based on Taiwan's Gross Domestic Product per capita, the strategy based on immunohistochemistry as a genetic test followed by BRAF mutation testing was considered to be highly cost-effective relative to no screening. Our probabilistic sensitivity analysis results also suggest that the strategy has a probability of 0.939 of being cost-effective relative to no screening based on the commonly used threshold of $50,000 to determine cost-effectiveness. To the best of our knowledge, this is the first cost-effectiveness analysis for evaluating different genetic testing strategies for LS in

Sending family history questionnaires to patients before a colonoscopy improves genetic counseling for hereditary colorectal cancer.

PubMed

Kessels, Koen; Eisinger, Joey D; Letteboer, Tom G; Offerhaus, G Johan A; Siersema, Peter D; Moons, Leon M G

2017-06-01

To investigate whether sending a family history questionnaire to patients prior to undergoing colonoscopy results in an increased availability of family history and better genetic counseling. A questionnaire was mailed to patients before they underwent outpatient colonoscopy at a university hospital in 2013. These patients' additional characteristics and referral for genetic evaluation were retrieved from the electronic medical records. Patients undergoing inpatient coloboscopy, with confirmed hereditary colorectal cancer (CRC) or inflammatory bowel disease were excluded. All study patients from 2010 to 2013 were matched with the database of the genetics department to determine who consulted a geneticist. A total of 6163 patients underwent colonoscopy from 2010 to 2013. Of 1421 who underwent colonoscopy in 2013, 53 (3.7%) consulted a geneticist, while 75 (1.6%) of 4742 patients undergoing colonoscopy between 2010 and 2012 did so (P < 0.01). A total of 974 patients undergoing colonoscopy in 2013 were included to evaluate the completed questionnaire. Of these, 282 (29.0%) completed the questionnaire. Family history was not recorded in the electronic medical records of 393 (40.3%). In 129 (32.8%), family history was obtained from the completed questionnaire. In 2013, 49 (60.5%) out of 81 patients referred for genetic counseling were referred based on their family history. Eight (9.9%) patients were referred based on the completed questionnaire. Screening for hereditary CRC in a population undergoing outpatient colonoscopy with a questionnaire sent by mail resulted in an increased availability of family histories and genetic counseling. © 2017 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.

Genetic variants in post myocardial infarction patients presenting with electrical storm of unstable ventricular tachycardia.

PubMed

Rangaraju, Advithi; Krishnan, Shuba; Aparna, G; Sankaran, Satish; Mannan, Ashraf U; Rao, B Hygriv

2018-01-30

Electrical storm (ES) is a life threatening clinical situation. Though a few clinical pointers exist, the occurrence of ES in a patient with remote myocardial infarction (MI) is generally unpredictable. Genetic markers for this entity have not been studied. In the present study, we carried out genetic screening in patients with remote myocardial infarction presenting with ES by next generation sequencing and identified 25 rare variants in 19 genes predominantly in RYR2, SCN5A, KCNJ11, KCNE1 and KCNH2, CACNA1B, CACNA1C, CACNA1D and desmosomal genes - DSP and DSG2 that could potentially be implicated in electrical storm. These genes have been previously reported to be associated with inherited syndromes of Sudden Cardiac Death. The present study suggests that the genetic architecture in patients with remote MI and ES of unstable ventricular tachycardia may be similar to that of Ion channelopathies. Identification of these variants may identify post MI patients who are predisposed to develop electrical storm and help in risk stratification. Copyright © 2018 Indian Heart Rhythm Society. Production and hosting by Elsevier B.V. All rights reserved.

A transposon-based genetic screen in mice identifies genes altered in colorectal cancer.

PubMed

Starr, Timothy K; Allaei, Raha; Silverstein, Kevin A T; Staggs, Rodney A; Sarver, Aaron L; Bergemann, Tracy L; Gupta, Mihir; O'Sullivan, M Gerard; Matise, Ilze; Dupuy, Adam J; Collier, Lara S; Powers, Scott; Oberg, Ann L; Asmann, Yan W; Thibodeau, Stephen N; Tessarollo, Lino; Copeland, Neal G; Jenkins, Nancy A; Cormier, Robert T; Largaespada, David A

2009-03-27

Human colorectal cancers (CRCs) display a large number of genetic and epigenetic alterations, some of which are causally involved in tumorigenesis (drivers) and others that have little functional impact (passengers). To help distinguish between these two classes of alterations, we used a transposon-based genetic screen in mice to identify candidate genes for CRC. Mice harboring mutagenic Sleeping Beauty (SB) transposons were crossed with mice expressing SB transposase in gastrointestinal tract epithelium. Most of the offspring developed intestinal lesions, including intraepithelial neoplasia, adenomas, and adenocarcinomas. Analysis of over 16,000 transposon insertions identified 77 candidate CRC genes, 60 of which are mutated and/or dysregulated in human CRC and thus are most likely to drive tumorigenesis. These genes include APC, PTEN, and SMAD4. The screen also identified 17 candidate genes that had not previously been implicated in CRC, including POLI, PTPRK, and RSPO2.

Mutation screening of the PCDH15 gene in Spanish patients with Usher syndrome type I.

PubMed

Jaijo, Teresa; Oshima, Aki; Aller, Elena; Carney, Carol; Usami, Shin-ichi; Millán, José M; Kimberling, William J

2012-01-01

PCDH15 codes for protocadherin-15, a cell-cell adhesion protein essential in the morphogenesis and cohesion of stereocilia bundles and in the function or preservation of photoreceptor cells. Mutations in the PCDH15 gene are responsible for Usher syndrome type I (USH1F) and non-syndromic hearing loss (DFNB23). The purpose of this work was to perform PCDH15 mutation screening to identify the genetic cause of the disease in a cohort of Spanish patients with Usher syndrome type I and establish phenotype-genotype correlation. Mutation analysis of PCDH15 included additional exons recently identified and was performed by direct sequencing. The screening was performed in 19 probands with USH already screened for mutations in the most prevalent USH1 genes, myosin VIIA (MYO7A) and cadherin-23 (CDH23), and for copy number variants in PCDH15. Seven different point mutations, five novel, were detected. Including the large PCDH15 rearrangements previously reported in our cohort of patients, a total of seven of 19 patients (36.8%) were carriers of at least one pathogenic allele. Thirteen out of the 38 screened alleles carried pathogenic PCDH15 variants (34.2%). Five out of the seven point mutations reported in the present study are novel, supporting the idea that most PCDH15 mutations are private. Furthermore, no mutational hotspots have been identified. In most patients, detected mutations led to a truncated protein, reinforcing the hypothesis that severe mutations cause the Usher I phenotype and that missense variants are mainly responsible for non-syndromic hearing impairment.

Genetic screening: programs, principles, and research--thirty years later. Reviewing the recommendations of the Committee for the Study of Inborn Errors of Metabolism (SIEM).

PubMed

Simopoulos, A P

2009-01-01

Screening programs for genetic diseases and characteristics have multiplied in the last 50 years. 'Genetic Screening: Programs, Principles, and Research' is the report of the Committee for the Study of Inborn Errors of Metabolism (SIEM Committee) commissioned by the Division of Medical Sciences of the National Research Council at the National Academy of Sciences in Washington, DC, published in 1975. The report is considered a classic in the field worldwide, therefore it was thought appropriate 30 years later to present the Committee's modus operandi and bring the Committee's recommendations to the attention of those involved in genetics, including organizational, educational, legal, and research aspects of genetic screening. The Committee's report anticipated many of the legal, ethical, economic, social, medical, and policy aspects of genetic screening. The recommendations are current, and future committees should be familiar with them. In 1975 the Committee stated: 'As new screening tests are devised, they should be carefully reviewed. If the experimental rate of discovery of new genetic characteristics means an accelerating rate of appearance of new screening tests, now is the time to develop the medical and social apparatus to accommodate what later on may otherwise turn out to be unmanageable growth.' What a prophetic statement that was. If the Committee's recommendations had been implemented on time, there would be today a federal agency in existence, responsive and responsible to carry out the programs and support research on various aspects of genetic screening, including implementation of a federal law that protects consumers from discrimination by their employers and the insurance industry on the basis of genetic information. Copyright 2008 S. Karger AG, Basel.

Lessons learnt from implementation of a Lynch syndrome screening program for patients with gynaecological malignancy.

PubMed

Najdawi, Fedaa; Crook, Ashley; Maidens, Jayne; McEvoy, Christopher; Fellowes, Andrew; Pickett, Justine; Ho, Musei; Nevell, David; McIlroy, Kirsten; Sheen, Amy; Sioson, Loretta; Ahadi, Mahsa; Turchini, John; Clarkson, Adele; Hogg, Russell; Valmadre, Sue; Gard, Greg; Dooley, Susan J; Scott, Rodney J; Fox, Stephen B; Field, Michael; Gill, Anthony J

2017-08-01

Despite a trend towards universal testing, best practice to screen patients presenting with gynaecological malignancy for Lynch syndrome (LS) is uncertain. We report our institutional experience of a co-ordinated gynaecological LS screening program. All patients with endometrial carcinoma or carcinosarcoma, or gynaecological endometrioid or clear cell carcinomas undergo reflex four panel immunohistochemistry (IHC) for MLH1, PMS2, MSH2 and MSH6 followed by cascade somatic hypermethylation analysis of the MLH1 promoter locus for dual MLH1/PMS2 negative tumours. On the basis of these results, genetic counselling and targeted germline mutation testing is then offered to patients considered at high risk of LS. From 1 August 2013 to 31 December 2015, 124 patients were screened (mean age 64.6 years). Thirty-six (29.0%) demonstrated abnormal MMR IHC: 26 (72.2%) showed dual loss of MLH1/PMS2, five (13.9%) dual loss of MSH2/MSH6, three (8.3%) isolated loss of MSH6, and two (5.6%) isolated loss of PMS2. Twenty-five of 26 (96.1%) patients with dual MLH1/PMS2 loss demonstrated MLH1 promoter methylation. Therefore, 11 (8.9%) patients screened were classified as high risk for LS, of whom nine (81.8%) accepted germline mutation testing. Three (2.4% of total screened) were confirmed to have LS, two with germline PMS2 and one with germline MSH2 mutation. Massive parallel sequencing of tumour tissue demonstrated somatic mutations which were concordant with the IHC results in the remainder. Interestingly, the one MLH1/PMS2 IHC negative but not hypermethylated tumour harboured only somatic MLH1 mutations, indicating that universal cascade methylation testing in MLH1/PMS2 IHC negative tumours is very low yield and could be reconsidered in a resource-poor setting. In conclusion, universal screening for LS in patients presenting with gynaecological malignancy using the algorithm described above identified LS in three of 124 (2.4%) of our population. Only three of nine (33.3%) patients

Frailty Screening Tools for Elderly Patients Incident to Dialysis.

PubMed

van Loon, Ismay N; Goto, Namiko A; Boereboom, Franciscus T J; Bots, Michiel L; Verhaar, Marianne C; Hamaker, Marije E

2017-09-07

A geriatric assessment is an appropriate method for identifying frail elderly patients. In CKD, it may contribute to optimize personalized care. However, a geriatric assessment is time consuming. The purpose of our study was to compare easy to apply frailty screening tools with the geriatric assessment in patients eligible for dialysis. A total of 123 patients on incident dialysis ≥65 years old were included <3 weeks before to ≤2 weeks after dialysis initiation, and all underwent a geriatric assessment. Patients with impairment in two or more geriatric domains on the geriatric assessment were considered frail. The diagnostic abilities of six frailty screening tools were compared with the geriatric assessment: the Fried Frailty Index, the Groningen Frailty Indicator, Geriatric8, the Identification of Seniors at Risk, the Hospital Safety Program, and the clinical judgment of the nephrologist. Outcome measures were sensitivity, specificity, positive predictive value, and negative predictive value. In total, 75% of patients were frail according to the geriatric assessment. Sensitivity of frailty screening tools ranged from 48% (Fried Frailty Index) to 88% (Geriatric8). The discriminating features of the clinical judgment were comparable with the other screening tools. The Identification of Seniors at Risk screening tool had the best discriminating abilities, with a sensitivity of 74%, a specificity of 80%, a positive predictive value of 91%, and a negative predictive value of 52%. The negative predictive value was poor for all tools, which means that almost one half of the patients screened as fit (nonfrail) had two or more geriatric impairments on the geriatric assessment. All frailty screening tools are able to detect geriatric impairment in elderly patients eligible for dialysis. However, all applied screening tools, including the judgment of the nephrologist, lack the discriminating abilities to adequately rule out frailty compared with a geriatric assessment

Human genetics in rheumatoid arthritis guides a high-throughput drug screen of the CD40 signaling pathway.

PubMed

Li, Gang; Diogo, Dorothée; Wu, Di; Spoonamore, Jim; Dancik, Vlado; Franke, Lude; Kurreeman, Fina; Rossin, Elizabeth J; Duclos, Grant; Hartland, Cathy; Zhou, Xuezhong; Li, Kejie; Liu, Jun; De Jager, Philip L; Siminovitch, Katherine A; Zhernakova, Alexandra; Raychaudhuri, Soumya; Bowes, John; Eyre, Steve; Padyukov, Leonid; Gregersen, Peter K; Worthington, Jane; Gupta, Namrata; Clemons, Paul A; Stahl, Eli; Tolliday, Nicola; Plenge, Robert M

2013-05-01

Although genetic and non-genetic studies in mouse and human implicate the CD40 pathway in rheumatoid arthritis (RA), there are no approved drugs that inhibit CD40 signaling for clinical care in RA or any other disease. Here, we sought to understand the biological consequences of a CD40 risk variant in RA discovered by a previous genome-wide association study (GWAS) and to perform a high-throughput drug screen for modulators of CD40 signaling based on human genetic findings. First, we fine-map the CD40 risk locus in 7,222 seropositive RA patients and 15,870 controls, together with deep sequencing of CD40 coding exons in 500 RA cases and 650 controls, to identify a single SNP that explains the entire signal of association (rs4810485, P = 1.4×10(-9)). Second, we demonstrate that subjects homozygous for the RA risk allele have ∼33% more CD40 on the surface of primary human CD19+ B lymphocytes than subjects homozygous for the non-risk allele (P = 10(-9)), a finding corroborated by expression quantitative trait loci (eQTL) analysis in peripheral blood mononuclear cells from 1,469 healthy control individuals. Third, we use retroviral shRNA infection to perturb the amount of CD40 on the surface of a human B lymphocyte cell line (BL2) and observe a direct correlation between amount of CD40 protein and phosphorylation of RelA (p65), a subunit of the NF-κB transcription factor. Finally, we develop a high-throughput NF-κB luciferase reporter assay in BL2 cells activated with trimerized CD40 ligand (tCD40L) and conduct an HTS of 1,982 chemical compounds and FDA-approved drugs. After a series of counter-screens and testing in primary human CD19+ B cells, we identify 2 novel chemical inhibitors not previously implicated in inflammation or CD40-mediated NF-κB signaling. Our study demonstrates proof-of-concept that human genetics can be used to guide the development of phenotype-based, high-throughput small-molecule screens to identify potential novel therapies in

Genetics Home Reference: homocystinuria

MedlinePlus

... reductase deficiency Orphanet: Homocystinuria without methylmalonic aciduria Screening, Technology, and Research in Genetics Virginia Department of Health (PDF) Patient Support and Advocacy Resources (6 links) Children Living with Inherited Metabolic Diseases (CLIMB) (UK) CLIMB: ...

Interpretation of genetic testing for lynch syndrome in patients with putative familial colorectal cancer.

PubMed

Rybak, Christina; Hall, Michael J

2011-11-01

Colorectal cancer (CRC) risk assessment involves the evaluation of an individual's personal and family history for characteristics of an inherited susceptibility to develop CRC. Lynch syndrome (LS), or hereditary nonpolyposis colorectal cancer, is the most common cause of hereditary CRC, underlying 2% to 3% of patients with newly diagnosed (incident) CRC. Risk assessment for LS is complex, and the interpretation of the many available tests can be challenging even for the genetics specialist. A move toward universal (reflex) LS screening for mismatch repair in all patients with incident CRC supports the importance of improving the awareness and understanding of LS testing, teaching rational testing approaches, and honing interpretive skills among cancer care providers. This article reviews important clinical features of LS genetic evaluation using 3 pedigree-based case examples from the Fox Chase Cancer Center Gastrointestinal Risk Assessment Clinic.

Patient-perceived barriers to a screening program for depression: a patient opinion survey of hemodialysis patients

PubMed Central

Beanlands, Heather; Logan, Alexander; Kurdyak, Paul; Jassal, Sarbjit Vanita

2017-01-01

Abstract Background Depression is a prevalent, yet underdiagnosed, psychiatric disorder among patients with end-stage renal disease. Active case identification through routine screening is suggested; however, patient-related barriers may reduce the effectiveness of screening for, and treating, depression. This study aimed to explore the perceived barriers that limit patients from participating in screening and treatment programs for depression. Methods In a cross-sectional study of chronic maintenance hemodialysis patients, the Perceived Barriers to Psychological Treatment questionnaire, adapted to include screening, was used to measure perceived barriers. The two-item Patient Health Questionnaire was used to identify patients with depressive symptoms. Results Of 160 participants, 73.1% reported at least one barrier preventing them from participation [95% confidence interval (95% CI) 66.2–80.0%]. Patients with depressive symptoms were more likely to perceive at least one barrier to a screening program for depression compared with those without depressive symptoms (96% versus 68.9%, respectively; odds ratio = 10.8; 95% CI 1.4–82.8; P = 0.005). The association of the barrier scores with depressive symptoms remained significant after adjustment for patient’s characteristics. The most common barriers that patients expressed were concerns about the side effects of any antidepressant medications that may be prescribed (40%), concerns about having more medications (32%), feeling that the problem is not severe enough (23%) and perceiving no risk of depression (23%). Conclusions Negative perceptions about depression and its treatment among hemodialysis patients constitute an important barrier to identifying this condition and first need to be addressed before implementing a screening program in this population. PMID:29225813

Genetics Home Reference: citrullinemia

MedlinePlus

... Type II MalaCards: citrullinemia, classic Orphanet: Citrullinemia Screening, Technology, and Research in Genetics Virginia Department of Health (PDF) Patient Support and Advocacy Resources (5 links) Children Living with Inherited Metabolic Diseases (CLIMB) (UK) National ...

A group approach to genetic counselling of cardiomyopathy patients: satisfaction and psychological outcomes sufficient for further implementation.

PubMed

Otten, Ellen; Birnie, Erwin; Ranchor, Adelita V; van Tintelen, J Peter; van Langen, Irene M

2015-11-01

The introduction of next-generation sequencing in everyday clinical genetics practise is increasing the number of genetic disorders that can be confirmed at DNA-level, and consequently increases the possibilities for cascade screening. This leads to a greater need for genetic counselling, whereas the number of professionals available to provide this is limited. We therefore piloted group genetic counselling for symptomatic cardiomyopathy patients at regional hospitals, to assess whether this could be an acceptable alternative to individual counselling. We performed a cohort study with pre- and post-counselling patient measurements using questionnaires, supplemented with evaluations of the group counselling format by the professionals involved. Patients from eight regional hospitals in the northern part of the Netherlands were included. Questionnaires comprised patient characteristics, psychological measures (personal perceived control (PPC), state and trait anxiety inventory (STAI)), and satisfaction with counsellors, counselling content and design. In total, 82 patients (mean age 57.5 year) attended one of 13 group sessions. Median PPC and STAI scores showed significantly higher control and lower anxiety after the counselling. Patients reported they were satisfied with the counsellors, and almost 75% of patients were satisfied with the group counselling. Regional professionals were also, overall, satisfied with the group sessions. The genetics professionals were less satisfied, mainly because of their perceived large time investment and less-than-expected group interaction. Hence, a group approach to cardiogenetic counselling is feasible, accessible, and psychologically effective, and could be one possible approach to counselling the increasing patient numbers in cardiogenetics.

A group approach to genetic counselling of cardiomyopathy patients: satisfaction and psychological outcomes sufficient for further implementation

PubMed Central

Otten, Ellen; Birnie, Erwin; Ranchor, Adelita V; van Tintelen, J Peter; van Langen, Irene M

2015-01-01

The introduction of next-generation sequencing in everyday clinical genetics practise is increasing the number of genetic disorders that can be confirmed at DNA-level, and consequently increases the possibilities for cascade screening. This leads to a greater need for genetic counselling, whereas the number of professionals available to provide this is limited. We therefore piloted group genetic counselling for symptomatic cardiomyopathy patients at regional hospitals, to assess whether this could be an acceptable alternative to individual counselling. We performed a cohort study with pre- and post-counselling patient measurements using questionnaires, supplemented with evaluations of the group counselling format by the professionals involved. Patients from eight regional hospitals in the northern part of the Netherlands were included. Questionnaires comprised patient characteristics, psychological measures (personal perceived control (PPC), state and trait anxiety inventory (STAI)), and satisfaction with counsellors, counselling content and design. In total, 82 patients (mean age 57.5 year) attended one of 13 group sessions. Median PPC and STAI scores showed significantly higher control and lower anxiety after the counselling. Patients reported they were satisfied with the counsellors, and almost 75% of patients were satisfied with the group counselling. Regional professionals were also, overall, satisfied with the group sessions. The genetics professionals were less satisfied, mainly because of their perceived large time investment and less-than-expected group interaction. Hence, a group approach to cardiogenetic counselling is feasible, accessible, and psychologically effective, and could be one possible approach to counselling the increasing patient numbers in cardiogenetics. PMID:25649380

A Neuron-Based Screening Platform for Optimizing Genetically-Encoded Calcium Indicators

PubMed Central

Schreiter, Eric R.; Hasseman, Jeremy P.; Tsegaye, Getahun; Fosque, Benjamin F.; Behnam, Reza; Shields, Brenda C.; Ramirez, Melissa; Kimmel, Bruce E.; Kerr, Rex A.; Jayaraman, Vivek; Looger, Loren L.; Svoboda, Karel; Kim, Douglas S.

2013-01-01

Fluorescent protein-based sensors for detecting neuronal activity have been developed largely based on non-neuronal screening systems. However, the dynamics of neuronal state variables (e.g., voltage, calcium, etc.) are typically very rapid compared to those of non-excitable cells. We developed an electrical stimulation and fluorescence imaging platform based on dissociated rat primary neuronal cultures. We describe its use in testing genetically-encoded calcium indicators (GECIs). Efficient neuronal GECI expression was achieved using lentiviruses containing a neuronal-selective gene promoter. Action potentials (APs) and thus neuronal calcium levels were quantitatively controlled by electrical field stimulation, and fluorescence images were recorded. Images were segmented to extract fluorescence signals corresponding to individual GECI-expressing neurons, which improved sensitivity over full-field measurements. We demonstrate the superiority of screening GECIs in neurons compared with solution measurements. Neuronal screening was useful for efficient identification of variants with both improved response kinetics and high signal amplitudes. This platform can be used to screen many types of sensors with cellular resolution under realistic conditions where neuronal state variables are in relevant ranges with respect to timing and amplitude. PMID:24155972

Evaluation of a novel electronic genetic screening and clinical decision support tool in prenatal clinical settings.

PubMed

Edelman, Emily A; Lin, Bruce K; Doksum, Teresa; Drohan, Brian; Edelson, Vaughn; Dolan, Siobhan M; Hughes, Kevin; O'Leary, James; Vasquez, Lisa; Copeland, Sara; Galvin, Shelley L; DeGroat, Nicole; Pardanani, Setul; Gregory Feero, W; Adams, Claire; Jones, Renee; Scott, Joan

2014-07-01

"The Pregnancy and Health Profile" (PHP) is a free prenatal genetic screening and clinical decision support (CDS) software tool for prenatal providers. PHP collects family health history (FHH) during intake and provides point-of-care risk assessment for providers and education for patients. This pilot study evaluated patient and provider responses to PHP and effects of using PHP in practice. PHP was implemented in four clinics. Surveys assessed provider confidence and knowledge and patient and provider satisfaction with PHP. Data on the implementation process were obtained through semi-structured interviews with administrators. Quantitative survey data were analyzed using Chi square test, Fisher's exact test, paired t tests, and multivariate logistic regression. Open-ended survey questions and interviews were analyzed using qualitative thematic analysis. Of the 83% (513/618) of patients that provided feedback, 97% felt PHP was easy to use and 98% easy to understand. Thirty percent (21/71) of participating physicians completed both pre- and post-implementation feedback surveys [13 obstetricians (OBs) and 8 family medicine physicians (FPs)]. Confidence in managing genetic risks significantly improved for OBs on 2/6 measures (p values ≤0.001) but not for FPs. Physician knowledge did not significantly change. Providers reported value in added patient engagement and reported mixed feedback about the CDS report. We identified key steps, resources, and staff support required to implement PHP in a clinical setting. To our knowledge, this study is the first to report on the integration of patient-completed, electronically captured and CDS-enabled FHH software into primary prenatal practice. PHP is acceptable to patients and providers. Key to successful implementation in the future will be customization options and interoperability with electronic health records.

Impact of human genome initiative-derived technology on genetic testing, screening and counseling: Cultural, ethical and legal issues. Progress report

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

Trottier, R.W.; Hodgin, F.C.; Imara, M.

Genetic medical services provided by the Georgia Division of Public Health in two northern and two central districts are compared to services provided in a district in which a tertiary care facility is located. Genetics outreach public health nurses play key roles in Georgia`s system of Children`s Health Services Genetics Program, including significant roles as counselors and information sources on special needs social services and support organizations. Unique features of individual health districts, (e.g., the changing face of some rural communities in ethnocultural diversity and socioeconomic character), present new challenges to current and future genetics services delivery. Preparedness as tomore » educational needs of both health professionals and the lay population is of foremost concern in light of the ever expanding knowledge and technology in medical genetics. Perspectives on genetics and an overview of services offered by a local private sector counselor are included for comparison to state supported services. The nature of the interactions which transpire between private and public genetic services resources in Georgia will be described. A special focus of this research includes issues associated with sickle cell disease newborn screening service delivery process in Georgia, with particular attention paid to patient follow-up and transition to primary care. Of particular interest to this focus is the problem of loss to follow-up in the current system. Critical factors in education and counseling of sickle cell patients and the expectations of expanding roles of primary care physicians are discussed. The Florida approach to the delivery of genetic services contrasts to the Georgia model by placing more emphasis on a consultant-specialist team approach.« less

Hospitalized Patients with Cirrhosis Should Be Screened for Clostridium difficile Colitis.

PubMed

Saab, Sammy; Alper, Theodore; Sernas, Ernesto; Pruthi, Paridhima; Alper, Mikhail A; Sundaram, Vinay

2015-10-01

Clostridium difficile infection (CDI) is an important public health problem in hospitalized patients. Patients with cirrhosis are particularly at risk of increased associated morbidity, mortality, and healthcare utilization from CDI. The aim of this study was to assess the pharmacoeconomic impact of CDI screening on hospitalized patients with cirrhosis. A Markov model was used to compare costs and outcomes of two strategies for the screening of CDI. The first strategy consisted of screening all patients for CDI and treating if detected (screening). In the second strategy, only patients found to have symptomatic CDI were treated (no screening). The probability of underlying CDI prevalence, symptomatic CDI infection, and likelihood of recurrent infection were varied in a sensitivity analysis. The costs of antibiotics and hospitalization were also assessed. Differences in outcome were expressed in ratio of the total costs associated with screening to the total costs associated without screening. The results of our model showed that screening for CDI was consistently associated with improved healthcare outcomes and decreased healthcare utilization across all variables in the one- and two-way sensitivity analyses. Using baseline assumptions, the costs associated with the no screening strategy were 3.54 times that of the screening strategy. Moreover, the mortality for symptomatic CDI was lower in the screening strategy than the no screening strategy. The screening strategy results in less healthcare utilization and improved clinical outcomes. Screening for CDI measures favorably.

Business and Breakthrough: Framing (Expanded) Genetic Carrier Screening for the Public.

PubMed

Holton, Avery E; Canary, Heather E; Wong, Bob

2017-09-01

A growing body of research has given attention to issues surrounding genetic testing, including expanded carrier screening (ECS), an elective medical test that allows planning or expecting parents to consider the potential occurrence of genetic diseases and disorders in their children. These studies have noted the role of the mass media in driving public perceptions about such testing, giving particular attention to ways in which coverage of genetics and genetic testing broadly may drive public attitudes and choices concerning the morality, legality, ethics, and parental well-being involved in genetic technologies. However, few studies have explored how mass media are covering the newer test, ECS. Drawing on health-related framing studies that have shown in varying degrees the impact particular frames such as gain/loss and thematic/episodic can have on the public, this study examines the frame selection employed by online media in its coverage of ECS. This analysis-combined with an analysis of the sources and topics used in such coverage and how they relate to selected frames-helps to clarify how mass media are covering an increasingly important medical test and offers considerations of how such coverage may inform mass media scholarship as well as health-related practices.

Business and Breakthrough: Framing (Expanded) Genetic Carrier Screening for the Public

PubMed Central

Holton, Avery E.; Canary, Heather E.; Wong, Bob

2018-01-01

A growing body of research has given attention to issues surrounding genetic testing, including expanded carrier screening (ECS), an elective medical test that allows planning or expecting parents to consider the potential occurrence of genetic diseases and disorders in their children. These studies have noted the role of the mass media in driving public perceptions about such testing, giving particular attention to ways in which coverage of genetics and genetic testing broadly may drive public attitudes and choices concerning the morality, legality, ethics, and parental well-being involved in genetic technologies. However, few studies have explored how mass media are covering the newer test, ECS. Drawing on health-related framing studies that have shown in varying degrees the impact particular frames such as gain/loss and thematic/episodic can have on the public, this study examines the frame selection employed by online media in its coverage of ECS. This analysis—combined with an analysis of the sources and topics used in such coverage and how they relate to selected frames—helps to clarify how mass media are covering an increasingly important medical test and offers considerations of how such coverage may inform mass media scholarship as well as health-related practices. PMID:27483980

Phenylketonuria Genetic Screening Simulation

ERIC Educational Resources Information Center

Erickson, Patti

2012-01-01

After agreeing to host over 200 students on a daylong genetics field trip, the author needed an easy-to-prepare genetics experiment to accompany the DNA-necklace and gel-electrophoresis activities already planned. One of the student's mothers is a pediatric physician at the local hospital, and she suggested exploring genetic-disease screening…

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.

Proof of concept: preimplantation genetic screening without embryo biopsy through analysis of cell-free DNA in spent embryo culture media.

PubMed

Shamonki, Mousa I; Jin, Helen; Haimowitz, Zachary; Liu, Lian

2016-11-01

To assess whether preimplantation genetic screening (PGS) is possible by testing for free embryonic DNA in spent IVF media from embryos undergoing trophectoderm biopsy. Prospective cohort analysis. Academic fertility center. Seven patients undergoing IVF and 57 embryos undergoing trophectoderm biopsy for PGS. On day 3 of development, each embryo was placed in a separate media droplet. All biopsied embryos received a PGS result by array comparative genomic hybridization. Preimplantation genetic screening was performed on amplified DNA extracted from media and results were compared with PGS results for the corresponding biopsy. [1] Presence of DNA in spent IVF culture media. [2] Correlation between genetic screening result from spent media and corresponding biopsy. Fifty-five samples had detectable DNA ranging from 2-642 ng/μL after a 2-hour amplification. Six samples with the highest DNA levels underwent PGS, rendering one result with a derivative log ratio SD (DLRSD) of <0.85 (a quality control metric of oligonucleotide array comparative genomic hybridization). The fluid sample and trophectoderm results were identical demonstrating (45XY, -13). Three samples were reamplified 1 hour later and tested showing improving DLRSD. One of the three samples with a DLRSD of 0.85 demonstrated (46XY), consistent with the biopsy. Overnight DNA amplification showed DNA in all samples. We demonstrate two novel findings: the presence of free embryonic DNA in spent media and a result that is consistent with trophectoderm biopsy. Improvements in DNA collection, amplification, and testing may allow for PGS without biopsy in the future. Copyright © 2016 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Universal screening for Lynch syndrome in endometrial cancers: frequency of germline mutations and identification of patients with Lynch-like syndrome.

PubMed

Dillon, Jessica L; Gonzalez, Jorge L; DeMars, Leslie; Bloch, Katarzyna J; Tafe, Laura J

2017-12-01

Lynch syndrome (LS) is an inherited clinical syndrome characterized by a high risk of colorectal, endometrial (lifetime risk of up to 60%), ovarian, and urinary tract cancers. The diagnosis is confirmed by identification of germline mutations in the DNA mismatch repair genes MLH1, PMS2, MSH2, MSH6, or EPCAM. In 2015, our institution implemented universal screening of endometrial cancer (EC) hysterectomy specimens by mismatch repair immunohistochemistry (IHC) with reflex MLH1 promoter hypermethylation analysis for tumors with loss of MLH1/PMS2 expression. Patients with tumors negative for MLH1 methylation and those with a loss of the heterodimer pair MSH2 and MSH6, or isolated loss of either PMS2 or MSH6 were referred to the Familial Cancer Program for genetic counseling and consideration of germline testing. Between May 2015 to Dec 2016, 233 EC patients were screened by IHC for LS with a median age of 63 years. Sixty tumors (27%) had abnormal IHC staining results. Fifty-one (22%) harbored heterodimeric loss of MLH1 and PMS2, 49 of which showed MLH1 promoter methylation (1 failure, 1 negative). One showed loss of MLH1/PMS2 and MSH6, 2 showed loss of MSH2/MSH6, and 6 had isolated loss of MSH6 only. Ten patients underwent genetic counseling, and germline testing was performed in 8; LS was confirmed in 5 patients (2.1%). In addition, 3 patients with negative germline testing and presumed Lynch-like syndrome were identified and offered additional somatic testing. Universal screening for LS in EC patients has yielded positive results for identification of patients at risk for this inherited syndrome. Copyright © 2017 Elsevier Inc. All rights reserved.

Incorporating genomics into breast and prostate cancer screening: assessing the implications

PubMed Central

Chowdhury, Susmita; Dent, Tom; Pashayan, Nora; Hall, Alison; Lyratzopoulos, Georgios; Hallowell, Nina; Hall, Per; Pharoah, Paul; Burton, Hilary

2013-01-01

Individual risk prediction and stratification based on polygenic profiling may be useful in disease prevention. Risk-stratified population screening based on multiple factors including a polygenic risk profile has the potential to be more efficient than age-stratified screening. In this article, we summarize the implications of personalized screening for breast and prostate cancers. We report the opinions of multidisciplinary international experts who have explored the scientific, ethical, and logistical aspects of stratified screening. We have identified (i) the need to recognize the benefits and harms of personalized screening as compared with existing screening methods, (ii) that the use of genetic data highlights complex ethical issues including discrimination against high-risk individuals by insurers and employers and patient autonomy in relation to genetic testing of minors, (iii) the need for transparency and clear communication about risk scores, about harms and benefits, and about reasons for inclusion and exclusion from the risk-based screening process, and (iv) the need to develop new professional competences and to assess cost-effectiveness and acceptability of stratified screening programs before implementation. We conclude that health professionals and stakeholders need to consider the implications of incorporating genetic information in intervention strategies for health-care planning in the future. Genet Med 2013:15(6):423–432 PMID:23412607

Directed evolution of stereoselective enzymes based on genetic selection as opposed to screening systems.

PubMed

Acevedo-Rocha, Carlos G; Agudo, Ruben; Reetz, Manfred T

2014-12-10

Directed evolution of stereoselective enzymes provides a means to generate useful biocatalysts for asymmetric transformations in organic chemistry and biotechnology. Almost all of the numerous examples reported in the literature utilize high-throughput screening systems based on suitable analytical techniques. Since the screening step is the bottleneck of the overall procedure, researchers have considered the use of genetic selection systems as an alternative to screening. In principle, selection would be the most elegant and efficient approach because it is based on growth advantage of host cells harboring stereoselective mutants, but devising such selection systems is very challenging. They must be designed so that the host organism profits from the presence of an enantioselective variant. Progress in this intriguing research area is summarized in this review, which also includes some examples of display systems designed for enantioselectivity as assayed by fluorescence-activated cell sorting (FACS). Although the combination of display systems and FACS is a powerful approach, we also envision innovative ideas combining metabolic engineering and genetic selection systems with protein directed evolution for the development of highly selective and efficient biocatalysts. Copyright © 2014 Elsevier B.V. All rights reserved.

Screening and identification of genetic loci involved in producing more/denser inclusion bodies in Escherichia coli

PubMed Central

2013-01-01

Background Many proteins and peptides have been used in therapeutic or industrial applications. They are often produced in microbial production hosts by fermentation. Robust protein production in the hosts and efficient downstream purification are two critical factors that could significantly reduce cost for microbial protein production by fermentation. Producing proteins/peptides as inclusion bodies in the hosts has the potential to achieve both high titers in fermentation and cost-effective downstream purification. Manipulation of the host cells such as overexpression/deletion of certain genes could lead to producing more and/or denser inclusion bodies. However, there are limited screening methods to help to identify beneficial genetic changes rendering more protein production and/or denser inclusion bodies. Results We report development and optimization of a simple density gradient method that can be used for distinguishing and sorting E. coli cells with different buoyant densities. We demonstrate utilization of the method to screen genetic libraries to identify a) expression of glyQS loci on plasmid that increased expression of a peptide of interest as well as the buoyant density of inclusion body producing E. coli cells; and b) deletion of a host gltA gene that increased the buoyant density of the inclusion body produced in the E. coli cells. Conclusion A novel density gradient sorting method was developed to screen genetic libraries. Beneficial host genetic changes could be exploited to improve recombinant protein expression as well as downstream protein purification. PMID:23638724

Screening and identification of genetic loci involved in producing more/denser inclusion bodies in Escherichia coli.

PubMed

Pandey, Neeraj; Sachan, Annapurna; Chen, Qi; Ruebling-Jass, Kristin; Bhalla, Ritu; Panguluri, Kiran Kumar; Rouviere, Pierre E; Cheng, Qiong

2013-05-02

Many proteins and peptides have been used in therapeutic or industrial applications. They are often produced in microbial production hosts by fermentation. Robust protein production in the hosts and efficient downstream purification are two critical factors that could significantly reduce cost for microbial protein production by fermentation. Producing proteins/peptides as inclusion bodies in the hosts has the potential to achieve both high titers in fermentation and cost-effective downstream purification. Manipulation of the host cells such as overexpression/deletion of certain genes could lead to producing more and/or denser inclusion bodies. However, there are limited screening methods to help to identify beneficial genetic changes rendering more protein production and/or denser inclusion bodies. We report development and optimization of a simple density gradient method that can be used for distinguishing and sorting E. coli cells with different buoyant densities. We demonstrate utilization of the method to screen genetic libraries to identify a) expression of glyQS loci on plasmid that increased expression of a peptide of interest as well as the buoyant density of inclusion body producing E. coli cells; and b) deletion of a host gltA gene that increased the buoyant density of the inclusion body produced in the E. coli cells. A novel density gradient sorting method was developed to screen genetic libraries. Beneficial host genetic changes could be exploited to improve recombinant protein expression as well as downstream protein purification.

Mutation screening of the PCDH15 gene in Spanish patients with Usher syndrome type I

PubMed Central

Jaijo, Teresa; Oshima, Aki; Aller, Elena; Carney, Carol; Usami, Shin-ichi; Kimberling, William J.

2012-01-01

Purpose PCDH15 codes for protocadherin-15, a cell-cell adhesion protein essential in the morphogenesis and cohesion of stereocilia bundles and in the function or preservation of photoreceptor cells. Mutations in the PCDH15 gene are responsible for Usher syndrome type I (USH1F) and non-syndromic hearing loss (DFNB23). The purpose of this work was to perform PCDH15 mutation screening to identify the genetic cause of the disease in a cohort of Spanish patients with Usher syndrome type I and establish phenotype-genotype correlation. Methods Mutation analysis of PCDH15 included additional exons recently identified and was performed by direct sequencing. The screening was performed in 19 probands with USH already screened for mutations in the most prevalent USH1 genes, myosin VIIA (MYO7A) and cadherin-23 (CDH23), and for copy number variants in PCDH15. Results Seven different point mutations, five novel, were detected. Including the large PCDH15 rearrangements previously reported in our cohort of patients, a total of seven of 19 patients (36.8%) were carriers of at least one pathogenic allele. Thirteen out of the 38 screened alleles carried pathogenic PCDH15 variants (34.2%). Conclusions Five out of the seven point mutations reported in the present study are novel, supporting the idea that most PCDH15 mutations are private. Furthermore, no mutational hotspots have been identified. In most patients, detected mutations led to a truncated protein, reinforcing the hypothesis that severe mutations cause the Usher I phenotype and that missense variants are mainly responsible for non-syndromic hearing impairment. PMID:22815625

A Value-Based Medicine cost-utility analysis of genetic testing for neovascular macular degeneration.

PubMed

Brown, Gary C; Brown, Melissa M; Lieske, Heidi B; Lieske, Philip A; Brown, Kathryn S

2015-01-01

There is a dearth of patient, preference-based cost-effectiveness analyses evaluating genetic testing for neovascular age-related macular degeneration (NVAMD). A Value-Based Medicine, 12-year, combined-eye model, cost-utility analysis evaluated genetic testing of Category 3 AMD patients at age 65 for progression to NVAMD. The benefit of genetic testing was predicated upon the fact that early-treatment ranibizumab therapy (baseline vision 20/40-20/80) for NVAMD confers greater patient value than late-treatment (baseline vision ≤20/160). Published genetic data and MARINA Study ranibizumab therapy data were utilized in the analysis. Patient value (quality-of-life gain) and financial value (2012 US real dollar) outcomes were discounted at 3 % annually. Genetic testing-enabled, early-treatment ranibizumab therapy per patient conferred mean 20/40 -1 vision, a 0.845 QALY gain and 14.1 % quality-of-life gain over sham therapy. Late-treatment ranibizumab therapy conferred mean 20/160 +2 vision, a 0.250 QALY gain and 4.2 % quality-of-life gain over sham therapy. The gain from early-treatment over late-treatment was 0.595 QALY (10.0 % quality-of-life gain). The per-patient cost for genetic testing/closer monitoring was $2205 per screened person, $2.082 billion for the 944,000 estimated new Category 3 AMD patients annually. Genetic testing/monitoring costs per early-treatment patient totaled $66,180. Costs per early-treatment patient included: genetic testing costs: $66,180 + direct non-ophthalmic medical costs: -$40,914 + caregiver costs: -$172,443 + employment costs: -$14,098 = a net societal cost saving of $160,582 per early treatment patient. When genetic screening facilitated an incremental 12,965 (8.0 %) of the 161,754, new annual NVAMD patients aged ≥65 in the US to undergo early-treatment ranibizumab therapy, each additional patient treated accrued an overall, net financial gain for society of $160,582. Genetic screening was cost-effective, using World

Systematic immunohistochemical screening for Lynch syndrome in colorectal cancer: a single centre experience of 486 patients.

PubMed

Zumstein, Valentin; Vinzens, Fabrizio; Zettl, Andreas; Heinimann, Karl; Koeberle, Dieter; von Flüe, Markus; Bolli, Martin

2016-01-01

Germline mutations in DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2 cause autosomal dominantly inherited Lynch syndrome. Lynch syndrome patients and their families benefit from life-saving intensive cancer surveillance. Approximately one in 30 colorectal cancers arises in the setting of Lynch syndrome. The aim of this study was to assess the detection rate of Lynch syndrome at our institution after introduction of systematic immunohistochemical screening for MMR deficiency in colorectal cancers from 2011 to 2015. Following the recommendations by the Evaluation of Genomic Applications in Practice and Prevention working group all colorectal cancers were immunohistochemically stained for the presence of MMR proteins MLH1, PMS2, MSH2 and MSH6, independent of clinical criteria. In the case of loss of MLH1, the somatic BRAF mutation V600E was assessed with molecular testing and/or immunohistochemistry. Clinical follow-up of potential Lynch syndrome carriers (patients with tumours showing loss of MLH1 expression with absence of BRAFV600E, loss of PMS2, MSH2 or MSH6) was evaluated. Of all patients (n = 486), loss of MMR protein expression was found in 73 (15.0%) tumours. Twenty-eight (6.0%) were classified as potential Lynch syndrome carriers. Of the genetically tested potential Lynch syndrome carriers (10 out of 28 patients), 40% were first diagnosed with Lynch syndrome. Implementation of systematic immunohistochemistry screening for Lynch syndrome showed that 6% of colorectal cancers were potentially Lynch-syndrome related. Tumour board protocols should systematically contain information on MMR status of all colorectal cancers and, in MMR deficient cases, include clear recommendations for genetic counselling for all potential Lynch syndrome patients.

Perceived genetic knowledge, attitudes towards genetic testing, and the relationship between these among patients with a chronic disease.

PubMed

Morren, Mattijn; Rijken, Mieke; Baanders, Arianne N; Bensing, Jozien

2007-02-01

Genetics increasingly permeate everyday medicine. When patients want to make informed decisions about genetic testing, they require genetic knowledge. This study examined the genetic knowledge and attitudes of patients with chronic diseases, and the relationship between both. In addition, patients were asked about their preferred source of genetic information. Questionnaires were mailed to participants of a nationwide representative sample of patients with chronic diseases in the Netherlands (n = 1916). The response rate was 82% (n = 1496). Perceived genetic knowledge was low, particularly among older and lower educated patients. Attitudes towards genetics were rather positive, especially among younger and higher educated patients. Some concerns were also documented, mainly about the consequences of genetic testing for employment and taking insurance. Patients who perceived to have little knowledge found it difficult to formulate an opinion about genetic testing. Higher levels of genetic knowledge were associated with a more favourable attitude towards genetics. Chronic patients prefer to receive genetic information from their GP. Chronic patients are ill prepared when they require genetic knowledge to make decisions regarding the treatment of their disease. This seems to result from a knowledge deficiency rather than from disagreement with the genetic developments. When chronic patients are in need of information about genetics or genetic testing, their general practitioner should provide this.

Patient-provider language concordance and colorectal cancer screening.

PubMed

Linsky, Amy; McIntosh, Nathalie; Cabral, Howard; Kazis, Lewis E

2011-02-01

Patient-provider language barriers may play a role in health-care disparities, including obtaining colorectal cancer (CRC) screening. Professional interpreters and language-concordant providers may mitigate these disparities. DESIGN, SUBJECTS, AND MAIN MEASURES: We performed a retrospective cohort study of individuals age 50 years and older who were categorized as English-Concordant (spoke English at home, n = 21,594); Other Language-Concordant (did not speak English at home but someone at their provider's office spoke their language, n = 1,463); or Other Language-Discordant (did not speak English at home and no one at their provider's spoke their language, n = 240). Multivariate logistic regression assessed the association of language concordance with colorectal cancer screening. Compared to English speakers, non-English speakers had lower use of colorectal cancer screening (30.7% vs 50.8%; OR, 0.63; 95% CI, 0.51-0.76). Compared to the English-Concordant group, the Language-Discordant group had similar screening (adjusted OR, 0.84; 95% CI, 0.58-1.21), while the Language-Concordant group had lower screening (adjusted OR, 0.57; 95% CI, 0.46-0.71). Rates of CRC screening are lower in individuals who do not speak English at home compared to those who do. However, the Language-Discordant cohort had similar rates to those with English concordance, while the Language-Concordant cohort had lower rates of CRC screening. This may be due to unmeasured differences among the cohorts in patient, provider, and health care system characteristics. These results suggest that providers should especially promote the importance of CRC screening to non-English speaking patients, but that language barriers do not fully account for CRC screening rate disparities in these populations.

[Validation of a nutritional screening tool for hospitalized pediatric patients].

PubMed

Lama More, R A; Moráis López, A; Herrero Álvarez, M; Caraballo Chicano, S; Galera Martínez, R; López Ruzafa, E; Rodríguez Martínez, G; de la Mano Hernández, A; Rivero de la Rosa, M C

2012-01-01

Malnutrition among hospitalized patients has clinical implications, and interest has arisen to find screening tools able to identify subjects under risk. At present, there is no consensus about the most suitable nutrition screening tool for pediatric patients. To validate STAMP (Screening Tool for the Assessment of Malnutrition in Pediatrics) pediatric screening tool in Spain. Descriptive cross-sectional study of patients admitted to a 3rd level children's hospital with both medical and surgical specialities. During the first 24 hours of admission, STAMP screening tool was applied. For its validation, results were compared with those obtained from a nutritional assessment performed by specialist staff, which included clinical, anthropometric and body composition data. A sample of 250 children was studied. Nutritional assessment identified 64 patients (25.6%) under risk, 40 of whom were malnourished (16%). STAMP classified 48.4% of the patients as being under nutritional risk. This tool showed 75% sensitivity and 60.8% specificity when identifying patients under risk according to nutritional assessment. It showed 90% sensitivity and 59.5% specificity when identifying malnourished patients. Malnutrition was less frequent than that reported in other European countries, although diagnosis technique was different. STAMP is a simple and useful tool for nutritional screening, avoiding the need to assess all patients on admission in order to identify those under nutritional risk.

Effect of Physician Notification Regarding Nonadherence to Colorectal Cancer Screening on Patient Participation in Fecal Immunochemical Test Cancer Screening

PubMed Central

Pogu, Corinne; Le Donné, Delphine; Latour, Chloé; Bianco, Gaelle; Nanin, France; Cowppli-Bony, Anne; Gaultier, Aurélie; Nguyen, Jean-Michel

2017-01-01

Importance Increasing participation in fecal screening tests is a major challenge in countries that have implemented colorectal cancer (CRC) screening programs. Objective To determine whether providing general practitioners (GPs) a list of patients who are nonadherent to CRC screening enhances patient participation in fecal immunochemical testing (FIT). Design, Setting, and Participants A 3-group, cluster-randomized study was conducted from July 14, 2015, to July 14, 2016, on the west coast of France, with GPs in 801 practices participating and involving adult patients (50-74 years) who were at average risk of CRC and not up-to-date with CRC screening. The final follow-up date was July 14, 2016. Interventions General practitioners were randomly assigned to 1 of 3 groups: 496 received a list of patients who had not undergone CRC screening (patient-specific reminders group, 10 476 patients), 495 received a letter describing region-specific CRC screening adherence rates (generic reminders group, 10 606 patients), and 455 did not receive any reminders (usual care group, 10 147 patients). Main Outcomes and Measures The primary end point was patient participation in CRC screening 1 year after the intervention. Results Among 1482 randomized GPs (mean age, 53.4 years; 576 women [38.9%]), 1446 participated; of the 33 044 patients of these GPs (mean age, 59.7 years; 17 949 women [54.3%]), follow-up at 1 year was available for 31 229 (94.5%). At 1 year, 24.8% (95% CI, 23.4%-26.2%) of patients in the specific reminders group, 21.7% (95% CI, 20.5%-22.8%) in the generic reminders group, and 20.6% (95% CI, 19.3%-21.8%) in the usual care group participated in the FIT screening. The between-group differences were 3.1% (95% CI, 1.3%-5.0%) for the patient-specific reminders group vs the generic reminders group, 4.2% (95% CI, 2.3%-6.2%) for the patient-specific reminders group vs the usual care group, and 1.1% (95% CI, −0.6% to 2.8%) for generic reminders group vs the

Stargardt macular dystrophy: common ABCA4 mutations in South Africa—establishment of a rapid genetic test and relating risk to patients

PubMed Central

Nossek, Christel A.; Greenberg, L. Jacquie; Ramesar, Rajkumar S.

2012-01-01

Purpose Based on the previous indications of founder ATP-binding cassette sub-family A member 4 gene (ABCA4) mutations in a South African subpopulation, the purpose was to devise a mechanism for identifying common disease-causing mutations in subjects with ABCA4-associated retinopathies (AARs). Facilitating patient access to this data and determining the frequencies of the mutations in the South African population would enhance the current molecular diagnostic service offered. Methods The majority of subjects in this study were of Caucasian ancestry and affected with Stargardt macular dystrophy. The initial cohort consisted of DNA samples from 181 patients, and was screened using the ABCR400 chip. An assay was then designed to screen a secondary cohort of 72 patients for seven of the most commonly occurring ABCA4 mutations in this population. A total of 269 control individuals were also screened for the seven ABCA4 mutations. Results Microarray screening results from a cohort of 181 patients affected with AARs revealed that seven ABCA4 mutations (p.Arg152*, c.768G>T, p.Arg602Trp, p.Gly863Ala, p.Cys1490Tyr, c.5461–10T>C, and p.Leu2027Phe) occurred at a relatively high frequency. The newly designed genetic assay identified two of the seven disease-associated mutations in 28/72 patients in a secondary patient cohort. In the control cohort, 12/269 individuals were found to be heterozygotes, resulting in an estimated background frequency of these mutations in this particular population of 4.46 per 100 individuals. Conclusions The relatively high detection rate of seven ABCA4 mutations in the primary patient cohort led to the design and subsequent utility of a multiplex assay. This assay can be used as a viable screening tool and to reduce costs and laboratory time. The estimated background frequency of the seven ABCA4 mutations, together with the improved diagnostic service, could be used by counselors to facilitate clinical and genetic management of South African

[Molecular genetic analysis and clinical aspects of patients with hereditary hemochromatosis].

PubMed

Lange, U; Teichmann, J; Dischereit, G

2014-08-01

The purpose of the study was to perform a molecular genetic analysis and to document clinical aspects in patients with hereditary hemochromatosis. The study included 33 outpatients (23 males average age 50.6 years and 10 females average age 60.6 years) with a disorder of iron metabolism (transferrin saturation > 75 %) as confirmation of hemochromatosis who were subjected to molecular genetic and clinical analyses. A homozygous mutation of the hemochromatosis (HFE) gene (C282YY) was detected in 63.6 %, a compound heterozygous mutation (C282Y/H63D) in 30.3% and no mutation of the HFE gene was detected in 6.1 %. The following organ manifestations could be objectified: arthralgia (78.8 %), liver disease (39.9 %), skin hyperpigmentation (30.3 %), osteoporosis (24.2 %), diabetes mellitus (24.2 %) and cardiomyopathy (12.1 %). Comparison between patients with heterozygous and homozygous hemochromatosis revealed the following differences: compound heterozygote patients presented less frequently with osteoarthritis of the metacarpophalangeal (MCP) joints and hands (85.7 %/71.4 % homozygotes vs. 60 %/60 % heterozygotes). Osteoarthritis of the shoulder joints and osteoporosis as well as hypothyroidism were more frequent in compound heterozygote patients, whereas osteoarthritis of the knee and hip joints as well as liver disease were more common in homozygote patients. No differences between both groups were seen with respect to the clinical manifestations of cardiomyopathy and diabetes mellitus. Prevalent causes of death in hereditary hemochromatosis are heart failure, liver disease (cirrhosis and hepatocellular carcinoma) and portal hypertension. Therefore, an early diagnosis, adequate therapy and genetic screening of family members are of great importance. Medicinal treatment will only effectively prevent deleterious organ involvement and subsequent complications if initiated at an early stage. Furthermore, an overview of the current data is given.

Centronuclear myopathies: genotype-phenotype correlation and frequency of defined genetic forms in an Italian cohort.

PubMed

Fattori, Fabiana; Maggi, Lorenzo; Bruno, Claudio; Cassandrini, Denise; Codemo, Valentina; Catteruccia, Michela; Tasca, Giorgio; Berardinelli, Angela; Magri, Francesca; Pane, Marika; Rubegni, Anna; Santoro, Lucio; Ruggiero, Lucia; Fiorini, Patrizio; Pini, Antonella; Mongini, Tiziana; Messina, Sonia; Brisca, Giacomo; Colombo, Irene; Astrea, Guja; Fiorillo, Chiara; Bragato, Cinzia; Moroni, Isabella; Pegoraro, Elena; D'Apice, Maria Rosaria; Alfei, Enrico; Mora, Marina; Morandi, Lucia; Donati, Alice; Evilä, Anni; Vihola, Anna; Udd, Bjarne; Bernansconi, Pia; Mercuri, Eugenio; Santorelli, Filippo Maria; Bertini, Enrico; D'Amico, Adele

2015-07-01

Centronuclear myopathies (CNMs) are a group of clinically and genetically heterogeneous muscle disorders. To date, mutation in 7 different genes has been reported to cause CNMs but 30 % of cases still remain genetically undefined. Genetic investigations are often expensive and time consuming. Clinical and morphological clues are needed to facilitate genetic tests and to choose the best approach for genetic screening. We aimed to describe genotype-phenotype correlation in an Italian cohort of patients affected by CNMs, to define the relative frequencies of its defined genetic forms and to draw a diagnostic algorithm to address genetic investigations. We recruited patients with CNMs from all the Italian tertiary neuromuscular centers following clinical and histological criteria. All selected patients were screened for the four 'canonical' genes related to CNMs: MTM1, DNM2, RYR1 and BIN1. Pathogenetic mutations were found in 38 of the 54 screened patients (70 %), mostly in patients with congenital onset (25 of 30 patients, 83 %): 15 in MTM1, 6 in DNM2, 3 in RYR1 and one in TTN. Among the 13 patients with a childhood-adolescence onset, mutations were found in 6 patients (46 %), all in DNM2. In the group of the 11 patients with adult onset, mutations were identified in 7 patients (63 %), again in DNM2, confirming that variants in this gene are relatively more common in late-onset phenotypes. The present study provides the relative molecular frequency of centronuclear myopathy and of its genetically defined forms in Italy and also proposes a diagnostic algorithm to be used in clinical practice to address genetic investigations.

Screening of Early and Late Onset Alzheimer's Disease Genetic Risk Factors in a Cohort of Dementia Patients from Liguria, Italy.

PubMed

Ferrari, Raffaele; Ferrara, Michela; Alinani, Anwar; Sutton, Roger Brian; Famà, Francesco; Picco, Agnese; Rodriguez, Guido; Nobili, Flavio; Momeni, Parastoo

2015-01-01

Cohorts from a defined geographical area enable ad hoc genotype-phenotype correlation studies providing novel and unique insight into disease. We analysed genetic risk factors associated with early and late onset Alzheimer's disease (EOAD and LOAD) in a population from Liguria (northern Italy), as part of an ongoing longitudinal study. We screened 37 AD, 8 mild cognitive impairment (MCI), 3 AD and CVD (cerebrovascular disease), 3 MCI and CVD, 8 frontotemporal dementia (FTD) and 2 progressive supranuclear palsy (PSP) patients, and 28 normal controls (NCs).We sequenced PSEN1, PSEN2 and APP (EOAD risk factors), as well as MAPT, GRN and TARDBP for all cases and NCs, and analysed the APOE, CLU, CR1 and PICALM genotypes as well as the MAPT and ACE haplotypes (LOAD risk factors) for the AD (n = 37) and AD + MCI (n = 45) cases and NCs (n = 28).We identified variants in PSEN1, PSEN2 and TARDBP across a range of phenotypes (AD, AD and CVD, FTD and PSP), suggesting that screening of all known candidate genes of Alzheimer's and non-Alzheimer's forms of dementias in all dementia cases might be warranted. The analysis of the LOAD risk factors revealed no association with AD or AD + MCI status after Bonferroni correction. Lack of association with APOE is supported by previous studies in the Italian population. Our data also evidenced: 1) a potentially protective haplotype at the PSEN2 locus; 2) a nominal association with the GWAS-risk allele A for rs3818361 in CR1 and; 3) a threefold prevalence of AD in the female population compared to men.Our results will need to be further assessed and confirmed in larger cohorts from this area. 

Dual gene activation and knockout screen reveals directional dependencies in genetic networks. | Office of Cancer Genomics

Cancer.gov

Understanding the direction of information flow is essential for characterizing how genetic networks affect phenotypes. However, methods to find genetic interactions largely fail to reveal directional dependencies. We combine two orthogonal Cas9 proteins from Streptococcus pyogenes and Staphylococcus aureus to carry out a dual screen in which one gene is activated while a second gene is deleted in the same cell. We analyze the quantitative effects of activation and knockout to calculate genetic interaction and directionality scores for each gene pair.

Considering culture in physician-- patient communication during colorectal cancer screening.

PubMed

Ge Gao; Burke, Nancy; Somkin, Carol P; Pasick, Rena

2009-06-01

Racial and ethnic disparities exist in both incidence and stage detection of colorectal cancer (CRC). We hypothesized that cultural practices (i.e., communication norms and expectations) influence patients' and their physicians' understanding and talk about CRC screening. We examined 44 videotaped observations of clinic visits that included a CRC screening recommendation and transcripts from semistructured interviews that doctors and patients separately completed following the visit. We found that interpersonal relationship themes such as power distance, trust, directness/ indirectness, and an ability to listen, as well as personal health beliefs, emerged as affecting patients' definitions of provider-patient effective communication. In addition, we found that in discordant physician-patient interactions (when each is from a different ethnic group), physicians did not solicit or address cultural barriers to CRC screening and patients did not volunteer culture-related concerns regarding CRC screening.

[Genetic diagnostics of pathogenic splicing abnormalities in the clinical laboratory--pitfalls and screening approaches].

PubMed

Niimi, Hideki; Ogawa, Tomomi; Note, Rhougou; Hayashi, Shirou; Ueno, Tomohiro; Harada, Kenu; Uji, Yoshinori; Kitajima, Isao

2010-12-01

In recent years, genetic diagnostics of pathogenic splicing abnormalities are increasingly recognized as critically important in the clinical genetic diagnostics. It is reported that approximately 10% of pathogenic mutations causing human inherited diseases are splicing mutations. Nonetheless, it is still difficult to identify splicing abnormalities in routine genetic diagnostic settings. Here, we studied two different kinds of cases with splicing abnormalities. The first case is a protein S deficiency. Nucleotide analyses revealed that the proband had a previously reported G to C substitution in the invariant AG dinucleotide at the splicing acceptor site of intronl/exon2, which produces multiple splicing abnormalities resulting in protein S deficiency. The second case is an antithrombin (AT) deficiency. This proband had a previously reported G to A substitution, at nucleotide position 9788 in intron 4, 14 bp in front of exon 5, which created a de novo exon 5 splice site and resulted in AT deficiency. From a practical standpoint, we discussed the pitfalls, attentions, and screening approaches in genetic diagnostics of pathogenic splicing abnormalities. Due to the difficulty with full-length sequence analysis of introns, and the lack of RNA samples, splicing mutations may escape identification. Although current genetic testing remains to be improved, to screen for splicing abnormalities more efficiently, it is significant to use an appropriate combination of various approaches such as DNA and/or RNA samples, splicing mutation databases, bioinformatic tools to detect splice sites and cis-regulatory elements, and in vitro and/or in vivo experimentally methods as needed.

Universal screening of both endometrial and colon cancers increases the detection of Lynch syndrome.

PubMed

Adar, Tomer; Rodgers, Linda H; Shannon, Kristen M; Yoshida, Makoto; Ma, Tianle; Mattia, Anthony; Lauwers, Gregory Y; Iafrate, Anthony J; Hartford, Nicole M; Oliva, Esther; Chung, Daniel C

2018-05-11

Lynch syndrome (LS) is the most common hereditary cause of colorectal cancer (CRC) and endometrial cancer (EC). Screening of all CRCs for LS is currently recommended, but screening of ECs is inconsistent. The objective of this study was to determine the added value of screening both CRC and EC tumors in the same population. A prospective, immunohistochemistry (IHC)-based screening program for all patients with newly diagnosed CRCs and ECs was initiated in 2011 and 2013, respectively, at 2 centers (primary and tertiary). Genetic testing was recommended for those who had tumors with absent mutS homolog 2 (MSH2), MSH6, or postmeiotoic segregation increased 2 (PMS2) expression and for those who had tumors with absent mutL homolog 1 (MLH1) expression and no v-Raf murine sarcoma viral oncogene homolog B (BRAF) mutation or MLH1 promoter methylation. Amsterdam II criteria, revised Bethesda criteria, and scores from prediction models for gene mutations (the PREMM 1,2,6 and PREMM 5 prediction models) were ascertained in patients with LS. In total, 1290 patients with CRC and 484 with EC were screened for LS, and genetic testing was recommended for 137 patients (10.6%) and 32 patients (6.6%), respectively (P = .01). LS was identified in 16 patients (1.2%) with CRC and in 8 patients (1.7%) with EC. Among patients for whom genetic testing was recommended, the LS diagnosis rate was higher among those with EC (25.0% vs 11.7%, P = .052). The Amsterdam II criteria, revised Bethesda criteria, and both PREMM calculators would have missed 62.5%, 50.0%, and 12.5% of the identified patients with LS, respectively. Expanding a universal screening program for LS to include patients who had EC identified 50% more patients with LS, and many of these patients would have been missed by risk assessment tools (including PREMM 5 ). Universal screening programs for LS should include both CRC and EC. Cancer 2018. © 2018 American Cancer Society. © 2018 American Cancer Society.

Patient reported outcomes and patient empowerment in clinical genetics services.

PubMed

McAllister, M; Dearing, A

2015-08-01

Evaluation of clinical genetics services (CGS), including genetic counseling and genetic testing, has been problematic. Patient mortality and morbidity are unlikely to be directly improved by interventions offered in CGS. Patient-reported outcomes (PROs) are not routinely measured in CGS evaluation, but this may change as patient-reported outcome measures (PROMs) become a key part of how healthcare services are managed and funded across the world. However, there is no clear consensus about which PROMs are most useful for CGS evaluation. This review summarizes the published research on how PROs from CGS have been measured and how patients may benefit from using those services, with a focus on patient empowerment. Many patient benefits (PROs) identified repeatedly in the research literature can be re-interpreted within a patient empowerment framework. Other important PROs identified include family functioning, social functioning, altruism, sense of purpose, enabling development of future research and treatment/participating in research. Well-validated measures are available to capture (dimensions of) patient empowerment. Although generic measures of family functioning are available, suitable measures capturing social functioning, development of future treatments, and altruism were not identified in this review. Patient empowerment provides one useful approach to measuring PROs from CGS. © 2014 The Authors. Clinical Genetics published by John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

A Low-Cost and Simple Genetic Screening for Cystic Fibrosis Provided by the Brazilian Public Health System.

PubMed

Rispoli, Thaiane; Martins de Castro, Simone; Grandi, Tarciana; Prado, Mayara; Filippon, Letícia; Dornelles da Silva, Cláudia Maria; Vargas, José Eduardo; Rossetti, Lucia Maria Rosa

2018-05-03

Cystic fibrosis newborn screening was implemented in Brazil by the Public Health System in 2012. Because of cost, only 1 mutation was tested - p.Phe508del. We developed a robust low-cost genetic test for screening 11 CFTR gene mutations with potential use in developing countries. Copyright © 2018 Elsevier Inc. All rights reserved.

Electrochemical sensor for multiplex screening of genetically modified DNA: identification of biotech crops by logic-based biomolecular analysis.

PubMed

Liao, Wei-Ching; Chuang, Min-Chieh; Ho, Ja-An Annie

2013-12-15

Genetically modified (GM) technique, one of the modern biomolecular engineering technologies, has been deemed as profitable strategy to fight against global starvation. Yet rapid and reliable analytical method is deficient to evaluate the quality and potential risk of such resulting GM products. We herein present a biomolecular analytical system constructed with distinct biochemical activities to expedite the computational detection of genetically modified organisms (GMOs). The computational mechanism provides an alternative to the complex procedures commonly involved in the screening of GMOs. Given that the bioanalytical system is capable of processing promoter, coding and species genes, affirmative interpretations succeed to identify specified GM event in terms of both electrochemical and optical fashions. The biomolecular computational assay exhibits detection capability of genetically modified DNA below sub-nanomolar level and is found interference-free by abundant coexistence of non-GM DNA. This bioanalytical system, furthermore, sophisticates in array fashion operating multiplex screening against variable GM events. Such a biomolecular computational assay and biosensor holds great promise for rapid, cost-effective, and high-fidelity screening of GMO. Copyright © 2013 Elsevier B.V. All rights reserved.

Pre- and post-test genetic counseling for chromosomal and Mendelian disorders.

PubMed

Fonda Allen, Jill; Stoll, Katie; Bernhardt, Barbara A

2016-02-01

Genetic carrier screening, prenatal screening for aneuploidy, and prenatal diagnostic testing have expanded dramatically over the past 2 decades. Driven in part by powerful market forces, new complex testing modalities have become available after limited clinical research. The responsibility for offering these tests lies primarily on the obstetrical care provider and has become more burdensome as the number of testing options expands. Genetic testing in pregnancy is optional, and decisions about undergoing tests, as well as follow-up testing, should be informed and based on individual patients' values and needs. Careful pre- and post-test counseling is central to supporting informed decision-making. This article explores three areas of technical expansion in genetic testing: expanded carrier screening, non-invasive prenatal screening for fetal aneuploidies using cell-free DNA, and diagnostic testing using fetal chromosomal microarray testing, and provides insights aimed at enabling the obstetrical practitioner to better support patients considering these tests. Copyright © 2016 Elsevier Inc. All rights reserved.

Screening for anxiety disorders in patients with coronary artery disease.

PubMed

Bunevicius, Adomas; Staniute, Margarita; Brozaitiene, Julija; Pop, Victor J M; Neverauskas, Julius; Bunevicius, Robertas

2013-03-11

Anxiety disorders are prevalent and associated with poor prognosis in patients with coronary artery disease (CAD). However, studies examining screening of anxiety disorders in CAD patients are lacking. In the present study we evaluated the prevalence of anxiety disorders in patients with CAD and diagnostic utility of self-rating scales for screening of anxiety disorders. Five-hundred and twenty-three CAD patients not receiving psychotropic treatments at initiation of rehabilitation program completed self-rating scales (Hospital Anxiety and Depression Scale or HADS; Spielberger State-Anxiety Inventory or SSAI; and Spielberger Trait-Anxiety Inventory or STAI) and were interviewed for generalized anxiety disorder (GAD), social phobia, panic disorder and agoraphobia (Mini-International Neuropsychiatric Interview or MINI). Thirty-eight (7%) patients were diagnosed with anxiety disorder(s), including GAD (5%), social phobia (2%), agoraphobia (1%) and panic disorder (1%). Areas under the ROC curve of the HADS Anxiety subscale (HADS-A), STAI and SSAI for screening of any anxiety disorder were .81, .80 and .72, respectively. Optimal cut-off values for screening of any anxiety disorders were ≥ 8 for the HADS-A (sensitivity = 82%; specificity = 76%; and positive predictive value (PPV) = 21%); ≥ 45 for the STAI (sensitivity = 89%; specificity = 56%; and PPV = 14%); and ≥ 40 for the SSAI (sensitivity = 84%; specificity = 55%; PPV = 13%). In a subgroup of patients (n = 340) scoring below the optimal major depressive disorder screening cut-off value of HADS-Depression subscale (score <5), the HADS-A, STAI and SSAI had moderate-high sensitivity (range from 69% to 89%) and low PPVs (≤ 22%) for GAD and any anxiety disorders. Anxiety disorders are prevalent in CAD patients but can be reliably identified using self-rating scales. Anxiety self-rating scales had comparable sensitivities but the HADS-A had greater specificity and PPV when compared to the STAI and SSAI for

Viral hepatitis screening in transgender patients undergoing gender identity hormonal therapy.

PubMed

Mangla, Neeraj; Mamun, Rifat; Weisberg, Ilan S

2017-11-01

Viral hepatitis is a global health issue and can lead to cirrhosis, liver failure, and hepatocellular carcinoma. Guidelines for viral hepatitis screening in the transgender population do not exist. Transgender patients may be at higher risk for contracting viral hepatitis due to socioeconomic and behavioral factors. The aim of this study was to measure the quality of screening, prevalence, and susceptibility of viral hepatitis, and to identify barriers to screening in transgender patients undergoing gender identity hormonal therapy. LGBTQ-friendly clinic visits from transgender patients older than 18 years in New York City from 2012 to 2015 were reviewed. Approximately 13% of patients were screened for any viral hepatitis on initial consultation. Screening rates for hepatitis C virus (HCV), hepatitis B virus (HBV), and hepatitis A virus (HAV) at any point were 27, 22, and 20%. HAV screening was performed in 28% of the female to male (FtM) patients and 16% of male to female (MtF) (P<0.05) patients. HBV screening was performed in 30% of FtM patients and 18% of MtF patients (P<0.05). Thirty-one percent of FtM, 24% of MtF, and 17% of genderqueer patients were tested for HCV (P>0.05). Prevalence of HCV, HBV, and HIV in FtM was 0, 0, and 0.44% and that in MtF was 1.78, 0.89, and 1.78%, respectively. Percentage of patients immune to hepatitis A in FtM and MtF subgroups were 55 and 47% (P>0.05). Percentage of patients immune to HBV in FtM and MtF subgroups were 54 and 48% (P>0.05). This study indicates a significant lack of hepatitis screening in the transgender population and a concerning proportion of patients susceptible to disease.

A genome-wide CRISPR library for high-throughput genetic screening in Drosophila cells.

PubMed

Bassett, Andrew R; Kong, Lesheng; Liu, Ji-Long

2015-06-20

The simplicity of the CRISPR/Cas9 system of genome engineering has opened up the possibility of performing genome-wide targeted mutagenesis in cell lines, enabling screening for cellular phenotypes resulting from genetic aberrations. Drosophila cells have proven to be highly effective in identifying genes involved in cellular processes through similar screens using partial knockdown by RNAi. This is in part due to the lower degree of redundancy between genes in this organism, whilst still maintaining highly conserved gene networks and orthologs of many human disease-causing genes. The ability of CRISPR to generate genetic loss of function mutations not only increases the magnitude of any effect over currently employed RNAi techniques, but allows analysis over longer periods of time which can be critical for certain phenotypes. In this study, we have designed and built a genome-wide CRISPR library covering 13,501 genes, among which 8989 genes are targeted by three or more independent single guide RNAs (sgRNAs). Moreover, we describe strategies to monitor the population of guide RNAs by high throughput sequencing (HTS). We hope that this library will provide an invaluable resource for the community to screen loss of function mutations for cellular phenotypes, and as a source of guide RNA designs for future studies. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Genetics Home Reference: isovaleric acidemia

MedlinePlus

... Consortium of Metabolic Programs Orphanet: Isovaleric acidemia Screening, Technology, and Research in Genetics Virginia Department of Health (PDF) Patient Support and Advocacy Resources (4 links) CLIMB (Children Living With Inherited Metabolic Diseases) (UK) National Organization ...

Genetics Home Reference: propionic acidemia

MedlinePlus

... Consortium of Metabolic Programs Orphanet: Propionic acidemia Screening, Technology, and Research in Genetics Virginia Department of Health (PDF) Patient Support and Advocacy Resources (6 links) CLIMB (Children Living With Inherited Metabolic Diseases) (UK) National Organization ...

Risk of abnormal triple screen for Down syndrome is significantly higher in patients with female fetuses.

PubMed

Spong, C Y; Ghidini, A; Stanley-Christian, H; Meck, J M; Seydel, F D; Pezzullo, J C

1999-04-01

Previous studies have shown that mid-trimester maternal serum alpha-fetoprotein (AFP) levels are significantly higher and human chorionic gonadotrophin (hCG) levels significantly lower in women with male compared with female fetuses. We have evaluated whether triple-screen criteria are more likely to identify women with female fetuses as at risk for Down syndrome. From the Georgetown University genetics database we obtained the absolute values and corresponding multiples of the median (MoM) for AFP, hCG and unconjugated oestriol (uE3) in singleton gestations for the period database November 1992 July 1996. A Down syndrome risk of 1/270 or greater at mid-trimester was considered as high risk. A total of 977 patients with triple screen and outcome information were identified, including 502 female and 475 male fetuses. Patients with female fetuses were significantly more likely to have lower serum AFP (p=0.003) and a positive triple screen for Down syndrome (72 (14 per cent) versus 45 (9 per cent), p<0.02) than those with male fetuses. The gestational age at triple screen, maternal serum hCG and uE3, race and diabetes were not significantly different between the two groups. Since Down syndrome is less common in female than male fetuses, and the rates of female and male Down syndrome fetuses detected by triple screen and subsequent amniocentesis are not significantly different, the excess of positive mid-trimester maternal serum triple screen in women with female fetuses is likely due to false-positive results.

Towards a systematic nationwide screening strategy for MODY.

PubMed

Shields, Beverley; Colclough, Kevin

2017-04-01

MODY is an early-onset monogenic form of diabetes. Correctly identifying MODY is of considerable importance as diagnosing the specific genetic subtype can inform the optimal treatment, with many patients being able to discontinue unnecessary insulin treatment. Diagnostic molecular genetic testing to confirm MODY is expensive, so screening strategies are required to identify the most appropriate patients for testing. In this issue of Diabetologia, Johansson and colleagues (DOI 10.1007/s00125-016-4167-1 ) describe a nationwide systematic screening approach to identify individuals with MODY in the paediatric age range. They focused testing on patients negative for both GAD and islet antigen 2 (IA-2) islet autoantibodies, thereby ruling out those with markers of type 1 diabetes, the most common form of diabetes in this age group. This commentary discusses the advantages and limitations of the approach, and the caution required when interpreting variants of uncertain pathogenicity identified from testing whole populations rather than targeting only patients with a strong MODY phenotype.

Organizational Factors Affecting the Likelihood of Cancer Screening Among VA Patients.

PubMed

Chou, Ann F; Rose, Danielle E; Farmer, Melissa; Canelo, Ismelda; Yano, Elizabeth M

2015-12-01

Preventive service delivery, including cancer screenings, continues to pose a challenge to quality improvement efforts. Although many studies have focused on person-level characteristics associated with screening, less is known about organizational influences on cancer screening. This study aims to understand the association between organizational factors and adherence to cancer screenings. This study employed a cross-sectional design using organizational-level, patient-level, and area-level data. Dependent variables included breast, cervical, and colorectal cancer screening. Organizational factors describing resource sufficiency were constructed using factor analyses from a survey of 250 Veterans Affairs primary care directors. We conducted random-effects logistic regression analyses, modeling cancer screening as a function of organizational factors, controlling for patient-level and area-level factors. Overall, 87% of the patients received mammograms, 92% received cervical and 78% had colorectal screening. Quality improvement orientation increased the odds of cervical [odds ratio (OR): 1.27; 95% confidence interval (CI), 1.03-1.57] and colorectal cancer screening (OR: 1.10; 95% CI, 1.00-1.20). Authority in determining primary care components increased the odds of mammography screening (OR: 1.23; 95% CI, 1.03-1.51). Sufficiency in clinical staffing increased the odds of mammography and cervical cancer screenings. Several patient-level factors, serving as control variables, were associated with achievement of screenings. Resource sufficiency led to increased odds of screening possibly because they promote excellence in patient care by conveying organizational goals and facilitate goal achievement with resources. Complementary to patient-level factors, our findings identified organizational processes associated with better performance, which offer concrete strategies in which facilities can evaluate their capabilities to implement best practices to foster and

Genetic features of myelodysplastic syndrome and aplastic anemia in pediatric and young adult patients

PubMed Central

Keel, Siobán B.; Scott, Angela; Sanchez-Bonilla, Marilyn; Ho, Phoenix A.; Gulsuner, Suleyman; Pritchard, Colin C.; Abkowitz, Janis L.; King, Mary-Claire; Walsh, Tom; Shimamura, Akiko

2016-01-01

The clinical and histopathological distinctions between inherited versus acquired bone marrow failure and myelodysplastic syndromes are challenging. The identification of inherited bone marrow failure/myelodysplastic syndromes is critical to inform appropriate clinical management. To investigate whether a subset of pediatric and young adults undergoing transplant for aplastic anemia or myelodysplastic syndrome have germline mutations in bone marrow failure/myelodysplastic syndrome genes, we performed a targeted genetic screen of samples obtained between 1990–2012 from children and young adults with aplastic anemia or myelodysplastic syndrome transplanted at the Fred Hutchinson Cancer Research Center. Mutations in inherited bone marrow failure/myelodysplastic syndrome genes were found in 5.1% (5/98) of aplastic anemia patients and 13.6% (15/110) of myelodysplastic syndrome patients. While the majority of mutations were constitutional, a RUNX1 mutation present in the peripheral blood at a 51% variant allele fraction was confirmed to be somatically acquired in one myelodysplastic syndrome patient. This highlights the importance of distinguishing germline versus somatic mutations by sequencing DNA from a second tissue or from parents. Pathological mutations were present in DKC1, MPL, and TP53 among the aplastic anemia cohort, and in FANCA, GATA2, MPL, RTEL1, RUNX1, SBDS, TERT, TINF2, and TP53 among the myelodysplastic syndrome cohort. Family history or physical examination failed to reliably predict the presence of germline mutations. This study shows that while any single specific bone marrow failure/myelodysplastic syndrome genetic disorder is rare, screening for these disorders in aggregate identifies a significant subset of patients with inherited bone marrow failure/myelodysplastic syndrome. PMID:27418648

Survival of patients with symptom- and screening-detected colorectal cancer.

PubMed

Brenner, Hermann; Jansen, Lina; Ulrich, Alexis; Chang-Claude, Jenny; Hoffmeister, Michael

2016-07-12

An increasing proportion of colorectal cancer (CRC) patients are diagnosed by screening rather than symptoms. We aimed to assess and compare prognosis of patients with screen-detected CRC and symptom-detected CRC. Overall and CRC specific mortality over a median follow-up of 4.8 years was assessed according to mode of diagnosis (symptoms, screening colonoscopy, fecal occult blood test [FOBT], other) in a multi-center cohort of 2,450 CRC patients aged 50-79 years recruited in Germany in 2003-2010. 68%, 11% and 10% were detected by symptoms, screening colonoscopy and FOBT, respectively. The screen-detected cancers had a more favorable stage distribution than the symptom-detected cancers (68% versus 50% in stage I or II). Age- and sex adjusted hazard ratios (HRs) of total mortality with 95% confidence intervals (95% CIs) compared to symptom-detected cancers were 0.35 (0.24-0.50) and 0.36 (0.25-0.53) for screening colonoscopy and FOBT detected CRCs, respectively. HRs were only slightly attenuated and remained highly significant after adjustment for stage and multiple other covariates (0.50 (0.34-0.73) and 0.54 (0.37-0.80), respectively). Even stronger associations were seen for CRC specific mortality. Patients with screen-detected stage III CRC had as good CRC specific survival as patients with symptom-detected stage I or II CRC. Patients with screen-detected CRC have a very good prognosis far beyond the level explained by their more favorable stage distribution. Mode of detection is an important, easy-to-obtain proxy indicator for favorable diagnosis beyond earlier stage at diagnosis and as such may be useful for risk stratification in treatment decisions.

Survival Analysis of Patients with Interval Cancer Undergoing Gastric Cancer Screening by Endoscopy

PubMed Central

Hamashima, Chisato; Shabana, Michiko; Okamoto, Mikizo; Osaki, Yoneatsu; Kishimoto, Takuji

2015-01-01

Aims Interval cancer is a key factor that influences the effectiveness of a cancer screening program. To evaluate the impact of interval cancer on the effectiveness of endoscopic screening, the survival rates of patients with interval cancer were analyzed. Methods We performed gastric cancer-specific and all-causes survival analyses of patients with screen-detected cancer and patients with interval cancer in the endoscopic screening group and radiographic screening group using the Kaplan-Meier method. Since the screening interval was 1 year, interval cancer was defined as gastric cancer detected within 1 year after a negative result. A Cox proportional hazards model was used to investigate the risk factors associated with gastric cancer-specific and all-causes death. Results A total of 1,493 gastric cancer patients (endoscopic screening group: n = 347; radiographic screening group: n = 166; outpatient group: n = 980) were identified from the Tottori Cancer Registry from 2001 to 2008. The gastric cancer-specific survival rates were higher in the endoscopic screening group than in the radiographic screening group and the outpatients group. In the endoscopic screening group, the gastric cancer-specific survival rate of the patients with screen-detected cancer and the patients with interval cancer were nearly equal (P = 0.869). In the radiographic screening group, the gastric cancer-specific survival rate of the patients with screen-detected cancer was higher than that of the patients with interval cancer (P = 0.009). For gastric cancer-specific death, the hazard ratio of interval cancer in the endoscopic screening group was 0.216 for gastric cancer death (95%CI: 0.054-0.868) compared with the outpatient group. Conclusion The survival rate and the risk of gastric cancer death among the patients with screen-detected cancer and patients with interval cancer were not significantly different in the annual endoscopic screening. These results suggest the potential of

Clinical and molecular genetic characterization of two patients with mutations in the phosphoglucomutase 1 (PGM1) gene.

PubMed

Ding, Yu; Li, Niu; Chang, Gouying; Li, Juan; Yao, Ruen; Shen, Yiping; Wang, Jian; Huang, Xiaodong; Wang, Xiumin

2018-06-02

The phosphoglucomutase 1 (PGM1) enzyme plays a central role in glucose homeostasis by catalyzing the inter-conversion of glucose 1-phosphate and glucose 6-phosphate. Recently, PGM1 deficiency has been recognized as a cause of the congenital disorders of glycosylation (CDGs). Two Chinese Han pediatric patients with recurrent hypoglycemia, hepatopathy and growth retardation are described in this study. Targeted gene sequencing (TGS) was performed to screen for causal genetic variants in the genome of the patients and their parents to determine the genetic basis of the phenotype. DNA sequencing identified three variations of the PGM1 gene (NM_002633.2). Patient 1 had a novel homozygous mutation (c.119delT, p.Ile40Thrfs*28). In patient 2, we found a compound heterozygous mutation of c.1172G>T(p.Gly391Val) (novel) and c.1507C>T(p.Arg503*) (known pathogenic). This report deepens our understanding of the clinical features of PGM1 mutation. The early molecular genetic analysis and multisystem assessment were here found to be essential to the diagnosis of PGM1-CDG and the provision of timely and proper treatment.

Does Patient Time Spent Viewing Computer-Tailored Colorectal Cancer Screening Materials Predict Patient-Reported Discussion of Screening with Providers?

ERIC Educational Resources Information Center

Sanders, Mechelle; Fiscella, Kevin; Veazie, Peter; Dolan, James G.; Jerant, Anthony

2016-01-01

The main aim is to examine whether patients' viewing time on information about colorectal cancer (CRC) screening before a primary care physician (PCP) visit is associated with discussion of screening options during the visit. We analyzed data from a multi-center randomized controlled trial of a tailored interactive multimedia computer program…

Genetic screening in sporadic ALS and FTD.

PubMed

Turner, Martin R; Al-Chalabi, Ammar; Chio, Adriano; Hardiman, Orla; Kiernan, Matthew C; Rohrer, Jonathan D; Rowe, James; Seeley, William; Talbot, Kevin

2017-12-01

The increasing complexity of the genetic landscape in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) presents a significant resource and physician training challenge. At least 10% of those diagnosed with ALS or FTD are known to carry an autosomal dominant genetic mutation. There is no consensus on what constitutes a positive family history, and ascertainment is unreliable for many reasons. However, symptomatic individuals often wish to understand as much as possible about the cause of their disease, and to share this knowledge with their family. While the right of an individual not to know is a key aspect of patient autonomy, and despite the absence of definitive therapy, many newly diagnosed individuals are likely to elect for genetic testing if offered. It is incumbent on the practitioner to ensure that they are adequately informed, counselled and supported in this decision. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Patient navigation reduces time to care for patients with breast symptoms and abnormal screening mammograms.

PubMed

McKevitt, Elaine; Dingee, Carol; Warburton, Rebecca; Pao, Jin-Si; Brown, Carl J; Wilson, Christine; Kuusk, Urve

2018-05-01

Concern has been raised about delays for patients presenting with breast symptoms in Canada. Our objective was to determine if our Rapid Access Breast Clinic (RABC) improved care for patients presenting with breast symptoms compared to the traditional system (TS). A retrospective chart review tabulated demographic, surgical, pathology and radiologic information. Wait times to care were determined for patients presenting with symptomatic and screen detected breast problems. Time from presentation to surgeon evaluation was shorter in the RABC group for patients with breast symptoms (81 vs 35 days, p < .0001) and abnormal screens (72 vs 40 days, p = .092). Cancer patients with abnormal screens had shorter wait times than patients with breast symptoms in the TS (47 vs 70 days, p = .036). Coordination of imaging and clinical care reduces wait times in patients with both abnormal screening mammograms and symptomatic breast presentations and should be expanded in our province. Copyright © 2018 Elsevier Inc. All rights reserved.

Genetic and clinical features of false-negative infants in a neonatal screening programme for cystic fibrosis.

PubMed

Padoan, R; Genoni, S; Moretti, E; Seia, M; Giunta, A; Corbetta, C

2002-01-01

A study was performed on the delayed diagnosis of cystic fibrosis (CF) in infants who had false-negative results in a neonatal screening programme. The genetic and clinical features of false-negative infants in this screening programme were assessed together with the efficiency of the screening procedure in the Lombardia region. In total, 774,687 newborns were screened using a two-step immunoreactive trypsinogen (IRT) (in the years 1990-1992), IRT/IRT + delF508 (1993-1998) or IRT/IRT + polymerase chain reaction (PCR) and oligonucleotide ligation assay (OLA) protocol (1998-1999). Out of 196 CF children born in the 10 y period 15 were false negative on screening (7.6%) and molecular analysis showed a high variability in the genotypes. The cystic fibrosis transmembrane regulator (CFTR) gene mutations identified were delF508, D1152H, R1066C, R334W, G542X, N1303K, F1052V, A120T, 3849 + 10kbC --> T, 2789 + 5G --> A, 5T-12TG and the novel mutation D110E. In three patients no mutation was identified after denaturing gradient gel electrophoresis of the majority of CFTR gene exons. The clinical phenotypes of CF children diagnosed by their symptoms at different ages were very mild. None of them presented with a severe lung disease. The majority of them did not seem to have been damaged by the delayed diagnosis. The combination of IRT assay plus genotype analysis (1998-1999) appears to be a more reliable method of detecting CF than IRT measurement alone or combined with only the delF508 mutation.

Screening for Lynch syndrome using risk assessment criteria in patients with ovarian cancer.

PubMed

Takeda, Takashi; Tsuji, Kosuke; Banno, Kouji; Yanokura, Megumi; Kobayashi, Yusuke; Tominaga, Eiichiro; Aoki, Daisuke

2018-05-01

Lynch syndrome is a cancer predisposition syndrome caused by germline mutation of DNA mismatch repair (MMR) genes. Lynch syndrome only causes about 0.4% of cases of ovarian cancer, which suggests that universal screening may not be cost-efficient. However, the frequency of Lynch syndrome in ovarian cancer is unclear in the Asian population. The goal of the study was to investigate a screening strategy using family history. The subjects were 129 patients with ovarian cancer. Clinical and family history were collected using a self-administered questionnaire, and Society of Gynecologic Oncology (SGO) criteria 2007 and PREMM₅ were used for risk assessment. Microsatellite instability, immunohistochemistry, and methylation of MMR genes were analyzed. Of the 129 cases, 25 (19.4%) met the SGO criteria, and 4 of these 25 had MSI-high and MMR deficiency. Two cases had loss of MSH2 and MSH6, indicating MSH2 mutation, and the other two had loss of MLH1 and PMS2, including one without MLH1 methylation indicating MLH1 mutation. These results show that screening using family history can detect Lynch syndrome in 12.0% (3/25) of ovarian cancer cases. The 3 cases were positive for PREMM₅, but negative for Amsterdam II criteria and revised Bethesda guidelines. Genetic testing in one case with MSH2 and MSH6 deficiency confirmed the diagnosis of Lynch syndrome with MSH2 mutation. This is the first study of screening for Lynch syndrome in ovarian cancer using clinical and family history in an Asian population. This approach may be effective for diagnosis in these patients. Copyright © 2018. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology.

Screening for Lynch syndrome using risk assessment criteria in patients with ovarian cancer

PubMed Central

2018-01-01

Objective Lynch syndrome is a cancer predisposition syndrome caused by germline mutation of DNA mismatch repair (MMR) genes. Lynch syndrome only causes about 0.4% of cases of ovarian cancer, which suggests that universal screening may not be cost-efficient. However, the frequency of Lynch syndrome in ovarian cancer is unclear in the Asian population. The goal of the study was to investigate a screening strategy using family history. Methods The subjects were 129 patients with ovarian cancer. Clinical and family history were collected using a self-administered questionnaire, and Society of Gynecologic Oncology (SGO) criteria 2007 and PREMM5 were used for risk assessment. Microsatellite instability, immunohistochemistry, and methylation of MMR genes were analyzed. Results Of the 129 cases, 25 (19.4%) met the SGO criteria, and 4 of these 25 had MSI-high and MMR deficiency. Two cases had loss of MSH2 and MSH6, indicating MSH2 mutation, and the other two had loss of MLH1 and PMS2, including one without MLH1 methylation indicating MLH1 mutation. These results show that screening using family history can detect Lynch syndrome in 12.0% (3/25) of ovarian cancer cases. The 3 cases were positive for PREMM5, but negative for Amsterdam II criteria and revised Bethesda guidelines. Genetic testing in one case with MSH2 and MSH6 deficiency confirmed the diagnosis of Lynch syndrome with MSH2 mutation. Conclusion This is the first study of screening for Lynch syndrome in ovarian cancer using clinical and family history in an Asian population. This approach may be effective for diagnosis in these patients. PMID:29400022

Multiplex Polymerase Chain Reaction for Identification of Shigellae and Four Shigella Species Using Novel Genetic Markers Screened by Comparative Genomics.

PubMed

Kim, Hyun-Joong; Ryu, Ji-Oh; Song, Ji-Yeon; Kim, Hae-Yeong

2017-07-01

In the detection of Shigella species using molecular biological methods, previously known genetic markers for Shigella species were not sufficient to discriminate between Shigella species and diarrheagenic Escherichia coli. The purposes of this study were to screen for genetic markers of the Shigella genus and four Shigella species through comparative genomics and develop a multiplex polymerase chain reaction (PCR) for the detection of shigellae and Shigella species. A total of seven genomic DNA sequences from Shigella species were subjected to comparative genomics for the screening of genetic markers of shigellae and each Shigella species. The primer sets were designed from the screened genetic markers and evaluated using PCR with genomic DNAs from Shigella and other bacterial strains in Enterobacteriaceae. A novel Shigella quintuplex PCR, designed for the detection of Shigella genus, S. dysenteriae, S. boydii, S. flexneri, and S. sonnei, was developed from the evaluated primer sets, and its performance was demonstrated with specifically amplified results from each Shigella species. This Shigella multiplex PCR is the first to be reported with novel genetic markers developed through comparative genomics and may be a useful tool for the accurate detection of the Shigella genus and species from closely related bacteria in clinical microbiology and food safety.

Sex selection for non-medical indications: a survey of current pre-implantation genetic screening practices among U.S. ART clinics.

PubMed

Capelouto, Sarah M; Archer, Sydney R; Morris, Jerrine R; Kawwass, Jennifer F; Hipp, Heather S

2018-03-01

This study aimed to determine the current percentage of United States (U.S.) assisted reproductive technology (ART) clinics offering sex selection via pre-implantation genetic screening (PGS) for non-medical purposes. The authors conducted website review and telephone interview survey of 493 U.S. ART clinics performing in vitro fertilization (IVF) in 2017. Main outcome measures were pre-implantation genetic screening (PGS)/pre-implantation genetic diagnosis (PGD) practices and non-medical sex selection practices including family balancing. Of the 493 ART clinics in the USA, 482 clinics (97.8%) responded to our telephone interview survey. Among all U.S. ART clinics, 91.9% (n = 449) reported offering PGS and/or PGD. Furthermore, 476 clinics responded to survey questions about sex selection practices. Of those ART clinics, 72.7% (n = 346) reported offering sex selection. More specifically among those clinics offering sex selection, 93.6% (n = 324) reported performing sex selection for family balancing, and 81.2% (n = 281) reported performing for elective purposes (patient preference, regardless of rationale for the request). For couples without infertility, 83.5% (n = 289) of clinics offer sex selection for family balancing and 74.6% (n = 258) for non-specific elective reasons. The majority of U.S. ART clinics offer non-medical sex selection, a percentage that has increased substantially since last reported in 2006.

Attitude towards Pre-Marital Genetic Screening among Students of Osun State Polytechnics in Nigeria

ERIC Educational Resources Information Center

Odelola, J. O.; Adisa, O.; Akintaro, O. A.

2013-01-01

This study investigated the attitude towards pre-marital genetic screening among students of Osun State Polytechnics. Descriptive survey design was used for the study. The instrument for data collection was self developed and structured questionnaire in four-point likert scale format. Descriptive statistics of frequency count and percentages were…

A rapid screening with direct sequencing from blood samples for the diagnosis of Leigh syndrome.

PubMed

Shimbo, Hiroko; Takagi, Mariko; Okuda, Mitsuko; Tsuyusaki, Yu; Takano, Kyoko; Iai, Mizue; Yamashita, Sumimasa; Murayama, Kei; Ohtake, Akira; Goto, Yu-Ichi; Aida, Noriko; Osaka, Hitoshi

2014-01-01

Large numbers of genes are responsible for Leigh syndrome (LS), making genetic confirmation of LS difficult. We screened our patients with LS using a limited set of 21 primers encompassing the frequently reported gene for the respiratory chain complexes I (ND1-ND6, and ND4L), IV(SURF1), and V(ATP6) and the pyruvate dehydrogenase E1α-subunit. Of 18 LS patients, we identified mutations in 11 patients, including 7 in mDNA (two with ATP6), 4 in nuclear (three with SURF1). Overall, we identified mutations in 61% of LS patients (11/18 individuals) in this cohort. Sanger sequencing with our limited set of primers allowed us a rapid genetic confirmation of more than half of the LS patients and it appears to be efficient as a primary genetic screening in this cohort.

Preoperative Obstructive Sleep Apnea Screening in Gynecologic Oncology Patients.

PubMed

Harrison, Ross F; Medlin, Erin E; Petersen, Chase B; Rose, Stephen L; Hartenbach, Ellen M; Kushner, David M; Spencer, Ryan J; Rice, Laurel W; Al-Niaimi, Ahmed N

2018-05-21

Women with a gynecologic cancer tend to be older, obese, and postmenopausal, characteristics that are associated with an increased risk for obstructive sleep apnea. However, there is limited investigation regarding the condition's prevalence in this population or its impact on postoperative outcomes. In other surgical populations, patients with obstructive sleep apnea have been observed to be at increased risk for adverse postoperative events. To estimate the prevalence of obstructive sleep apnea among gynecologic oncology patients undergoing elective surgery and to investigate for a relationship between obstructive sleep apnea and postoperative outcomes. Patients referred to an academic gynecologic oncology practice were approached for enrollment in this prospective, observational study. Patients were considered eligible for study enrollment if they were scheduled for a non-emergent inpatient surgery and could provide informed consent. Enrolled patients were evaluated for a preexisting diagnosis of obstructive sleep apnea. Those without a prior diagnosis were screened using the validated, 4-item STOP [i.e. Snore loudly, daytime Tiredness, Observed apnea, elevated blood Pressure] questionnaire. All patients who screened positive for obstructive sleep apnea were referred for polysomnography. The primary outcome was the prevalence of women with obstructive sleep apnea or those who screened at high risk for the condition. Secondary outcomes examined the correlation between body mass index (kg/m 2 ) with obstructive sleep apnea and assessed for a relationship between obstructive sleep apnea and postoperative outcomes. Over a 22-month accrual period, 383 eligible patients were consecutively approached to participate in the study. A cohort of 260 patients were enrolled. A total of 33/260 patients (13%) were identified as having a previous diagnosis of obstructive sleep apnea. An additional 66/260 (25%) screened at risk for the condition using the STOP questionnaire. Of

Genetic Counselors' Perspectives About Cell-Free DNA: Experiences, Challenges, and Expectations for Obstetricians.

PubMed

Agatisa, Patricia K; Mercer, Mary Beth; Coleridge, Marissa; Farrell, Ruth M

2018-06-27

The expansion of cell-free fetal DNA (cfDNA) screening for a larger and diverse set of genetic variants, in addition for use among the low-risk obstetric population, presents important clinical challenges for all healthcare providers involved in the delivery of prenatal care. It is unclear how to leverage the different members of the healthcare team to respond to these challenges. We conducted interviews with 25 prenatal genetic counselors to understand their experience with the continued expansion of cfDNA screening. Participants supported the use of cfDNA screening for the common autosomal aneuploidies, but noted some reservations for its use to identify fetal sex and microdeletions. Participants reported several barriers to ensuring that patients have the information and support to make informed decisions about using cfDNA to screen for these different conditions. This was seen as a dual-sided problem, and necessitated additional education interventions that addressed patients seeking cfDNA screening, and obstetricians who introduce the concepts of genetic risk and cfDNA to patients. In addition, participants noted that they have a professional responsibility to educate obstetricians about cfDNA so they can be prepared to be gatekeepers of counseling and education about this screening option for use among the general obstetric population.

Clinically guided genetic screening in a large cohort of italian patients with pheochromocytomas and/or functional or nonfunctional paragangliomas.

PubMed

Mannelli, Massimo; Castellano, Maurizio; Schiavi, Francesca; Filetti, Sebastiano; Giacchè, Mara; Mori, Luigi; Pignataro, Viviana; Bernini, Gianpaolo; Giachè, Valentino; Bacca, Alessandra; Biondi, Bernadette; Corona, Giovanni; Di Trapani, Giuseppe; Grossrubatscher, Erika; Reimondo, Giuseppe; Arnaldi, Giorgio; Giacchetti, Gilberta; Veglio, Franco; Loli, Paola; Colao, Annamaria; Ambrosio, Maria Rosaria; Terzolo, Massimo; Letizia, Claudio; Ercolino, Tonino; Opocher, Giuseppe

2009-05-01

The aim of the study was to define the frequency of hereditary forms and the genotype/phenotype correlations in a large cohort of Italian patients with pheochromocytomas and/or functional or nonfunctional paragangliomas. We examined 501 consecutive patients with pheochromocytomas and/or paragangliomas (secreting or nonsecreting). Complete medical and family histories, as well as the results of clinical, laboratory, and imaging studies, were recorded in a database. Patients were divided into different groups according to their family history, the presence of lesions outside adrenals/paraganglia considered syndromic for VHL disease, MEN2, and NF1, and the number and types of pheochromocytomas and/or paragangliomas. Germ-line mutations in known susceptibility genes were investigated by gene sequencing (VHL, RET, SDHB, SDHC, SDHD) or diagnosed according to phenotype (NF1). In 160 patients younger than 50 yr with a wild-type profile, multiplex ligation-dependent probe amplification assays were performed to detect genomic rearrangements. Germline mutations were detected in 32.1% of cases, but frequencies varied widely depending on the classification criteria and ranged from 100% in patients with associated syndromic lesions to 11.6% in patients with a single tumor and a negative family history. The types and number of pheochromocytomas/paragangliomas as well as age at presentation and malignancy suggest which gene should be screened first. Genomic rearrangements were found in two of 160 patients (1.2%). The frequency of the hereditary forms of pheochromocytoma/paraganglioma varies depending on the family history and the clinical presentation. A positive family history and an accurate clinical evaluation of patients are strong indicators of which genes should be screened first.

Genetics Home Reference: carnitine-acylcarnitine translocase deficiency

MedlinePlus

... translocase deficiency Orphanet: Carnitine-acylcarnitine translocase deficiency Screening, Technology, and Research in Genetics Patient Support and Advocacy Resources (3 links) Children Living with Inherited Metabolic Diseases (CLIMB) FOD (Fatty ...

Genetics Home Reference: N-acetylglutamate synthase deficiency

MedlinePlus

... Hyperammonemia due to N-acetylglutamate synthase deficiency Screening, Technology and Research in Genetics Patient Support and Advocacy Resources (4 links) Children Living with Inherited Metabolic Diseases National Organization for ...

Colorectal Cancer in Iran: Molecular Epidemiology and Screening Strategies

PubMed Central

Dolatkhah, Roya; Somi, Mohammad Hossein; Bonyadi, Mortaza Jabbarpour; Asvadi Kermani, Iraj; Farassati, Faris; Dastgiri, Saeed

2015-01-01

Purpose. The increasing incidence of colorectal cancer (CRC) in the past three decades in Iran has made it a major public health burden. This study aimed to report its epidemiologic features, molecular genetic aspects, survival, heredity, and screening pattern in Iran. Methods. A comprehensive literature review was conducted to identify the relevant published articles. We used medical subject headings, including colorectal cancer, molecular genetics, KRAS and BRAF mutations, screening, survival, epidemiologic study, and Iran. Results. Age standardized incidence rate of Iranian CRCs was 11.6 and 10.5 for men and women, respectively. Overall five-year survival rate was 41%, and the proportion of CRC among the younger age group was higher than that of western countries. Depending on ethnicity, geographical region, dietary, and genetic predisposition, mutation genes were considerably diverse and distinct among CRCs across Iran. The high occurrence of CRC in records of relatives of CRC patients showed that family history of CRC was more common among young CRCs. Conclusion. Appropriate screening strategies for CRC which is amenable to early detection through screening, especially in relatives of CRCs, should be considered as the first step in CRC screening programs. PMID:25685149

The relative importance of patient-reported barriers to colorectal cancer screening.

PubMed

Jones, Resa M; Woolf, Steven H; Cunningham, Tina D; Johnson, Robert E; Krist, Alex H; Rothemich, Stephen F; Vernon, Sally W

2010-05-01

Colorectal cancer (CRC) screening rates are suboptimal. The most important barriers identified by patients are poorly understood. A comprehensive assessment of barriers to all recommended modalities is needed. In 2007, a questionnaire was mailed to 6100 patients, aged 50-75 years, from 12 family medicine practices in the Virginia Ambulatory Care Outcomes Research Network. People aged 65-75 years and African Americans were oversampled. Patients were asked to rate 19-21 barriers to each of four recommended tests. In 2008, responses were coded on a 5-point scale; higher scores reflected stronger barrier endorsement. The response rate was 55% (n=3357). Approximately 40% of respondents were aged >/=65 years, 30% were African-American, and 73% were adherent to screening. A clinician's failure to suggest screening and not knowing testing was necessary received the highest mean scores as barriers. Financial concerns and misconceptions were also cited. Barrier scores differed depending on whether respondents were never screened, overdue for screening, or adherent to guidelines. The top five barriers for each modality included test-specific barriers (e.g., handling stool, bowel preparation), which often outranked generic barriers to screening. Not knowing testing was necessary was a top barrier for all tests but colonoscopy. Although physician advice and awareness of the need for screening are important, barriers to screening are not homogenous across tests, and test-specific barriers warrant consideration in designing strategies to improve screening rates. Barrier scores differ by screening status, highlighting the need to address prior screening experience. Evidence that patients are more familiar with colonoscopy than with other modalities suggests an opportunity to improve screening rates by educating patients about alternative tests. 2010 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.

Considering Culture in Physician– Patient Communication During Colorectal Cancer Screening

PubMed Central

Gao, Ge; Burke, Nancy; Somkin, Carol P.; Pasick, Rena

2010-01-01

Racial and ethnic disparities exist in both incidence and stage detection of colorectal cancer (CRC). We hypothesized that cultural practices (i.e., communication norms and expectations) influence patients’ and their physicians’ understanding and talk about CRC screening. We examined 44 videotaped observations of clinic visits that included a CRC screening recommendation and transcripts from semistructured interviews that doctors and patients separately completed following the visit. We found that interpersonal relationship themes such as power distance, trust, directness/indirectness, and an ability to listen, as well as personal health beliefs, emerged as affecting patients’ definitions of provider–patient effective communication. In addition, we found that in discordant physician–patient interactions (when each is from a different ethnic group), physicians did not solicit or address cultural barriers to CRC screening and patients did not volunteer culture-related concerns regarding CRC screening. PMID:19363141

Genetics Home Reference: holocarboxylase synthetase deficiency

MedlinePlus

... holocarboxylase synthetase deficiency Orphanet: Multiple carboxylase deficiency Screening, Technology, and Research in Genetics Virginia Department of Health (PDF) Patient Support and Advocacy Resources (3 links) Children Living with Inherited Metabolic Diseases Organic Acidemia Association ...

Genetics Home Reference: beta-ketothiolase deficiency

MedlinePlus

... Beta Ketothiolase Deficiency Orphanet: Beta-ketothiolase deficiency Screening, Technology And Research in Genetics Virginia Department of Health (PDF) Patient Support and Advocacy Resources (2 links) Children Living with Inherited Metabolic Diseases Organic Acidemia Association ...

Molecular screening of ADAMTSL2 gene in 33 patients reveals the genetic heterogeneity of geleophysic dysplasia.

PubMed

Allali, Slimane; Le Goff, Carine; Pressac-Diebold, Isabelle; Pfennig, Gwendoline; Mahaut, Clémentine; Dagoneau, Nathalie; Alanay, Yasemin; Brady, Angela F; Crow, Yanick J; Devriendt, Koen; Drouin-Garraud, Valérie; Flori, Elisabeth; Geneviève, David; Hennekam, Raoul C; Hurst, Jane; Krakow, Deborah; Le Merrer, Martine; Lichtenbelt, Klaske D; Lynch, Sally A; Lyonnet, Stanislas; MacDermot, Kay; Mansour, Sahar; Megarbané, André; Santos, Heloisa G; Splitt, Miranda; Superti-Furga, Andrea; Unger, Sheila; Williams, Denise; Munnich, Arnold; Cormier-Daire, Valérie

2011-06-01

Geleophysic dysplasia (GD, OMIM 231050) is an autosomal recessive disorder characterised by short stature, small hands and feet, stiff joints, and thick skin. Patients often present with a progressive cardiac valvular disease which can lead to an early death. In a previous study including six GD families, we have mapped the disease gene on chromosome 9q34.2 and identified mutations in the A Disintegrin And Metalloproteinase with Thrombospondin repeats-like 2 gene (ADAMTSL2). Following this study, we have collected the samples of 30 additional GD families, including 33 patients and identified ADAMTSL2 mutations in 14/33 patients, comprising 13 novel mutations. The absence of mutation in 19 patients prompted us to compare the two groups of GD patients, namely group 1, patients with ADAMTSL2 mutations (n=20, also including the 6 patients from our previous study), and group 2, patients without ADAMTSL2 mutations (n=19). The main discriminating features were facial dysmorphism and tip-toe walking, which were almost constantly observed in group 1. No differences were found concerning heart involvement, skin thickness, recurrent respiratory and ear infections, bronchopulmonary insufficiency, laryngo-tracheal stenosis, deafness, and radiographic features. It is concluded that GD is a genetically heterogeneous condition. Ongoing studies will hopefully lead to the identification of another disease gene.

Screening adherence and cancer risk perceptions in colorectal cancer survivors with Lynch-like syndrome.

PubMed

Katz, L H; Burton-Chase, A M; Advani, S; Fellman, B; Polivka, K M; Yuan, Y; Lynch, P M; Peterson, S K

2016-03-01

Cancer screening recommendations for patients with Lynch-like syndrome (LLS) are not well defined. We evaluated adherence to Lynch syndrome (LS) screening recommendations, cancer risk perceptions, and communication within the families among colorectal cancer (CRC) survivors with LLS. Thirty-four participants with LLS completed a questionnaire about risk perception, adherence to LS screening recommendations, and communication with relatives. Clinical data were obtained from medical records. Most participants (76%) believed they should undergo colonoscopy every 1-2 years. Only 41% correctly interpreted their genetic tests as uninformative negative or as variant of unknown significance for LS. Less than half had had an upper gastrointestinal endoscopy for screening purpose. Among female participants, 86% had been screened for endometrial cancer (EC) and 71% for ovarian cancer. Most participants had informed relatives about the CRC diagnosis and advised them to undergo CRC screening, but only 50% advised female relatives to be screened for EC and only one-third advised relatives to have genetic counseling. Most CRC survivors with LLS follow the same cancer screening recommended for LS patients but do not understand the meaning of LLS. Greater care must be devoted to communicating the implications of nondiagnostic germline mutation testing among patients with LLS. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Screening adherence and cancer risk perceptions in colorectal cancer survivors with Lynch-like syndrome

PubMed Central

Katz, Lior H.; Burton-Chase, Allison M.; Advani, Shailesh; Fellman, Bryan; Polivka, Katrina M.; Yuan, Ying; Lynch, Patrick M.; Peterson, Susan K.

2016-01-01

Background Cancer screening recommendations for patients with Lynch-like syndrome (LLS) are not well defined. We evaluated adherence to Lynch syndrome (LS) screening recommendations, cancer risk perceptions, and communication within the families among colorectal cancer (CRC) survivors with LLS. Methods Thirty-four participants with LLS completed a questionnaire about risk perception, adherence to LS screening recommendations, and communication with relatives. Clinical data were obtained from medical records. Results Most participants (76%) believed they should undergo colonoscopy every 1-2 years. Only 41% correctly interpreted their genetic tests as uninformative negative or as variant of unknown significance for LS. Less than half had had an upper GI endoscopy for screening purpose. Among female participants, 86% had been screened for endometrial cancer and 71% for ovarian cancer. Most participants had informed relatives about the CRC diagnosis and advised them to undergo CRC screening, but only 50% advised female relatives to be screened for endometrial cancer and only one-third advised relatives to have genetic counseling. Conclusions Most CRC survivors with LLS follow the same cancer screening recommended for LS patients but do not understand the meaning of LLS. Greater care must be devoted to communicating the implications of non-diagnostic germline mutation testing among patients with LLS. PMID:26272410

Screening for Intimate Partner Violence in Orthopedic Patients: A Comparison of Three Screening Tools

ERIC Educational Resources Information Center

Sprague, Sheila; Madden, Kim; Dosanjh, Sonia; Petrisor, Brad; Schemitsch, Emil H.; Bhandari, Mohit

2012-01-01

Accurately identifying victims of intimate partner violence (IPV) can be a challenge for clinicians and clinical researchers. Multiple instruments have been developed and validated to identify IPV in patients presenting to health care practitioners, including the Woman Abuse Screening Tool (WAST) and the Partner Violence Screen (PVS). The purpose…

The UCSF screening exam effectively screens cognitive and behavioral impairment in patients with ALS.

PubMed

Murphy, Jennifer; Ahmed, Fizaa; Lomen-Hoerth, Catherine

2015-03-01

The University of California San Francisco (UCSF) Screening Battery provides clinicians with a uniquely tailored tool to measure ALS patients' cognitive and behavioral changes, adjusting for dysarthria and hand weakness. The battery consists of the ALS-CBS ( 1 ), Written Fluency Test ( 2 ), and a new revision of the Frontal Behavior Inventory (FBI-ALS) ( 3 ). The validity of each component was tested by comparing results with a gold standard neuropsychological exam (GNE). Consensus criteria-based GNE diagnoses ( 4 ) were assigned (n = 24) and concurrent validity was tested for each screening exam component. Results showed that each of the four cognitive and behavioral screening test components were significantly associated with diagnoses confirmed by GNE. GNE diagnoses were significantly associated with FBI-ALS negative score, written S-words score, and ALS-CBS cognitive score. The total FBI-ALS score and C-words tests were less predictive of GNE-diagnosed impairment. In conclusion, the UCSF Cognitive Screening Battery demonstrates good external validity compared with GNE in this modest sample, encouraging its use in larger investigations. These data suggest that this battery may provide an effective screen to identify ALS patients who will then benefit from a full examination to confirm their diagnosis.

To screen or not to screen? Celiac antibodies in liver diseases

PubMed Central

Narciso-Schiavon, Janaína Luz; Schiavon, Leonardo Lucca

2017-01-01

Celiac disease (CD) is a systemic immune-mediated disorder triggered by dietary gluten in genetically predisposed individuals. The typical symptoms are anemia, diarrhea, fatigue, weight loss, and abdominal pain. CD has been reported in patients with primary sclerosing cholangitis, primary biliary cholangitis, autoimmune hepatitis, aminotransferase elevations, nonalcoholic fatty liver disease, hepatitis B, hepatitis C, portal hypertension and liver cirrhosis. We evaluate recommendations for active screening for CD in patients with liver diseases, and the effect of a gluten-free diet in these different settings. Active screening for CD is recommended in patients with liver diseases, particularly in those with autoimmune disorders, steatosis in the absence of metabolic syndrome, noncirrhotic intrahepatic portal hypertension, cryptogenic cirrhosis, and in the context of liver transplantation. In hepatitis C, diagnosis of CD can be important as a relative contraindication to interferon use. Gluten-free diet ameliorates the symptoms associated with CD; however, the associated liver disease may improve, remain the same, or progress. PMID:28223722

A systematic variant screening in familial cases of congenital heart defects demonstrates the usefulness of molecular genetics in this field

PubMed Central

El Malti, Rajae; Liu, Hui; Doray, Bérénice; Thauvin, Christel; Maltret, Alice; Dauphin, Claire; Gonçalves-Rocha, Miguel; Teboul, Michel; Blanchet, Patricia; Roume, Joëlle; Gronier, Céline; Ducreux, Corinne; Veyrier, Magali; Marçon, François; Acar, Philippe; Lusson, Jean-René; Levy, Marilyne; Beyler, Constance; Vigneron, Jacqueline; Cordier-Alex, Marie-Pierre; Heitz, François; Sanlaville, Damien; Bonnet, Damien; Bouvagnet, Patrice

2016-01-01

The etiology of congenital heart defect (CHD) combines environmental and genetic factors. So far, there were studies reporting on the screening of a single gene on unselected CHD or on familial cases selected for specific CHD types. Our goal was to systematically screen a proband of familial cases of CHD on a set of genetic tests to evaluate the prevalence of disease-causing variant identification. A systematic screening of GATA4, NKX2-5, ZIC3 and Multiplex ligation-dependent probe amplification (MLPA) P311 Kit was setup on the proband of 154 families with at least two cases of non-syndromic CHD. Additionally, ELN screening was performed on families with supravalvular arterial stenosis. Twenty-two variants were found, but segregation analysis confirmed unambiguously the causality of 16 variants: GATA4 (1 ×), NKX2-5 (6 ×), ZIC3 (3 ×), MLPA (2 ×) and ELN (4 ×). Therefore, this approach was able to identify the causal variant in 10.4% of familial CHD cases. This study demonstrated the existence of a de novo variant even in familial CHD cases and the impact of CHD variants on adult cardiac condition even in the absence of CHD. This study showed that the systematic screening of genetic factors is useful in familial CHD cases with up to 10.4% elucidated cases. When successful, it drastically improved genetic counseling by discovering unaffected variant carriers who are at risk of transmitting their variant and are also exposed to develop cardiac complications during adulthood thus prompting long-term cardiac follow-up. This study provides an important baseline at dawning of the next-generation sequencing era. PMID:26014430

A qualitative exploration of Malaysian cancer patients' perceptions of cancer screening.

PubMed

Farooqui, Maryam; Hassali, Mohamed Azmi; Knight, Aishah; Shafie, Asrul Akmal; Farooqui, Muhammad Aslam; Saleem, Fahad; Haq, Noman-ul; Aljadhey, Hisham

2013-01-18

Despite the existence of different screening methods, the response to cancer screening is poor among Malaysians. The current study aims to examine cancer patients' perceptions of cancer screening and early diagnosis. A qualitative methodology was used to collect in-depth information from cancer patients. After obtaining institutional ethical approval, patients with different types and stages of cancer from the three major ethnic groups (Malay, Chinese and Indian) were approached. Twenty semi-structured interviews were conducted. All interviews were audiotaped, transcribed verbatim, and translated into English for thematic content analysis. Thematic content analysis yielded four major themes: awareness of cancer screening, perceived benefits of cancer screening, perceived barriers to cancer screening, and cues to action. The majority of respondents had never heard of cancer screening before their diagnosis. Some participants reported hearing about mammogram and Pap smear tests but did not undergo screening due to a lack of belief in personal susceptibility. Those who had negative results from screening prior to diagnosis perceived such tests as untrustworthy. Lack of knowledge and financial constraints were reported as barriers to cancer screening. Finally, numerous suggestions were given to improve screening behaviour among healthy individuals, including the role of mass media in disseminating the message 'prevention is better than cure'. Patients' narratives revealed some significant issues that were in line with the Health Belief Model which could explain negative health behaviour. The description of the personal experiences of people with cancer could provide many cues to action for those who have never encountered this potentially deadly disease, if incorporated into health promotion activities.

Clinical endpoints for developing pharmaceuticals to manage patients with sporadic or genetic risk of colorectal cancer

PubMed Central

Rial, Nathaniel S.; Zell, Jason A.; Cohen, Alfred M.; Gerner, Eugene W.

2013-01-01

To reduce the morbidity and mortality from colorectal cancer, current clinical practice focuses on screening for early detection and polypectomy as a form of secondary prevention, complemented with surgical interventions when appropriate. No pharmaceutical agent is currently approved for use in clinical practice for the management of patients with risk of colorectal cancer. This article will review earlier attempts to develop pharmaceuticals for use in managing patients with sporadic or genetic risk of colorectal cancer. It will also discuss therapeutic endpoints under evaluation in current efforts to develop drugs for treating colorectal cancer risk factors. PMID:22928902

Depression screening with patient-targeted feedback in cardiology: DEPSCREEN-INFO randomised clinical trial.

PubMed

Löwe, Bernd; Blankenberg, Stefan; Wegscheider, Karl; König, Hans-Helmut; Walter, Dirk; Murray, Alexandra M; Gierk, Benjamin; Kohlmann, Sebastian

2017-02-01

International guidelines advocate depression screening in patients with coronary heart disease (CHD) and other chronic illnesses, but evidence is lacking. To test the differential efficacy of written patient-targeted feedback v. no written patient feedback after depression screening. Patients with CHD or hypertension from three cardiology settings were randomised and screened for depression (ClinicalTrials.gov Identifier: NCT01879111). Compared with the control group, where only cardiologists received written feedback, in the intervention group both cardiologists and patients received written feedback regarding depression status. Depression severity was measured 1 month (primary outcome) and 6 months after screening. The control group (n = 220) and the patient-feedback group (n = 155) did not differ in depression severity 1 month after screening. Six months after screening, the patient-feedback group showed significantly greater improvements in depression severity and was twice as likely to seek information about depression compared with the control group. Patient-targeted feedback in addition to screening has a significant but small effect on depression severity after 6 months and may encourage patients to take an active role in the self-management of depression. © The Royal College of Psychiatrists 2017.

Genetics Home Reference: methylmalonic acidemia with homocystinuria

MedlinePlus

... Orphanet: Methylmalonic acidemia with homocystinuria, type cblD Screening, Technology, and Research in Genetics (STAR-G) Patient Support and Advocacy Resources (3 links) Children Living with Inherited Metabolic Diseases (CLIMB) (UK) Organic ...

Continuity of care and colorectal cancer screening by Vietnamese American patients.

PubMed

Tu, Shin-Ping; Yip, Mei-Po; Li, Lin; Chun, Alan; Taylor, Vicky; Yasui, Yutaka

2010-01-01

Colorectal cancer (CRC) screening rates among Asian Americans are 30-50% lower than among Whites. Using practice management and electronic medical records data from a community health center, we examined the association of CRC screening with continuity of care and comorbidity. These variables have not previously been studied in Asian American and limited-English proficient populations. After obtaining IRB approval, we extracted data in 2009 on age-eligible Vietnamese patients who had one or more clinic visits in the prior 24 months. Our analysis examined associations between CRC screening (per current US Preventive Services Task Force guidelines) and clinic site, demographics, insurance status, continuity of care, comorbidities, and provider characteristics. We identified a total of 1,016 eligible patients (604 at Clinic 1 and 412 at Clinic 2). Adherence to CRC screening was lower for patients who were male; lacked insurance; had only one medical visit in the past 12 months; and had no assigned primary care provider. Our multivariable models showed higher screening rates among patients who were female; had public health insurance; and had more than one medical visit in the past 12 months, regardless of high or low continuity of care. We found no association between higher continuity of care and CRC screening. Additional primary care systems research is needed to guide cancer screening interventions for limited-English proficient patients.

Depression screening: utility of the patient health questionnaire in patients with acute coronary syndrome.

PubMed

McGuire, Anthony W; Eastwood, Jo-Ann; Macabasco-O'Connell, Aurelia; Hays, Ron D; Doering, Lynn V

2013-01-01

Depression screening in cardiac patients has been recommended by the American Heart Association, but the best approach remains unclear. To evaluate nurse-administered versions of the Patient Health Questionnaire for depression screening in patients hospitalized for acute coronary syndrome. Staff nurses in an urban cardiac care unit administered versions 2, 9, and 10 of the questionnaire to 100 patients with acute coronary syndrome. The Depression Interview and Structured Hamilton was administered by advanced practice nurses blinded to the results of the Patient Health Questionnaire. With the results of the Depression Interview and Structured Hamilton as a criterion, receiver operating characteristic analyses were done for each version of the Patient Health Questionnaire. The Delong method was used for pairwise comparisons. Cutoff scores balancing false-negatives and false-positives were determined by using the Youden Index. Each version of the questionnaire had excellent area-under- the-curve statistics: 91.2%, 92.6%, and 93.4% for versions 2, 9, and 10, respectively. Differences among the 3 versions were not significant. Each version yielded higher symptom scores in depressed patients than in nondepressed patients: version 2 scores, 3.4 vs 0.6, P = .001; version 9 scores, 13 vs 3.4, P < .001; and version 10 scores, 14.5 vs 3.6, P < .001. For depression screening in hospitalized patients with acute coronary syndrome, the Patient Health Questionnaire 2 is as accurate as longer versions when administered by nurses. Further study is needed to determine if screening with this tool changes clinical decision making or improves outcomes in these patients.

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

Review of the Lynch syndrome: history, molecular genetics, screening, differential diagnosis, and medicolegal ramifications

PubMed Central

Lynch, HT; Lynch, PM; Lanspa, SJ; Snyder, CL; Lynch, JF; Boland, CR

2010-01-01

More than one million patients will manifest colorectal cancer (CRC) this year of which, conservatively, approximately 3% (~30,700 cases) will have Lynch syndrome (LS), the most common hereditary CRC predisposing syndrome. Each case belongs to a family with clinical needs that require genetic counseling, DNA testing for mismatch repair genes (most frequently MLH1 or MSH2) and screening for CRC. Colonoscopy is mandated, given CRC’s proximal occurrence (70–80% proximal to the splenic flexure). Due to its early age of onset (average 45 years of age), colonoscopy needs to start by age 25, and because of its accelerated carcinogenesis, it should be repeated every 1 to 2 years through age 40 and then annually thereafter. Should CRC occur, subtotal colectomy may be necessary, given the marked frequency of synchronous and metachronous CRC. Because 40–60% of female patients will manifest endometrial cancer, tailored management is essential. Additional extracolonic cancers include ovary, stomach, small bowel, pancreas, hepatobiliary tract, upper uroepithelial tract, brain (Turcot variant) and sebaceous adenomas/carcinomas (Muir-Torre variant). LS explains only 10–25% of familial CRC. PMID:19659756

Molecular screening of ADAMTSL2 gene in 33 patients reveals the genetic heterogeneity of geleophysic dysplasia

PubMed Central

Allali, Slimane; Le Goff, Carine; PressaceDiebold, Isabelle; Pfennig, Gwendoline; Mahaut, Clémentine; Dagoneau, Nathalie; Alanay, Yasemin; Brady, Angela F; Crow, Yanick J; Devriendt, Koen; Drouin-Garraud, Valérie; Flori, Elisabeth; Geneviève, David; Hennekam, Raoul C; Hurst, Jane; Krakow, Deborah; Le Merrer, Martine; Lichtenbelt, Klaske D; Lynch, Sally A; Lyonnet, Stanislas; MacDermot, Kay; Mansour, Sahar; Megarbané, André; Santos, Heloisa G; Splitt, Miranda; Superti-Furga, Andrea; Unger, Sheila; Williams, Denise; Munnich, Arnold; Cormier-Daire, Valérie

2012-01-01

Background Geleophysic dysplasia (GD, OMIM 231050) is an autosomal recessive disorder characterized by short stature, small hands and feet, stiff joints, and thick skin. Patients often present with a progressive cardiac valvular disease which can lead to an early death. In a previous study including six GD families, we have mapped the disease gene on chromosome 9q34.2 and identified mutations in the A Disintegrin And Metalloproteinase with Thrombospondin repeats-like 2gene (ADAMTSL2). Methods Following this study, we have collected the samples of 30 additional GD families, including 33 patients and identified ADAMTSL2 mutations in 14/33 patients, comprising 13 novel mutations. The absence of mutation in 19 patients prompted us to compare the two groups of GD patients, namely group 1, patients with ADAMTSL2 mutations (n¼20, also including the 6 patients from our previous study), and group 2, patients without ADAMTSL2 mutations (n¼19). Results The main discriminating features were facial dysmorphism and tip-toe walking, which were almost constantly observed in group 1. No differences were found concerning heart involvement, skin thickness, recurrent respiratory and ear infections, bronchopulmonary insufficiency, laryngo-tracheal stenosis, deafness, and radiographic features. Conclusions It is concluded that GD is a genetically heterogeneous condition. Ongoing studies will hopefully lead to the identification of another disease gene. PMID:21415077

Statement of The American Society of Human Genetics on cystic fibrosis carrier screening

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

Not Available

The identification in 1989 of the cystic fibrosis (CF) gene and its most common mutation immediately raised the possibility of CF carrier detection by DNA analysis. The American Society of Human Genetics (ASHG) issued a statement recommending that CF carrier testing should be made available to individuals with a family history of CF. It was also stated that screening of individuals or couples in the general population should not be offered until the rate of CF carrier detection improves. An additional prerequisite emphasized the need for the establishment of effective educational and counseling programs consistent with previous widely accepted principles.more » An NIH workshop reached similar conclusions. ASHG recommendations are that screening be limited to individuals with a family history of CF, testing should be accompanied by education and counseling, screening should be voluntary and confidential with appropriate laboratory quality controls, and efforts should be expanded to educate health care providers and the public.« less

[Screening for malnutrition among hospitalized patients in a Colombian University Hospital].

PubMed

Cruz, Viviana; Bernal, Laura; Buitrago, Giancarlo; Ruiz, Álvaro J

2017-04-01

On admission, 30 to 50% of hospitalized patients have some degree of malnutrition, which is associated with longer length of stay, higher rates of complications, mortality and greater costs. To determine the frequency of screening for risk of malnutrition in medical records and assess the usefulness of the Malnutrition Screening Tool (MST). In a cross-sectional study, we searched for malnutrition screening in medical records, and we applied the MST tool to hospitalized patients at the Internal Medicine Wards of San Ignacio University Hospital. Of 295 patients included, none had been screened for malnutrition since hospital admission. Sixty one percent were at nutritional risk, with a higher prevalence among patients with HIV (85.7%), cancer (77.5%) and pneumonia. A positive MST result was associated with a 3.2 days increase in length of hospital stay (p = 0.024). The prevalence of malnutrition risk in hospitalized patients is high, but its screening is inadequate and it is underdiagnosed. The MST tool is simple, fast, low-cost, and has a good diagnostic performance.

Should acute Q-fever patients be screened for valvulopathy to prevent endocarditis?

PubMed

de Lange, Marit M A; Gijsen, Laura E V; Wielders, Cornelia C H; van der Hoek, Wim; Scheepmaker, Arko; Schneeberger, Peter M

2018-02-20

Echocardiographic screening of acute Q-fever patients and antibiotic prophylaxis for patients with cardiac valvulopathy are considered an important approach to prevent chronic Q-fever-related endocarditis. During a large Q-fever epidemic in the Netherlands, routine screening echocardiography was discontinued, raising controversy in the international literature. We followed a cohort of acute Q-fever patients to estimate the risk for developing chronic Q-fever, and we evaluated the impact of screening in patients who were not yet known to have a valvulopathy. The study population consisted of patients diagnosed with acute Q-fever in 2007 and 2008. We retrospectively reviewed all screening echocardiographs and checked for development of chronic Q-fever eight years after the acute episode. Risks of developing chronic Q-fever in relation to the presence or absence of valvulopathy were analysed with logistic regression. The cohort included 509 patients, of whom 306 received echocardiographic screening. There was no significant difference (p-value=0.22) in occurrence of chronic Q-fever between patients with a newly detected valvulopathy (2/84, 2.4%) and those with no valvulopathy (12/202, 5.9%). Two patients with a newly detected valvulopathy, who did not receive antibiotic prophylaxis, developed chronic Q-fever at a later stage. We found no difference in outcome between patients with and without a valvulopathy newly detected by echocardiographic screening. In retrospect, the two above-mentioned patients could have benefitted from antibiotic prophylaxis, but its omission must be weighed against the unnecessary large-scale and long-term use of antibiotics that would have resulted from universal echocardiographic screening.

In person versus Computer Screening for Intimate Partner Violence Among Pregnant Patients

PubMed Central

Dado, Diane; Schussler, Sara; Hawker, Lynn; Holland, Cynthia L.; Burke, Jessica G.; Cluss, Patricia A.

2012-01-01

Objective To compare in person versus computerized screening for intimate partner violence (IPV) in a hospital-based prenatal clinic and explore women’s assessment of the screening methods. Methods We compared patient IPV disclosures on a computerized questionnaire to audio-taped first obstetric visits with an obstetric care provider and performed semi-structured interviews with patient participants who reported experiencing IPV. Results Two-hundred and fifty patient participants and 52 provider participants were in the study. Ninety-one (36%) patients disclosed IPV either via computer or in person. Of those who disclosed IPV, 60 (66%) disclosed via both methods, but 31 (34%) disclosed IPV via only one of the two methods. Twenty-three women returned for interviews. They recommended using both types together. While computerized screening was felt to be non-judgmental and more anonymous, in person screening allowed for tailored questioning and more emotional connection with the provider. Conclusion Computerized screening allowed disclosure without fear of immediate judgment. In person screening allows more flexibility in wording of questions regarding IPV and opportunity for interpersonal rapport. Practice Implications Both computerized or self-completed screening and in person screening is recommended. Providers should address IPV using non-judgmental, descriptive language, include assessments for psychological IPV, and repeat screening in person, even if no patient disclosure occurs via computer. PMID:22770815

In person versus computer screening for intimate partner violence among pregnant patients.

PubMed

Chang, Judy C; Dado, Diane; Schussler, Sara; Hawker, Lynn; Holland, Cynthia L; Burke, Jessica G; Cluss, Patricia A

2012-09-01

To compare in person versus computerized screening for intimate partner violence (IPV) in a hospital-based prenatal clinic and explore women's assessment of the screening methods. We compared patient IPV disclosures on a computerized questionnaire to audio-taped first obstetric visits with an obstetric care provider and performed semi-structured interviews with patient participants who reported experiencing IPV. Two-hundred and fifty patient participants and 52 provider participants were in the study. Ninety-one (36%) patients disclosed IPV either via computer or in person. Of those who disclosed IPV, 60 (66%) disclosed via both methods, but 31 (34%) disclosed IPV via only one of the two methods. Twenty-three women returned for interviews. They recommended using both types together. While computerized screening was felt to be non-judgmental and more anonymous, in person screening allowed for tailored questioning and more emotional connection with the provider. Computerized screening allowed disclosure without fear of immediate judgment. In person screening allows more flexibility in wording of questions regarding IPV and opportunity for interpersonal rapport. Both computerized or self-completed screening and in person screening is recommended. Providers should address IPV using non-judgmental, descriptive language, include assessments for psychological IPV, and repeat screening in person, even if no patient disclosure occurs via computer. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Integrated in vivo genetic and pharmacologic screening identifies co-inhibition of EGRF and ROCK as a potential treatment regimen for triple-negative breast cancer.

PubMed

Iskit, Sedef; Lieftink, Cor; Halonen, Pasi; Shahrabi, Aida; Possik, Patricia A; Beijersbergen, Roderick L; Peeper, Daniel S

2016-07-12

Breast cancer is the second most common cause of cancer-related deaths worldwide among women. Despite several therapeutic options, 15% of breast cancer patients succumb to the disease owing to tumor relapse and acquired therapy resistance. Particularly in triple-negative breast cancer (TNBC), developing effective treatments remains challenging owing to the lack of a common vulnerability that can be exploited by targeted approaches. We have previously shown that tumor cells have different requirements for growth in vivo than in vitro. Therefore, to discover novel drug targets for TNBC, we performed parallel in vivo and in vitro genetic shRNA dropout screens. We identified several potential drug targets that were required for tumor growth in vivo to a greater extent than in vitro. By combining pharmacologic inhibitors acting on a subset of these candidates, we identified a synergistic interaction between EGFR and ROCK inhibitors. This combination effectively reduced TNBC cell growth by inducing cell cycle arrest. These results illustrate the power of in vivo genetic screens and warrant further validation of EGFR and ROCK as combined pharmacologic targets for breast cancer.

Fall risk screening protocol for older hearing clinic patients.

PubMed

Criter, Robin E; Honaker, Julie A

2017-10-01

The primary purposes of this study were (1) to describe measures that may contrast audiology patients who fall from those who do not fall and (2) to evaluate the clinical performance of measures that could be easily used for fall risk screening in a mainstream audiology hearing clinic. Cross-sectional study Study sample: Thirty-six community-dwelling audiology patient participants and 27 community-dwelling non-audiology patients over 60 years of age. The Hearing Handicap Inventory for the Elderly (HHIE) most accurately identified patients with a recent fall (sensitivity: 76.0%), while the Dizziness Handicap Inventory (DHI) most accurately identified patients without a recent fall (specificity: 90.9%). A combination of measures used in a protocol-including HHIE, DHI, number of medications, and the Timed Up and Go test-resulted in good, accurate identification of patients with or without a recent history of falls (92.0% sensitivity, 100% specificity). This study reports good sensitivity and excellent specificity for identifying patients with and without a recent history of falls when measures were combined into a screening protocol. Despite previously reported barriers, effective fall risk screenings may be performed in hearing clinic settings with measures often readily accessible to audiologists.

Use of a patient decision aid for prenatal screening for Down syndrome: what do pregnant women say?

PubMed

Portocarrero, Maria Esther Leiva; Giguère, Anik M C; Lépine, Johanie; Garvelink, Mirjam M; Robitaille, Hubert; Delanoë, Agathe; Lévesque, Isabelle; Wilson, Brenda J; Rousseau, François; Légaré, France

2017-03-20

Patient decision aids (PtDAs) help people make difficult, values-sensitive decisions. Prenatal screening for assessing the risk of genetic conditions in the fetus is one such decision and patient decision aids are rarely used in this clinical context. We sought to identify factors influencing pregnant women's use of a patient decision aid for deciding about prenatal screening for Down syndrome (DS). This qualitative study was embedded in a sequential mixed-methods research program whose main aim is to implement shared decision-making (SDM) in the context of prenatal screening for DS in the province of Quebec, Canada. We planned to recruit a purposive sample of 45 pregnant women with low-risk pregnancy consulting for prenatal care at three clinical sites. Participating women watched a video depicting a prenatal care follow-up during which a pregnant woman, her partner and a health professional used a PtDA to decide about prenatal screening for DS. The women were then interviewed about factors that would influence the use of this PtDA using questions based on the Theoretical Domains Framework (TDF). We performed content analysis of transcribed verbatim interviews. Out of 216 eligible women, 100 agreed to participate (46% response rate) and 46 were interviewed. Regarding the type of health professional responsible for their prenatal care, 19 participants (41%) reported having made a decision about prenatal screening for DS with an obstetrician-gynecologist, 13 (28%) with a midwife, 12 (26%) with a family physician, and two (4%) decided on their own. We identified 54 factors that were mapped onto nine of the 12 TDF domains. The three most frequently-mentioned were: opinion of the pregnant woman's partner (n = 33, 72%), presentation of the PtDA by health professional and a discussion (n = 27, 72%), and not having encountered a PtDA (n = 26, 57%). This study allowed us to identify factors influencing pregnant women's use of a PtDA for prenatal screening for

Screening tests for aphasia in patients with stroke: a systematic review.

PubMed

El Hachioui, Hanane; Visch-Brink, Evy G; de Lau, Lonneke M L; van de Sandt-Koenderman, Mieke W M E; Nouwens, Femke; Koudstaal, Peter J; Dippel, Diederik W J

2017-02-01

Aphasia has a large impact on the quality of life and adds significantly to the costs of stroke care. Early recognition of aphasia in stroke patients is important for prognostication and well-timed treatment planning. We aimed to identify available screening tests for differentiating between aphasic and non-aphasic stroke patients, and to evaluate test accuracy, reliability, and feasibility. We searched PubMed, EMbase, Web of Science, and PsycINFO for published studies on screening tests aimed at assessing aphasia in stroke patients. The reference lists of the selected articles were scanned, and several experts were contacted to detect additional references. Of each screening test, we estimated the sensitivity, specificity, likelihood ratio of a positive test, likelihood ratio of a negative test, and diagnostic odds ratio (DOR), and rated the degree of bias of the validation method. We included ten studies evaluating eight screening tests. There was a large variation across studies regarding sample size, patient characteristics, and reference tests used for validation. Many papers failed to report on the consecutiveness of patient inclusion, time between aphasia onset and administration of the screening test, and blinding. Of the three studies that were rated as having an intermediate or low risk of bias, the DOR was highest for the Language Screening Test and ScreeLing. Several screening tools for aphasia in stroke are available, but many tests have not been verified properly. Methodologically sound validation studies of aphasia screening tests are needed to determine their usefulness in clinical practice.

Myositis-specific autoantibodies are specific for myositis compared to genetic muscle disease.

PubMed

Mammen, Andrew L; Casciola-Rosen, Livia; Christopher-Stine, Lisa; Lloyd, Thomas E; Wagner, Kathryn R

2015-12-01

To determine the specificity of myositis-specific autoantibodies (MSAs) for autoimmune myopathy compared with inherited muscle diseases. Serum samples from 47 patients with genetically confirmed inherited muscle diseases were screened for the most common MSAs, including those recognizing TIF1γ, NXP2, Mi2, MDA5, Jo1, SRP, and HMGCR. We compared these results with the findings in a cohort of patients with dermatomyositis (DM) previously screened for anti-TIF1γ, -NXP2, -Mi2, -MDA5, and -Jo1. Overall, the presence of anti-TIF1γ, -NXP2, -Mi2, -MDA5, or -Jo1 was 96% specific and 67% sensitive for DM compared to patients with genetic muscle diseases. No patients with inherited muscle disease had anti-SRP or anti-HMGCR autoantibodies. Only 2 patients with genetic muscle disease had a MSA. One patient with anti-Mi2 autoantibodies had both genetically confirmed facioscapulohumeral dystrophy and dermatomyositis based on a typical skin rash and partial response to immunosuppressive medications. A second patient with anti-Jo-1 autoantibodies had both genetically defined limb-girdle muscular dystrophy type 2A (i.e., calpainopathy) and a systemic autoimmune process based on biopsy-confirmed lupus nephritis, sicca symptoms, and anti-Ro52 autoantibodies. The MSAs tested for in this study are highly specific for autoimmune muscle disease and are rarely, if ever, found in patients who only have genetic muscle disease. In patients with genetic muscle disease, the presence of a MSA should suggest the possibility of a coexisting autoimmune process.

Myositis-specific autoantibodies are specific for myositis compared to genetic muscle disease

PubMed Central

Casciola-Rosen, Livia; Christopher-Stine, Lisa; Lloyd, Thomas E.; Wagner, Kathryn R.

2015-01-01

Objective: To determine the specificity of myositis-specific autoantibodies (MSAs) for autoimmune myopathy compared with inherited muscle diseases. Methods: Serum samples from 47 patients with genetically confirmed inherited muscle diseases were screened for the most common MSAs, including those recognizing TIF1γ, NXP2, Mi2, MDA5, Jo1, SRP, and HMGCR. We compared these results with the findings in a cohort of patients with dermatomyositis (DM) previously screened for anti-TIF1γ, -NXP2, -Mi2, -MDA5, and -Jo1. Results: Overall, the presence of anti-TIF1γ, -NXP2, -Mi2, -MDA5, or -Jo1 was 96% specific and 67% sensitive for DM compared to patients with genetic muscle diseases. No patients with inherited muscle disease had anti-SRP or anti-HMGCR autoantibodies. Only 2 patients with genetic muscle disease had a MSA. One patient with anti-Mi2 autoantibodies had both genetically confirmed facioscapulohumeral dystrophy and dermatomyositis based on a typical skin rash and partial response to immunosuppressive medications. A second patient with anti-Jo-1 autoantibodies had both genetically defined limb-girdle muscular dystrophy type 2A (i.e., calpainopathy) and a systemic autoimmune process based on biopsy-confirmed lupus nephritis, sicca symptoms, and anti-Ro52 autoantibodies. Conclusions: The MSAs tested for in this study are highly specific for autoimmune muscle disease and are rarely, if ever, found in patients who only have genetic muscle disease. In patients with genetic muscle disease, the presence of a MSA should suggest the possibility of a coexisting autoimmune process. PMID:26668818

Genetics Home Reference: mitochondrial trifunctional protein deficiency

MedlinePlus

... protein deficiency Orphanet: Mitochondrial trifunctional protein deficiency Screening, Technology, and Research in Genetics Virginia Department of Health (PDF) Patient Support and Advocacy Resources (4 links) Children Living with Inherited Metabolic Diseases (CLIMB) Children's Mitochondrial ...

A genetic screen for zygotic embryonic lethal mutations affecting cuticular morphology in the wasp Nasonia vitripennis.

PubMed Central

Pultz, M A; Zimmerman, K K; Alto, N M; Kaeberlein, M; Lange, S K; Pitt, J N; Reeves, N L; Zehrung, D L

2000-01-01

We have screened for zygotic embryonic lethal mutations affecting cuticular morphology in Nasonia vitripennis (Hymenoptera; Chalcidoidea). Our broad goal was to investigate the use of Nasonia for genetically surveying conservation and change in regulatory gene systems, as a means to understand the diversity of developmental strategies that have arisen during the course of evolution. Specifically, we aim to compare anteroposterior patterning gene functions in two long germ band insects, Nasonia and Drosophila. In Nasonia, unfertilized eggs develop as haploid males while fertilized eggs develop as diploid females, so the entire genome can be screened for recessive zygotic mutations by examining the progeny of F1 females. We describe 74 of >100 lines with embryonic cuticular mutant phenotypes, including representatives of coordinate, gap, pair-rule, segment polarity, homeotic, and Polycomb group functions, as well as mutants with novel phenotypes not directly comparable to those of known Drosophila genes. We conclude that Nasonia is a tractable experimental organism for comparative developmental genetic study. The mutants isolated here have begun to outline the extent of conservation and change in the genetic programs controlling embryonic patterning in Nasonia and Drosophila. PMID:10866651

The Beck Depression Inventory (BDI-II) and a single screening question as screening tools for depressive disorder in Dutch advanced cancer patients.

PubMed

Warmenhoven, Franca; van Rijswijk, Eric; Engels, Yvonne; Kan, Cornelis; Prins, Judith; van Weel, Chris; Vissers, Kris

2012-02-01

Depression is highly prevalent in advanced cancer patients, but the diagnosis of depressive disorder in patients with advanced cancer is difficult. Screening instruments could facilitate diagnosing depressive disorder in patients with advanced cancer. The aim of this study was to determine the validity of the Beck Depression Inventory (BDI-II) and a single screening question as screening tools for depressive disorder in advanced cancer patients. Patients with advanced metastatic disease, visiting the outpatient palliative care department, were asked to fill out a self-questionnaire containing the Beck Depression Inventory (BDI-II) and a single screening question "Are you feeling depressed?" The mood section of the PRIME-MD was used as a gold standard. Sixty-one patients with advanced metastatic disease were eligible to be included in the study. Complete data were obtained from 46 patients. The area under the curve of the receiver operating characteristics analysis of the BDI-II was 0.82. The optimal cut-off point of the BDI-II was 16 with a sensitivity of 90% and a specificity of 69%. The single screening question showed a sensitivity of 50% and a specificity of 94%. The BDI-II seems an adequate screening tool for a depressive disorder in advanced cancer patients. The sensitivity of a single screening question is poor.

Genetics Home Reference: isobutyryl-CoA dehydrogenase deficiency

MedlinePlus

... dehydrogenase deficiency Orphanet: Isobutyryl-CoA dehydrogenase deficiency Screening, Technology and Research in Genetics Patient Support and Advocacy Resources (3 links) Children's Cardiomyopathy Foundation CLIMB (Children Living with Inherited Metabolic ...

Genetics of pancreatic cancer and implications for therapy.

PubMed

Bhosale, Priya; Cox, Veronica; Faria, Silvana; Javadi, Sanaz; Viswanathan, Chitra; Koay, Eugene; Tamm, Eric

2018-02-01

Pancreatic cancer is a highly lethal disease with a dismal 5-year prognosis. Knowledge of its genetics may help in identifying new methods for patient screening, and cancer treatment. In this review, we will describe the most common mutations responsible for the genesis of pancreatic cancer and their impact on screening, patterns of disease progression, and therapy.

["Screening" in special situations. Assessing predictive genetic screening for hereditary breast and colorectal cancer].

PubMed

Jonas, Susanna; Wild, Claudia; Schamberger, Chantal

2003-02-01

mastectomy (PM) reduces the relative breast cancer risk by approximately 90%. The question is if PM has an impact on mortality. The acceptance of PM is culture-dependent. Colectomy can be used as a prophylactic (FAP) and therapeutic method. After surgery, the cancer risk remains high and so early detection examinations are still necessary. EVIDENCE-BASED STATEMENTS: The evidence is often fragmentary and of limited quality. For objective test result presentation information about sensitivity, specificity, positive predictive value, and number needed to screen and treat, respectively, are necessary. New identification of mutations and demand will lead to an increase of predictive genetic counselling and testing. There is a gap between predictive genetic diagnosis and prediction, prevention, early detection and surgical interventions. These circumstances require a basic strategy. Since predictive genetic diagnosis is a very sensitive issue it is important to deal with it carefully in order to avoid inappropriate hopes. Thus, media, experts and politicians need to consider opportunities and limitations in their daily decision-making processes.

Genetics Home Reference: glutaric acidemia type I

MedlinePlus

... Acidemia I Orphanet: Glutaryl-CoA dehydrogenase deficiency Screening, Technology and Research in Genetics Virginia Department of Health (PDF) Patient Support and Advocacy Resources (3 links) Children Living with Inherited Metabolic Diseases (CLIMB) National Organization ...

[Screening for bipolar disorder in primary care patients with psychological symptoms].

PubMed

Aragonès, Enric; López-Rodríguez, Juan A; Escobar-Rabadán, Francisco; Téllez-Lapeira, Juan; Mínguez, José; Párraga, Ignacio; Suárez-Hernández, Tatiana; Piñero, María José; Guzón, Marta-Magdalena

2015-03-01

To estimate the proportion of positive results in the screening of bipolar disorder (BD) among primary care patients presenting with psychological symptoms, and to analyze their characteristics. Multicenter cross-sectional study. Nineteen Primary Care clinics in different Spanish regions. A total of 360 consecutive primary care patients aged 18 to 70, presenting with psychological symptoms. Screening for BP was performed by means of the Mood Disorders Questionnaire. Data on quality of life (EuroQol-5D) and functional impairment (Sheehan Disability Inventory) were obtained. Data on psychiatric comorbidity and data on the use of psychotropic medication were acquired by review of medical records. Of the patients screened, 11.9% were positive (95%CI: 8.8%-15.7%). Only two patients had a diagnosis of BP in their clinical records and, although more than half received treatment with antidepressants, only two received treatment with mood stabilizers. Positive screening is associated with work, social and family dysfunction, greater perceived stress and poor quality of life. BD screening in primary care patients with psychological problems leads to a striking proportion of positive results, indicating that there may be a significant prevalence of BP patients, most of them undiagnosed and untreated. Further research is needed to determine the role that Primary Care can or should assume in the screening, diagnosis and management of this disorder. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

Why hasn't this patient been screened for colon cancer? An Iowa Research Network study.

PubMed

Levy, Barcey T; Nordin, Terri; Sinift, Suzanne; Rosenbaum, Marcy; James, Paul A

2007-01-01

Less than half of eligible Americans have been screened for colorectal cancer (CRC). The objective of this study was to describe physicians' reasons for screening or not screening specific patients for CRC and their approach to CRC testing discussions. This study used mixed-methods. Physicians described their reasons for screening or not screening 6 randomly chosen patients who were eligible for CRC screening (3 screened and 3 not screened) whose CRC testing status was ascertained by medical record review. Verbatim transcripts from physicians responding to structured interview questions were used to identify themes. Specific elements of discussion were examined for their association with each physician's screening rate. Fifteen randomly chosen Iowa family physicians from the Iowa Research Network stratified by privileges to perform colonoscopy, flexible sigmoidoscopy, or neither procedure dictated the reasons why 43 patients were screened and 40 patients were not screened. Reasons patients were not up to date fell into 2 major categories: (1) no discussion by physician (50%) and (2) patient refusal (43%). Reasons for no discussion included lack of opportunity, assessment that cost would be prohibitive, distraction by other life issues/health problems, physician forgetfulness, and expected patient refusal. Patients declined because of cost, lack of interest, autonomy, other life issues, fear of screening, and lack of symptoms. Patients who were up to date received (1) diagnostic testing (for previous colon pathology or symptoms; 56%) or (2) asymptomatic screening (44%). Physicians who were more adamant about screening had higher screening rates (P<.05; Wilcoxon rank sum). Physicians framed their recommendations differently ("I recommend" vs "They recommend"), with lower screening rates among physicians who used "they recommend" (P=.05; Wilcoxon rank sum). Reasons many patients remain unscreened for CRC include (1) factors related to the health care system, patient

Genetics of congenital hypogonadotropic hypogonadism in Denmark.

PubMed

Tommiska, Johanna; Känsäkoski, Johanna; Christiansen, Peter; Jørgensen, Niels; Lawaetz, Jacob Gerner; Juul, Anders; Raivio, Taneli

2014-07-01

Congenital hypogonadotropic hypogonadism (CHH) is a rare disorder characterized by incomplete/absent puberty caused by deficiency or defective action of gonadotropin-releasing hormone (GnRH). The phenotypic features of patients with CHH vary from genital hypoplasia and absent puberty to reversal of HH later in life. We examined the genetics and clinical features of CHH in Denmark. Forty-one male patients were screened for mutations in KAL1, FGFR1, FGF8, PROK2, PROKR2, GNRHR, TAC3, TACR3, and KISS1R. CHD7 was screened in two patients with hearing loss. In 12 patients, a molecular genetic cause for CHH was found. Four patients had mutations in KAL1 (C105VfsX13, C53X, ex5-8del, R257X), and five in FGFR1 (G97S, R209C, A512V, R646W, and c.1614C>T, (p.I538I), predicted to affect splicing). All 9 had severe HH (cryptorchidism and/or micropenis), and 2 had cleft lip/palate. One patient with a previously reported homozygous R262Q mutation in GNRHR displayed fascinating temporal variation in his phenotype. Two patients with hearing loss had CHD7 mutations (c.7832_7841del (p.K2611MfsX25) and c.2443-2A>C), confirming that CHH patients with CHARGE syndrome-associated features should be screened for mutations in CHD7. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Genome-wide recessive genetic screening in mammalian cells with a lentiviral CRISPR-guide RNA library.

PubMed

Koike-Yusa, Hiroko; Li, Yilong; Tan, E-Pien; Velasco-Herrera, Martin Del Castillo; Yusa, Kosuke

2014-03-01

Identification of genes influencing a phenotype of interest is frequently achieved through genetic screening by RNA interference (RNAi) or knockouts. However, RNAi may only achieve partial depletion of gene activity, and knockout-based screens are difficult in diploid mammalian cells. Here we took advantage of the efficiency and high throughput of genome editing based on type II, clustered, regularly interspaced, short palindromic repeats (CRISPR)-CRISPR-associated (Cas) systems to introduce genome-wide targeted mutations in mouse embryonic stem cells (ESCs). We designed 87,897 guide RNAs (gRNAs) targeting 19,150 mouse protein-coding genes and used a lentiviral vector to express these gRNAs in ESCs that constitutively express Cas9. Screening the resulting ESC mutant libraries for resistance to either Clostridium septicum alpha-toxin or 6-thioguanine identified 27 known and 4 previously unknown genes implicated in these phenotypes. Our results demonstrate the potential for efficient loss-of-function screening using the CRISPR-Cas9 system.

Patients and Computers as Reminders to Screen for Diabetes in Family Practice

PubMed Central

Kenealy, Tim; Arroll, Bruce; Petrie, Keith J

2005-01-01

Background In New Zealand, more than 5% of people aged 50 years and older have undiagnosed diabetes; most of them attend family practitioners (FPs) at least once a year. Objectives To test the effectiveness of patients or computers as reminders to screen for diabetes in patients attending FPs. Design A randomized-controlled trial compared screening rates in 4 intervention arms: patient reminders, computer reminders, both reminders, and usual care. The trial lasted 2 months. The patient reminder was a diabetes risk self-assessment sheet filled in by patients and given to the FP during the consultation. The computer reminder was an icon that flashed only for patients considered eligible for screening. Participants One hundred and seven FPs. Measurements The primary outcome was whether each eligible patient, who attended during the trial, was or was not tested for blood glucose. Analysis was by intention to treat and allowed for clustering by FP. Results Patient reminders (odds ratio [OR] 1.72, 95% confidence interval [CI] 1.21, 2.43), computer reminders (OR 2.55, 1.68, 3.88), and both reminders (OR 1.69, 1.11, 2.59) were all effective compared with usual care. Computer reminders were more effective than patient reminders (OR 1.49, 1.07, 2.07). Patients were more likely to be screened if they visited the FP repeatedly, if patients were non-European, if they were “regular” patients of the practice, and if their FP had a higher screening rate prior to the study. Conclusions Patient and computer reminders were effective methods to increase screening for diabetes. However, the effects were not additive. PMID:16191138

Development and validation of duplex, triplex, and pentaplex real-time PCR screening assays for the detection of genetically modified organisms in food and feed.

PubMed

Huber, Ingrid; Block, Annette; Sebah, Daniela; Debode, Frédéric; Morisset, Dany; Grohmann, Lutz; Berben, Gilbert; Stebih, Dejan; Milavec, Mojca; Zel, Jana; Busch, Ulrich

2013-10-30

Worldwide, qualitative methods based on PCR are most commonly used as screening tools for genetically modified material in food and feed. However, the increasing number and diversity of genetically modified organisms (GMO) require effective methods for simultaneously detecting several genetic elements marking the presence of transgenic events. Herein we describe the development and validation of a pentaplex, as well as complementary triplex and duplex real-time PCR assays, for the detection of the most common screening elements found in commercialized GMOs: P-35S, T-nos, ctp2-cp4-epsps, bar, and pat. The use of these screening assays allows the coverage of many GMO events globally approved for commercialization. Each multiplex real-time PCR assay shows high specificity and sensitivity with an absolute limit of detection below 20 copies for the targeted sequences. We demonstrate by intra- and interlaboratory tests that the assays are robust as well as cost- and time-effective for GMO screening if applied in routine GMO analysis.

Screening for substance abuse risk in cancer patients using the Opioid Risk Tool and urine drug screen.

PubMed

Barclay, Joshua S; Owens, Justine E; Blackhall, Leslie J

2014-07-01

The use of opioids for management of cancer-related pain has increased significantly and has been associated with a substantial rise in rates of substance abuse and diversion. There is a paucity of data not only on the prevalence of substance abuse in cancer patients, but also for issues of drug use and diversion in family caregivers. This study aimed to evaluate the frequency of risk factors for substance abuse and diversion, and abnormal urine drug screens in cancer patients receiving palliative care. A retrospective chart review was performed for patients with cancer who were seen in the University of Virginia Palliative Care Clinic during the month of September 2012. We evaluated Opioid Risk Tool variables and total scores, insurance status, and urine drug screen results. Of the 114 cancer patients seen in September 2012, the mean Opioid Risk Tool score was 3.79, with 43% of patients defined as medium to high risk. Age (16-45 years old, 23%) and a personal history of alcohol (23%) or illicit drugs (21%) were the most common risk factors identified. We obtained a urine drug screen on 40% of patients, noting abnormal findings in 45.65%. Opioids are an effective treatment for cancer-related pain, yet substantial risk for substance abuse exits in the cancer population. Screening tools, such as the Opioid Risk Tool, should be used as part of a complete patient assessment to balance risk with appropriate relief of suffering.

Identification of Spen as a Crucial Factor for Xist Function through Forward Genetic Screening in Haploid Embryonic Stem Cells

PubMed Central

Monfort, Asun; Di Minin, Giulio; Postlmayr, Andreas; Freimann, Remo; Arieti, Fabiana; Thore, Stéphane; Wutz, Anton

2015-01-01

Summary In mammals, the noncoding Xist RNA triggers transcriptional silencing of one of the two X chromosomes in female cells. Here, we report a genetic screen for silencing factors in X chromosome inactivation using haploid mouse embryonic stem cells (ESCs) that carry an engineered selectable reporter system. This system was able to identify several candidate factors that are genetically required for chromosomal repression by Xist. Among the list of candidates, we identify the RNA-binding protein Spen, the homolog of split ends. Independent validation through gene deletion in ESCs confirms that Spen is required for gene repression by Xist. However, Spen is not required for Xist RNA localization and the recruitment of chromatin modifications, including Polycomb protein Ezh2. The identification of Spen opens avenues for further investigation into the gene-silencing pathway of Xist and shows the usefulness of haploid ESCs for genetic screening of epigenetic pathways. PMID:26190100

Use of preimplantation genetic diagnosis and preimplantation genetic screening in the United States: a Society for Assisted Reproductive Technology Writing Group paper.

PubMed

Ginsburg, Elizabeth S; Baker, Valerie L; Racowsky, Catherine; Wantman, Ethan; Goldfarb, James; Stern, Judy E

2011-10-01

To comprehensively report Society for Assisted Reproductive Technology (SART) member program usage of preimplantation genetic testing (PGT), preimplantation genetic diagnosis (PGD) for diagnosis of specific conditions, and preimplantation genetic screening for aneuploidy (PGS). Retrospective study. United States SART cohort data. Women undergoing a PGT cycle in which at least one embryo underwent biopsy. PGT. PGT use, indications, and delivery rates. Of 190,260 fresh, nondonor assisted reproductive technology (ART) cycles reported to SART CORS in 2007-2008, 8,337 included PGT. Of 6,971 cycles with a defined indication, 1,382 cycles were for genetic diagnosis, 3,645 for aneuploidy screening (PGS), 527 for translocation, and 1,417 for elective sex election. Although the total number of fresh, autologous cycles increased by 3.6% from 2007 to 2008, the percentage of cycles with PGT decreased by 5.8% (4,293 in 2007 and 4,044 in 2008). As a percentage of fresh, nondonor ART cycles, use dropped from 4.6% (4,293/93,433) in 2007 to 4.2% (4,044/96,827) in 2008. The primary indication for PGT was PGS: cycles performed for this indication decreased (-8.0%). PGD use for single-gene defects (+3.2%), elective sex selection (+5.3%), and translocation analysis (+0.5%) increased. PGT usage varied significantly by geographical region. PGT usage in the United States decreased between 2007 and 2008 owing to a decrease in PGS. Use of elective sex selection increased. High transfer cancellation rates correlated with reduced live-birth rates for some PGT indications. Copyright © 2011 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Familial Breast/Ovarian Cancer and BRCA1/2 Genetic Screening: The Role of Immunohistochemistry as an Additional Method in the Selection of Patients

PubMed Central

Vaz, Fátima H.; Machado, Patrícia M.; Brandão, Rita D.; Laranjeira, Cátia T.; Eugénio, Joana S.; Fernandes, Aires H.; André, Saudade P.

2007-01-01

Only 20–25% of families screened for BRCA1/2 mutations are found positive. Because only a positive result is informative, we studied the role of BRCA1/2 immunohistochemistry as an additional method for patient selection. From 53 high-risk-affected probands, 18 (34%) had available paraffin blocks of their tumors and were selected for this study. Mutation screening was done by conformation-sensitive gel electrophoresis and multiplex ligation-dependent probe amplification. For immunohistochemistry, 21 neoplastic specimens (15 breast carcinomas, 5 ovary neoplasms, and 1 rectal adenocarcinoma) were analyzed with BRCA1 (monoclonal antibody, Ab-1, oncogene) and BRCA2 (polyclonal antibody, Ab-2, oncogene) antibodies. Absence of the BRCA1 protein was confirmed in negative tumors by Western blotting. Seven patients were positive for BRCA1/2 mutations: 5 for BRCA1 and 2 for BRCA2. Four out of five positive patients had tumors negative for BRCA1 immunostaining, and the remaining 13 BRCA1-negative patients had positive BRCA1 immunostaining in all tumor samples. Sensitivity to predict for BRCA1 mutation carriers was 80%, and specificity was 100%, with a positive predictive value of 100% and a negative predictive value of 93%. This correlation was statistically significant (p=0.001). No correlation was observed for BRCA2. If larger studies confirm these results, high-risk patients with BRCA1-negative tumors should be screened first for this gene. PMID:17625228

Patient compliance based on genetic medicine: a literature review.

PubMed

Schneider, Kai Insa; Schmidtke, Jörg

2014-01-01

For this literature review, medical literature data bases were searched for studies on patient compliance after genetic risk assessment. The review focused on conditions where secondary or tertiary preventive options exist, namely cancer syndromes (BRCA-related cancer, HNPCC/colon cancer), hemochromatosis, thrombophilia, smoking cessation, and obesity. As a counterpart, patient compliance was assessed regarding medication adherence and medical advice in some of the most epidemiologically important conditions (including high blood pressure, metabolic syndrome, and coronary heart disease) after receiving medical advice based on nongenetic risk information or a combination of genetic and nongenetic risk information. In the majority of studies based on genetic risk assessments, patients were confronted with predictive rather than diagnostic genetic profiles. Most of the studies started from a knowledge base around 10 years ago when DNA testing was at an early stage, limited in scope and specificity, and costly. The major result is that overall compliance of patients after receiving a high-risk estimate from genetic testing for a given condition is high. However, significant behavior change does not take place just because the analyte is "genetic." Many more factors play a role in the complex process of behavioral tuning. Without adequate counseling and guidance, patients may interpret risk estimates of predictive genetic testing with an increase in fear and anxiety.

Patient-completed or symptom-based screening tools for endometriosis: a scoping review.

PubMed

Surrey, Eric; Carter, Cathryn M; Soliman, Ahmed M; Khan, Shahnaz; DiBenedetti, Dana B; Snabes, Michael C

2017-08-01

The objective of this review was to evaluate existing patient-completed screening questionnaires and/or symptom-based predictive models with respect to their potential for use as screening tools for endometriosis in adult women. Validated instruments were of particular interest. We conducted structured searches of PubMed and targeted searches of the gray literature to identify studies reporting on screening instruments used in endometriosis. Studies were screened according to inclusion and exclusion criteria that followed the PICOS (population, intervention, comparison, outcomes, study design) framework. A total of 16 studies were identified, of which 10 described measures for endometriosis in general, 2 described measures for endometriosis at specific sites, and 4 described measures for deep-infiltrating endometriosis. Only 1 study evaluated a questionnaire that was solely patient-completed. Most measures required physician, imaging, or laboratory assessments in addition to patient-completed questionnaires, and several measures relied on complex scoring. Validation for use as a screening tool in adult women with potential endometriosis was lacking in all studies, as most studies focused on diagnosis versus screening. This literature review did not identify any fully validated, symptom-based, patient-reported questionnaires for endometriosis screening in adult women.

Development of an inter-professional screening instrument for cancer patients' education process.

PubMed

Vaartio-Rajalin, Heli; Huumonen, Tuula; Iire, Liisa; Jekunen, Antti; Leino-Kilpi, Helena; Minn, Heikki; Paloniemi, Jenni; Zabalegui, Adelaida

2016-02-01

The aim of this paper is to describe the development of an inter-professional screening instrument for cancer patients' cognitive resources, knowledge expectations and inter-professional collaboration within patient education. Four empirical datasets during 2012-2014 were analyzed in order to identify main categories, subcategories and items for inter-professional screening instrument. Our inter-professional screening instrument integrates the critical moments of cancer patient education and the knowledge expectation types obtained from patient datasets to assessment of patients' cognitive resources, knowledge expectations and comprehension; and intra; and inter-professional. Copyright © 2015 Elsevier Inc. All rights reserved.

Genetic screening of non-classic CAH females with hyperandrogenemia identifies a novel CYP11B1 gene mutation.

PubMed

Shammas, Christos; Byrou, Stefania; Phelan, Marie M; Toumba, Meropi; Stylianou, Charilaos; Skordis, Nicos; Neocleous, Vassos; Phylactou, Leonidas A

2016-04-01

Congenital adrenal hyperplasia (CAH) is an endocrine autosomal recessive disorder with various symptoms of diverse severity. Mild hyperandrogenemia is the most commonclinical feature in non-classic CAH patients and 95% of the cases are identified by mutations in the CYP21A2 gene. In the present study, the second most common cause for non-classic CAH (NC-CAH), 11β-hydroxylase deficiency due to mutations in the CYP11B1 gene, is investigated. Screening of the CYP21A2 and CYP11B1 genes by direct sequencing was carried out for the detection of possible genetic defects in patients with suspected CAH. It wasobserved that CYP11B1 variants co-exist only in rare cases along with mutations in CYP21A2 in patients clinically diagnosed with CAH. A total of 23 NC-CAH female patients out of 75 were identified with only one mutation in the CYP21A2 gene. The novel CYP11B1 gene mutation, p.Val484Asp, was identified in a patient with CAH in the heterozygous state. The structural characterization of the novel p.Val484Asp was found to likely cause distortion of the surrounding beta sheet and indirect destabilization of the cavity that occurs on the opposite face of the structural elements, leading to partial impairment of the enzymatic activity. CYP21A2 gene mutations are the most frequent genetic defects in cases of NC-CAH even when these patients are in the heterozygous state. These mutations have a diverse phenotype giving rise to a variable extent of cortisol synthesis impairment; it is also clear that CYP11B1 mutants are a rare type of defects causing CAH.

Screening of female family members of von Willebrand disease patients: utility of a modified screening tool in a high-risk population.

PubMed

Faiz, A S; Kaveney, A; Guo, S; Murphy, S; Philipp, C S

2017-09-01

Family members of Von Willebrand disease (VWD) patients may have low levels of VWF without major bleeding episodes and often remain undiagnosed. The purpose of this study was to assess the utility of a modified Screening Tool in identifying previously untested reproductive age female family members of VWD patients for haemostatic evaluation. Ninety-four reproductive age women including 41 previously untested family members of VWD patients, 26 previously diagnosed VWD patients and 27 healthy controls were administered a modified Screening Tool and had blood drawn for CBC, ferritin, and VWF testing. Participants completed a pictorial blood assessment chart (PBAC) with menses. The modified Screening Tool was positive in 32% family members, 77% VWD patients, and 19% controls (P < 0.001). Combined with low ferritin, the modified Screening Tool was positive in 66% family members, 92% VWD patients, and 44% controls (P = 0.001). In family members, incorporating low ferritin with the modified Screening Tool resulted in a sensitivity of 86% (95% CI, 42-100) and negative predictive value of 93% (95% CI, 66-100). In the control group, NPV was between 92% and 95% for the modified Screening Tool and also for the modified Screening Tool combined with low ferritin or a positive PBAC. These data in a racially diverse population suggest the usefulness of a simple, easy to administer modified Screening Tool. In conjunction with ferritin it could be used in a primary care setting to stratify reproductive age women with a family history of VWD for haemostatic evaluation. © 2017 John Wiley & Sons Ltd.

Integrating high-throughput genetic interaction mapping and high-content screening to explore yeast spindle morphogenesis

PubMed Central

Vizeacoumar, Franco J.; van Dyk, Nydia; S.Vizeacoumar, Frederick; Cheung, Vincent; Li, Jingjing; Sydorskyy, Yaroslav; Case, Nicolle; Li, Zhijian; Datti, Alessandro; Nislow, Corey; Raught, Brian; Zhang, Zhaolei; Frey, Brendan; Bloom, Kerry

2010-01-01

We describe the application of a novel screening approach that combines automated yeast genetics, synthetic genetic array (SGA) analysis, and a high-content screening (HCS) system to examine mitotic spindle morphogenesis. We measured numerous spindle and cellular morphological parameters in thousands of single mutants and corresponding sensitized double mutants lacking genes known to be involved in spindle function. We focused on a subset of genes that appear to define a highly conserved mitotic spindle disassembly pathway, which is known to involve Ipl1p, the yeast aurora B kinase, as well as the cell cycle regulatory networks mitotic exit network (MEN) and fourteen early anaphase release (FEAR). We also dissected the function of the kinetochore protein Mcm21p, showing that sumoylation of Mcm21p regulates the enrichment of Ipl1p and other chromosomal passenger proteins to the spindle midzone to mediate spindle disassembly. Although we focused on spindle disassembly in a proof-of-principle study, our integrated HCS-SGA method can be applied to virtually any pathway, making it a powerful means for identifying specific cellular functions. PMID:20065090

Screening for secondary endocrine hypertension in young patients.

PubMed

Trifanescu, Raluca; Carsote, Mara; Caragheorgheopol, Andra; Hortopan, Dan; Dumitrascu, Anda; Dobrescu, Mariana; Poiana, Catalina

2013-06-01

Secondary endocrine hypertension accounts for 5-12% of hypertension's causes. In selected patients (type 2 diabetes mellitus, sleep apnea syndrome with resistant hypertension, sudden deterioration in hypertension control), prevalence could be higher. To present etiology of endocrine secondary hypertension in a series of patients younger than 40 years at hypertension's onset. Medical records of 80 patients (39M/41F), aged 30.1 ± 8.2 years (range: 12-40 years), with maximum systolic blood pressure=190.4 ± 29.2 mm Hg, range: 145-300 mm Hg, maximum diastolic blood pressure=107.7 ± 16.9 mm Hg, range: 80-170 mm Hg) referred by cardiologists for endocrine hypertension screening were retrospectively reviewed. Cardiac and renal causes of secondary hypertension were previously excluded. In all patients, plasma catecholamines were measured by ELISA and plasma cortisol by immunochemiluminescence. Orthostatic aldosterone (ELISA) and direct renin (chemiluminescence) were measured in 48 patients. Secondary endocrine hypertension was confirmed in 16 out of 80 patients (20%). Primary hyperaldosteronism was diagnosed in 7 (4M/3F) out of 48 screened patients (14.6%). i.e. 8.75% from whole group: 5 patients with adrenal tumors (3 left/2 right), 2 patients with bilateral adrenal hyperplasia; all patients were hypokalemic at diagnostic (average nadir K+ levels = 2.5 ± 0.5 mmol/L); four patients were hypokalaemic on diuretic therapy (indapamidum); other 3 patients were hypokalaemic in the absence of diuretic therapy. Cushing's syndrome was diagnosed in 6 patients (7.5%): subclinical Cushing due to 4 cm right adrenal tumour - n = 1, overt ACTH-independent Cushing's syndrome due to: macronodular adrenal hyperplasia associated with primary hyperparathyroidism - n = 1; due to adrenal carcinoma - n = 1; due to adrenal adenomas - n = 2; Cushing's disease - n = 1). Pheochromocytomas were diagnosed in 3 patients (3.75%). Primary hyperaldosteronism was the most frequent cause of secondary

HIV screening among newly diagnosed TB patients: a cross sectional study in Lima, Peru.

PubMed

Ramírez, Suzanne; Mejía, Fernando; Rojas, Marlene; Seas, Carlos; Van der Stuyft, Patrick; Gotuzzo, Eduardo; Otero, Larissa

2018-03-20

Since 2006, the Peruvian National TB program (NTP) recommends voluntary counseling and testing (VCT) for all tuberculosis (TB) patients. Responding to the differential burden of both diseases in Peru, TB is managed in peripheral health facilities while HIV is managed in referral centers. This study aims to determine the coverage of HIV screening among TB patients and the characteristics of persons not screened. From March 2010 to December 2011 we enrolled new smear-positive pulmonary TB adults in 34 health facilities in a district in Lima. NTP staff offered VCT to all TB patients. Patients with an HIV positive result were referred for confirmation tests and management. We interviewed patients to collect their demographic and clinical characteristics and registered if patients opted in or out of the screening. Of the 1295 enrolled TB patients, nine had a known HIV diagnosis. Of the remaining, 76.1% (979) were screened for HIV. Among the 23.9% (307) not screened, 38.4% (118) opted out of the screening. TB patients at one of the health care facilities of the higher areas of the district (OR = 3.38, CI 95% 2.17-5.28 for the highest area and OR = 2.82, CI 95% 1.78-4.49 for the high area) as well as those reporting illegal drug consumption (OR = 1.65, CI 95% 1.15-2.37) were more likely not to be screened. Twenty-four were HIV positive (1.9% of all patients 1295, or 2.4% of those screened). Of 15 patients diagnosed with HIV during the TB episode, ten were enrolled in an HIV program. The median time between the result of the HIV screening and the first consultation at the HIV program was 82 days (IQR, 32-414). The median time between the result of the HIV screening and antiretroviral initiation was 148.5 days (IQR 32-500). An acceptable proportion of TB patients were screened for HIV in Lima. Referral systems of HIV positive patients should be strengthened for timely ART initiation.

Genetic testing in congenital heart disease: A clinical approach

PubMed Central

Chaix, Marie A; Andelfinger, Gregor; Khairy, Paul

2016-01-01

Congenital heart disease (CHD) is the most common type of birth defect. Traditionally, a polygenic model defined by the interaction of multiple genes and environmental factors was hypothesized to account for different forms of CHD. It is now understood that the contribution of genetics to CHD extends beyond a single unified paradigm. For example, monogenic models and chromosomal abnormalities have been associated with various syndromic and non-syndromic forms of CHD. In such instances, genetic investigation and testing may potentially play an important role in clinical care. A family tree with a detailed phenotypic description serves as the initial screening tool to identify potentially inherited defects and to guide further genetic investigation. The selection of a genetic test is contingent upon the particular diagnostic hypothesis generated by clinical examination. Genetic investigation in CHD may carry the potential to improve prognosis by yielding valuable information with regards to personalized medical care, confidence in the clinical diagnosis, and/or targeted patient follow-up. Moreover, genetic assessment may serve as a tool to predict recurrence risk, define the pattern of inheritance within a family, and evaluate the need for further family screening. In some circumstances, prenatal or preimplantation genetic screening could identify fetuses or embryos at high risk for CHD. Although genetics may appear to constitute a highly specialized sector of cardiology, basic knowledge regarding inheritance patterns, recurrence risks, and available screening and diagnostic tools, including their strengths and limitations, could assist the treating physician in providing sound counsel. PMID:26981213

Development of a Mobile Tool That Semiautomatically Screens Patients for Stroke Clinical Trials.

PubMed

Spokoyny, Ilana; Lansberg, Maarten; Thiessen, Rosita; Kemp, Stephanie M; Aksoy, Didem; Lee, YongJae; Mlynash, Michael; Hirsch, Karen G

2016-10-01

Despite several national coordinated research networks, enrollment in many cerebrovascular trials remains challenging. An electronic tool was needed that would improve the efficiency and efficacy of screening for multiple simultaneous acute clinical stroke trials by automating the evaluation of inclusion and exclusion criteria, improving screening procedures and streamlining the communication process between the stroke research coordinators and the stroke clinicians. A multidisciplinary group consisting of physicians, study coordinators, and biostatisticians designed and developed an electronic clinical trial screening tool on a HIPAA (Health Insurance Portability and Accountability Act)-compliant platform. A web-based tool was developed that uses branch logic to determine eligibility for simultaneously enrolling clinical trials and automatically notifies the study coordinator teams about eligible patients. After 12 weeks of use, 225 surveys were completed, and 51 patients were enrolled in acute stroke clinical trials. Compared with the 12 weeks before implementation of the tool, there was an increase in enrollment from 16.5% of patients screened to 23.4% of patients screened (P<0.05). Clinicians and coordinators reported increased satisfaction with the process and improved ease of screening. We created a semiautomated electronic screening tool that uses branch logic to screen patients for stroke clinical trials. The tool has improved efficiency and efficacy of screening, and it could be adapted for use at other sites and in other medical fields. © 2016 American Heart Association, Inc.

Optimization of PSA screening policies: a comparison of the patient and societal perspectives.

PubMed

Zhang, Jingyu; Denton, Brian T; Balasubramanian, Hari; Shah, Nilay D; Inman, Brant A

2012-01-01

To estimate the benefit of PSA-based screening for prostate cancer from the patient and societal perspectives. A partially observable Markov decision process model was used to optimize PSA screening decisions. Age-specific prostate cancer incidence rates and the mortality rates from prostate cancer and competing causes were considered. The model trades off the potential benefit of early detection with the cost of screening and loss of patient quality of life due to screening and treatment. PSA testing and biopsy decisions are made based on the patient's probability of having prostate cancer. Probabilities are inferred based on the patient's complete PSA history using Bayesian updating. The results of all PSA tests and biopsies done in Olmsted County, Minnesota, from 1993 to 2005 (11,872 men and 50,589 PSA test results). Patients' perspective: to maximize expected quality-adjusted life years (QALYs); societal perspective: to maximize the expected monetary value based on societal willingness to pay for QALYs and the cost of PSA testing, prostate biopsies, and treatment. From the patient perspective, the optimal policy recommends stopping PSA testing and biopsy at age 76. From the societal perspective, the stopping age is 71. The expected incremental benefit of optimal screening over the traditional guideline of annual PSA screening with threshold 4.0 ng/mL for biopsy is estimated to be 0.165 QALYs per person from the patient perspective and 0.161 QALYs per person from the societal perspective. PSA screening based on traditional guidelines is found to be worse than no screening at all. PSA testing done with traditional guidelines underperforms and therefore underestimates the potential benefit of screening. Optimal screening guidelines differ significantly depending on the perspective of the decision maker.

Newborn Screening for Lysosomal Storage Disorders: Views of Genetic Healthcare Providers.

PubMed

Lisi, Emily C; McCandless, Shawn E

2016-04-01

Lysosomal storage diseases (LSDs), lysosomal enzyme deficiencies causing multi-system organ damage, have come to the forefront in newborn screening (NBS) initiatives due to new screening technologies and emerging treatments. We developed a qualitative discussion tool to explore opinions of genetic healthcare providers (HCPs) regarding population-based NBS for MPS types 1 and 2, Pompe, Gaucher, Fabry, and Krabbe diseases. Thirty-eight telephone interviews conducted by a single researcher were analyzed and coded for thematic trends. Six major themes emerged: 1) treatment availability and efficacy is crucial; 2) early age of disease onset is important; 3) ambiguity regarding prognosis is undesirable; 4) parents' ability to make reproductive decisions is seen by some as a benefit of NBS; 5) paucity of resources for follow-up exists; and 6) the decision-making process for adding conditions to mandated NBS is concerning to HCPs. Among the LSDs discussed, Pompe was considered most appropriate, and Krabbe least appropriate, for NBS. MPS1 and MPS2 were overall considered favorably for screening, but MPS1 ranked higher, due to a perception of better efficacy of therapeutic options. Fabry and Gaucher diseases were viewed less favorably due to later age of onset. The themes identified in this study must be addressed by decision-makers in expanding NBS for LSDs and may be applied to many diseases being considered for NBS in the future.

Effects of Screening for Psychological Distress on Patient Outcomes in Cancer: a Systematic Review

PubMed Central

Meijer, Anna; Roseman, Michelle; Delisle, Vanessa C.; Milette, Katherine; Levis, Brooke; Syamchandra, Achyuth; Stefanek, Michael E.; Stewart, Donna E.; de Jonge, Peter; Coyne, James C.; Thombs, Brett D.

2013-01-01

Objective Several practice guidelines recommend routine screening for psychological distress in cancer care. The objective was to evaluate the effect of screening cancer patients for psychological distress by assessing the (1) effectiveness of interventions to reduce distress among patients identified as distressed; and (2) effects of screening for distress on distress outcomes. Methods CINAHL, Cochrane, EMBASE, ISI, MEDLINE, PsycINFO, and SCOPUS databases were searched through April 6, 2011 with manual searches of 45 relevant journals, reference list review, citation tracking of included articles, and trial registry reviews through June 30, 2012. Articles in any language on cancer patients were included if they (1) compared treatment for patients with psychological distress to placebo or usual care in a randomized controlled trial (RCT); or (2) assessed the effect of screening on psychological distress in a RCT. Results There were 14 eligible RCTs for treatment of distress, and 1 RCT on the effects of screening on patient distress. Pharmacological, psychotherapy and collaborative care interventions generally reduced distress with small to moderate effects. One study investigated effects of screening for distress on psychological outcomes, and it found no improvement. Conclusion Treatment studies reported modest improvement in distress symptoms, but only a single eligible study was found on the effects of screening cancer patients for distress, and distress did not improve in screened patients versus those receiving usual care. Because of the lack of evidence of beneficial effects of screening cancer patients for distress, it is premature to recommend or mandate implementation of routine screening. PMID:23751231

The Rising Incidence of Younger Patients With Colorectal Cancer: Questions About Screening, Biology, and Treatment.

PubMed

Connell, Louise C; Mota, José Mauricio; Braghiroli, Maria Ignez; Hoff, Paulo M

2017-04-01

Colorectal cancer (CRC) is the third leading cancer diagnosed globally and an important cause of cancer-related mortality. Of interest, while we have witnessed a declining incidence trend over the past few decades in the older population, incidence rates for adolescents and young adults have been increasing steadily. Several factors may well explain this apparent epidemic in the young, namely a lack of routine screening and emerging lifestyle issues such as obesity, lack of exercise, and dietary factors. It is known that both environmental and genetic factors can increase the likelihood of developing CRC. Although inherited susceptibility is associated with the most striking increases in risk, and must always be considered in a young patient with CRC, the majority of CRCs are in fact sporadic rather than familial. Early-onset CRC is a truly heterogeneous disease, with mounting evidence to suggest that this patient population has a distinctive molecular profile, very different to late-onset CRC cases. Currently, both younger and older patients with CRC are treated in essentially the same manner, but with a better understanding of the molecular mechanisms underlying CRC in the young, we will have the opportunity to specifically tailor screening and clinical management strategies in this unique patient population in an effort to improve outcomes. The aim of this review is to outline our current knowledge of the distinguishing features of early-onset CRC, the ongoing research efforts, and the evolving evidence in this field.

[Chemical-genetics based screening for furanonaphthoquinone producing endophytic actinomycetes from seeds of Trewia nudiflora].

PubMed

Li, Fang; Kang, Qianjin; Yao, Xiaoling; Li, Yanyan; Wei, Maolong; Cao, Yong; Lin, Shuangjun; Bai, Linquan; Ma, Wei; Deng, Zixin

2012-04-04

The seeds of Trewia nudiflora containing maytansine (an anticancer agent), was investigated to explore the endophytic actinomycetes diversity and screen for naphthoquinones producing strain. The seeds of Trewia nudiflora were sliced and plated on different selective media after surface sterilization. Clones that looked like actinomycetes were selected, and classified according to the 16S rRNA sequences. Isolated strains were screened for furanonaphthoquinone biosynthesis gene by PCR, and tested for antibacterial and antifungal activity using Staphyloccocusaureus, Pseudomon-asaeruginosa, Bacillus subtilis, Rhizoctoniasolani and Gibberellasaubinetii. LC-MS and NMR were used to determine the structure of candidate compounds. More than 100 endophytic bacteria were isolated. Among them 66 were streptomycetes. FNQ6 (polyketide synthase Type III) and FNQ21 (carboxymuconate cycloisomerase) were only detected in Streptomyces sp. HTZ 27. We got 5 mg pure furanonaphthoquinone (FNQI) from 1 liter Streptomyces sp. HTZ 27 agar fermentation medium. The use of chemical-genetics method increased the efficiency of screening for target compound producing bacteria.

Pre-implantation genetic screening using fluorescence in situ hybridization in couples of Indian ethnicity: Is there a scope?

PubMed Central

Saxena, Shailaja Gada; Desai, Kundanbala; Shewale, Lata; Ranjan, Prabhat

2014-01-01

CONTEXT: There is a high incidence of numerical chromosomal aberration in couples with repeated in vitro fertilization (IVF) failure, advanced maternal age, repeated unexplained abortions, severe male factor infertility and unexplained infertility. Pre-implantation genetic screening (PGS), a variant of pre-implantation genetic diagnosis, screens numerical chromosomal aberrations in couples with normal karyotype, experiencing poor reproductive outcome. The present study includes the results of the initial pilot study on 9 couples who underwent 10 PGS cycles. AIM: The aim of the present study was to evaluate the beneficial effects of PGS in couples with poor reproductive outcome. SETTINGS AND DESIGN: Data of initial 9 couples who underwent 10 PGS for various indications was evaluated. SUBJECTS AND METHODS: Blastomere biopsy was performed on cleavage stage embryos and subjected to two round fluorescence in situ hybridization (FISH) testing for chromosomes 13, 18, 21, X and Y as a two-step procedure. RESULTS: Six of the 9 couples (10 PGS cycles) conceived, including a twin pregnancy in a couple with male factor infertility, singleton pregnancies in a couple with secondary infertility, in three couples with adverse obstetric outcome in earlier pregnancies and in one couple with repeated IVF failure. CONCLUSION: In the absence of availability of array-comparative genomic hybridization in diagnostic clinical scenario for PGS and promising results with FISH based PGS as evident from the current pilot study, it is imperative to offer the best available services in the present scenario for better pregnancy outcome for patients. PMID:24829527

"Is It Worth Knowing?" Focus Group Participants' Perceived Utility of Genomic Preconception Carrier Screening.

PubMed

Schneider, Jennifer L; Goddard, Katrina A B; Davis, James; Wilfond, Benjamin; Kauffman, Tia L; Reiss, Jacob A; Gilmore, Marian; Himes, Patricia; Lynch, Frances L; Leo, Michael C; McMullen, Carmit

2016-02-01

As genome sequencing technology advances, research is needed to guide decision-making about what results can or should be offered to patients in different clinical settings. We conducted three focus groups with individuals who had prior preconception genetic testing experience to explore perceived advantages and disadvantages of genome sequencing for preconception carrier screening, compared to usual care. Using a discussion guide, a trained qualitative moderator facilitated the audio-recorded focus groups. Sixteen individuals participated. Thematic analysis of transcripts started with a grounded approach and subsequently focused on participants' perceptions of the value of genetic information. Analysis uncovered two orientations toward genomic preconception carrier screening: "certain" individuals desiring all possible screening information; and "hesitant" individuals who were more cautious about its value. Participants revealed valuable information about barriers to screening: fear/anxiety about results; concerns about the method of returning results; concerns about screening necessity; and concerns about partner participation. All participants recommended offering choice to patients to enhance the value of screening and reduce barriers. Overall, two groups of likely users of genome sequencing for preconception carrier screening demonstrated different perceptions of the advantages or disadvantages of screening, suggesting tailored approaches to education, consent, and counseling may be warranted with each group.

Gestational surrogacy and the role of routine embryo screening: Current challenges and future directions for preimplantation genetic testing.

PubMed

Sills, E Scott; Anderson, Robert E; McCaffrey, Mary; Li, Xiang; Arrach, Nabil; Wood, Samuel H

2016-03-01

Preimplantation genetic screening (PGS) is a component of IVF entailing selection of an embryo for transfer on the basis of chromosomal normalcy. If PGS were integrated with single embryo transfer (SET) in a surrogacy setting, this approach could improve pregnancy rates, minimize miscarriage risk, and limit multiple gestations. Even without PGS, pregnancy rates for IVF surrogacy cases are generally satisfactory, especially when treatment utilizes embryos derived from young oocytes and transferred to a healthy surrogate. However, there could be a more general role for PGS in surrogacy, since background aneuploidy in embryos remains a major factor driving implantation failure and miscarriage for all infertility patients. At present, the proportion of IVF cases involving GS is limited, while the number of IVF patients requesting PGS appears to be increasing. In this report, the relevance of PGS for surrogacy in the rapidly changing field of assisted fertility medicine is discussed. © 2015 Wiley Periodicals, Inc.

Screening for genetic causes of growth hormone hypersecretion.

PubMed

Rostomyan, Liliya; Beckers, Albert

Growth hormone (GH) secreting pituitary tumors may be caused by genetic abnormalities in a variety of genes including AIP, MEN1, CDKN1B, and PRKAR1A. These can lead to GH secreting pituitary adenomas as an isolated occurrence (e.g. as aggressive sporadic adenomas or in familial isolated pituitary adenomas (FIPA)) or as part of syndromic conditions such as MEN1 or Carney complex. These tumors have more aggressive features than sporadic acromegaly, including a younger age at disease onset and larger tumor size, and they can be challenging to manage. In addition to mutations or deletions, copy number variation at the GPR101 locus may also lead to mixed GH and prolactin secreting pituitary adenomas in the setting of X-linked acrogigantism (X-LAG syndrome). In X-LAG syndrome and in McCune Albright syndrome, mosaicism for GPR101 duplications and activating GNAS1 mutations, respectively, contribute to the genetic pathogenesis. As only 5% of pituitary adenomas have a known cause, efficient deployment of genetic testing requires detailed knowledge of clinical characteristics and potential associated syndromic features in the patient and their family. Copyright © 2016 Elsevier Ltd. All rights reserved.

Hepatitis A and B screening and vaccination rates among patients with chronic liver disease.

PubMed

Ramirez, Jonathan C; Ackerman, Kimberly; Strain, Sasha C; Ahmed, Syed T; de Los Santos, Mario J; Sears, Dawn

2016-01-01

Vaccinations against hepatitis A virus (HAV) and hepatitis B virus (HBV) are recommended for patients with chronic liver disease (CLD), yet implementation of these recommendations is lacking. This study reviewed HAV and HBV antibody testing and vaccination status of patients with CLD. In 2008, we began using pre-printed liver order sets, which included vaccination options. We compared Scott & White liver clinic CLD patient records from 2005 (238) with patient records from 2008 (792). Screening rates for immunity and vaccination rates of those lacking immunity were calculated. In 2005, 66% of CLD patients were screened for HAV immunity. In 2008, 56% of CLD patients were screened. The HAV vaccination completion rate was 37% in 2005, while in 2008, the rate was 46%. In 2005, 66% of CLD patients were screened for HBV immunity; in 2008, 56 % CLD patients were screened. The HBV vaccination completion rate was 26% in 2005 compared with 36% in 2008. Although there was a lower percentage of screening in 2008, the overall number of patients tripled between 2005 and 2008. There was a significant increase in the total number of patients screened and vaccinated in 2008. Some physicians may have vaccinated their patients without checking for immunity. In January 2008, we implemented pre-printed order sets with checkboxes to help remind providers to order labs to screen for immunity against HAV and HBV and to order vaccinations for those who lacked immunity. The use of these sets may have aided in the increase of vaccination completion rates.

Genetics Home Reference: 5q minus syndrome

MedlinePlus

... in patients with del(5q) myelodysplastic syndromes: linking mechanism of action to clinical outcomes. Ann Hematol. 2014 Jan;93( ... Celebrates Its 15th Anniversary Genetic Information Non-Discrimination Act (GINA) Turns 10 All ... is newborn screening? New Pages Lyme disease ...

Patient navigation to improve breast cancer screening in Bosnian refugees and immigrants.

PubMed

Percac-Lima, Sanja; Milosavljevic, Bosiljka; Oo, Sarah Abernethy; Marable, Danelle; Bond, Barbara

2012-08-01

Refugee women have low breast cancer screening rates. This study highlights the culturally competent implementation and reports the outcomes of a breast cancer screening patient navigation program for refuge/immigrant women from Bosnia. Refugees/immigrant women from Bosnia age 40-79 were contacted by a Serbo-Croatian speaking patient navigator who addressed patient-reported barriers to breast cancer screening and, using individually tailored interventions, helped women obtain screening. The proportion of women up-to-date for mammography was compared at baseline and after 1-year using McNemar's Chi-Square test. 91 Serbo-Croatian speaking women were eligible for mammography screening. At baseline, 44.0% of women had a mammogram within the previous year, with the proportion increasing to 67.0% after 1-year (P = 0.001). A culturally-tailored, language-concordant navigator program designed to overcome specific barriers to breast cancer screening can significantly improve mammography rates in refugees/immigrants.

Development and interlaboratory validation of quantitative polymerase chain reaction method for screening analysis of genetically modified soybeans.

PubMed

Takabatake, Reona; Onishi, Mari; Koiwa, Tomohiro; Futo, Satoshi; Minegishi, Yasutaka; Akiyama, Hiroshi; Teshima, Reiko; Kurashima, Takeyo; Mano, Junichi; Furui, Satoshi; Kitta, Kazumi

2013-01-01

A novel real-time polymerase chain reaction (PCR)-based quantitative screening method was developed for three genetically modified soybeans: RRS, A2704-12, and MON89788. The 35S promoter (P35S) of cauliflower mosaic virus is introduced into RRS and A2704-12 but not MON89788. We then designed a screening method comprised of the combination of the quantification of P35S and the event-specific quantification of MON89788. The conversion factor (Cf) required to convert the amount of a genetically modified organism (GMO) from a copy number ratio to a weight ratio was determined experimentally. The trueness and precision were evaluated as the bias and reproducibility of relative standard deviation (RSDR), respectively. The determined RSDR values for the method were less than 25% for both targets. We consider that the developed method would be suitable for the simple detection and approximate quantification of GMO.

Circadian variations of transferrin saturation levels in iron-overloaded patients: implications for the screening of C282Y-linked haemochromatosis.

PubMed

Guillygomarc'h, Anne; Christian, Jacquelinet; Romain, Moirand; Vincent, Quentin; Véronique, David; Deugnier, Yves

2003-01-01

The phenotypic screening for genetic haemochromatosis (GH) relies upon the determination of transferrin saturation (TS). In large-scale screening programs, the time of blood sampling can be uneasy to control. We studied the circadian variations of TS at 08.00 hours, 12.00 hours, 18.00 hours and 00.00 hours in 46 C282Y homozygous patients (GH) and 47 non-GH patients (NH), to determine whether the time of blood sampling influenced the results of screening. In both groups, there were significant circadian variations in TS, with the highest values at 08.00 hours and the lowest at 00.00 hours. For any given time-point, TS was significantly higher in the GH group when compared with the NH group (P < 0.0001). For both groups, there was a significant decrease in TS between 08.00 hours and 00.00 hours (P < 0.0001) but this decrease was not as significant in GH when compared with NH patients (interaction P < 0.0073). Receiver operating characteristics (ROC) curves generated for TS at 08.00 hours, 12.00 hours, 18.00 hours and 00.00 hours, presented the same efficiency of diagnosis of GH, with TS threshold varying between 64% at 08.00 hours and 36% at 00.00 hours. In conclusion, for screening studies of C282Y homozygosity, determination of transferrin saturation may be performed at any time during the day.

Genetics Home Reference: 3-hydroxyacyl-CoA dehydrogenase deficiency

MedlinePlus

... short chain 3-hydroxylacyl-CoA dehydrogenase deficiency Screening, Technology and Research in Genetics (STAR-G) Patient Support and Advocacy Resources (3 links) Children Living with Inherited Metabolic Diseases (CLIMB) FOD (Fatty ...

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

Predictive Accuracy of the Liverpool Lung Project Risk Model for Stratifying Patients for Computed Tomography Screening for Lung Cancer

PubMed Central

Raji, Olaide Y.; Duffy, Stephen W.; Agbaje, Olorunshola F.; Baker, Stuart G.; Christiani, David C.; Cassidy, Adrian; Field, John K.

2013-01-01

Background External validation of existing lung cancer risk prediction models is limited. Using such models in clinical practice to guide the referral of patients for computed tomography (CT) screening for lung cancer depends on external validation and evidence of predicted clinical benefit. Objective To evaluate the discrimination of the Liverpool Lung Project (LLP) risk model and demonstrate its predicted benefit for stratifying patients for CT screening by using data from 3 independent studies from Europe and North America. Design Case–control and prospective cohort study. Setting Europe and North America. Patients Participants in the European Early Lung Cancer (EUELC) and Harvard case–control studies and the LLP population-based prospective cohort (LLPC) study. Measurements 5-year absolute risks for lung cancer predicted by the LLP model. Results The LLP risk model had good discrimination in both the Harvard (area under the receiver-operating characteristic curve [AUC], 0.76 [95% CI, 0.75 to 0.78]) and the LLPC (AUC, 0.82 [CI, 0.80 to 0.85]) studies and modest discrimination in the EUELC (AUC, 0.67 [CI, 0.64 to 0.69]) study. The decision utility analysis, which incorporates the harms and benefit of using a risk model to make clinical decisions, indicates that the LLP risk model performed better than smoking duration or family history alone in stratifying high-risk patients for lung cancer CT screening. Limitations The model cannot assess whether including other risk factors, such as lung function or genetic markers, would improve accuracy. Lack of information on asbestos exposure in the LLPC limited the ability to validate the complete LLP risk model. Conclusion Validation of the LLP risk model in 3 independent external data sets demonstrated good discrimination and evidence of predicted benefits for stratifying patients for lung cancer CT screening. Further studies are needed to prospectively evaluate model performance and evaluate the optimal population

Integration of geriatric mental health screening into a primary care practice: a patient satisfaction survey.

PubMed

Samuels, S; Abrams, R; Shengelia, R; Reid, M C; Goralewicz, R; Breckman, R; Anderson, M A; Snow, C E; Woods, E C; Stern, A; Eimicke, J P; Adelman, R D

2015-05-01

Colocation of mental health screening, assessment, and treatment in primary care reduces stigma, improves access, and increases coordination of care between mental health and primary care providers. However, little information exists regarding older adults' attitudes about screening for mental health problems in primary care. The objective of this study was to evaluate older primary care patients' acceptance of and satisfaction with screening for depression and anxiety. The study was conducted at an urban, academically affiliated primary care practice serving older adults. Study patients (N = 107) were screened for depression/anxiety and underwent a post-screening survey/interview to assess their reactions to the screening experience. Most patients (88.6%) found the length of the screening to be "just right." A majority found the screening questions somewhat or very acceptable (73.4%) and not at all difficult (81.9%). Most participants did not find the questions stressful (84.9%) or intrusive (91.5%); and a majority were not at all embarrassed (93.4%), upset (93.4%), or uncomfortable (88.8%) during the screening process. When asked about frequency of screening, most patients (72.4%) desired screening for depression/anxiety yearly or more. Of the 79 patients who had spoken with their physicians about mental health during the visit, 89.8% reported that it was easy or very easy to talk with their physicians about depression/anxiety. Multivariate results showed that patients with higher anxiety had a lower positive reaction to the screen when controlling for gender, age, and patient-physician communication. These results demonstrate strong patient support for depression and anxiety screening in primary care. Copyright © 2014 John Wiley & Sons, Ltd.

Intent to treat analysis of in vitro fertilization and preimplantation genetic screening versus expectant management in patients with recurrent pregnancy loss.

PubMed

Murugappan, Gayathree; Shahine, Lora K; Perfetto, Candice O; Hickok, Lee R; Lathi, Ruth B

2016-08-01

In an intent to treat analysis, are clinical outcomes improved in recurrent pregnancy loss (RPL) patients undergoing IVF and preimplantation genetic screening (PGS) compared with patients who are expectantly managed (EM)? Among all attempts at PGS or EM among RPL patients, clinical outcomes including pregnancy rate, live birth (LB) rate and clinical miscarriage (CM) rate were similar. The standard of care for management of patients with RPL is EM. Due to the prevalence of aneuploidy in CM, PGS has been proposed as an alternate strategy for reducing CM rates and improving LB rates. Retrospective cohort study of 300 RPL patients treated between 2009 and 2014. Among two academic fertility centers, 112 RPL patients desired PGS and 188 patients chose EM. Main outcomes measured were pregnancy rate and LB per attempt and CM rate per pregnancy. One attempt was defined as an IVF cycle followed by a fresh embryo transfer or a frozen embryo transfer (PGS group) and 6 months trying to conceive (EM group). In the IVF group, 168 retrievals were performed and 38 cycles canceled their planned PGS. Cycles in which PGS was intended but cancelled had a significantly lower LB rate (15 versus 36%, P = 0.01) and higher CM rate (50 versus 14%, P < 0.01) compared with cycles that completed PGS despite similar maternal ages. Of the 130 completed PGS cycles, 74% (n = 96) yielded at least one euploid embryo. Clinical pregnancy rate per euploid embryo transfer was 72% and LB rate per euploid embryo transfer was 57%. Among all attempts at PGS or EM, clinical outcomes were similar. Median time to pregnancy was 6.5 months in the PGS group and 3.0 months in the EM group. The largest limitation is the retrospective study design, in which patients who elected for IVF/PGS may have had different clinical prognoses than patients who elected for expectant management. In addition, the definition of one attempt at conception for PGS and EM groups was different between the groups and can introduce

Screening UBQLN-2 in French frontotemporal lobar degeneration and frontotemporal lobar degeneration-amyotrophic lateral sclerosis patients.

PubMed

Lattante, Serena; Le Ber, Isabelle; Camuzat, Agnès; Pariente, Jérémie; Brice, Alexis; Kabashi, Edor

2013-08-01

The ubiquilin-2 gene (UBQLN-2) is the only amyotrophic lateral sclerosis (ALS)-related gene mapping on the X chromosome. Mutations in the PXX domain of UBQLN-2 have been first described in ALS patients with a mutational frequency of 2.6% in familial ALS cases with no evidence of male-to-male transmission. Different populations have been further tested with mutations largely distributed in the gene and lower frequency of positive cases. To determine the genetic contribution of UBQLN-2 in frontotemporal lobar degeneration (FTLD) and FTLD-ALS, we screened a cohort of 136 French patients, identifying a missense variant (c.1006A>G; p.T336A) in 1 FTLD patient whose biological relevance to disease is questionable. We conclude that UBQLN-2 mutations related to ALS/FTLD are extremely rare in French FTLD and FTLD-ALS patients and should not be analyzed systematically. Copyright © 2013. Published by Elsevier Inc.

Improved 5-year survival of patients with immunochemical faecal blood test-screen-detected colorectal cancer versus non-screening cancers in northern Italy.

PubMed

Parente, Fabrizio; Vailati, Cristian; Boemo, Cinzia; Bonoldi, Emanuela; Ardizzoia, Antonio; Ilardo, Antonina; Tortorella, Franco; Cereda, Danilo; Cremaschini, Marco; Moretti, Roberto

2015-01-01

Colorectal cancer screening may reduce disease-related mortality by early-stage detection of cancers. To study the effect of a single immunochemical faecal occult blood test (i-FOBt) screening round on reduction in colorectal cancer-related-mortality among average risk subjects. Comparison of 5-year mortality rates in 3 cohorts from a Northern Italian province: (1) colorectal cancers detected at the 1st biennial round of a mass-screening programme targeting 50-69 years old subjects, (2) non-screening cancers symptomatically diagnosed during the same time period, and (3) cancers detected in the pre-screening biennium. Multivariate analyses were performed with the Cox regression model including tumour node metastasis (TNM) stage at diagnosis, anatomical distribution of cancers, age at diagnosis, gender and patient group. Kaplan-Meyer survival estimates and log-rank test for equality of survivor functions were calculated. Stage distribution significantly differed between screening and non-screening colorectal cancers: 73% of screen-detected colorectal cancers were stages I and II versus 43% and 40% of non-screening and pre-screening colorectal cancers. Cumulative 5-year mortality rate was significantly lower in screening compared to non-screening or pre-screening colorectal cancers patients (19% versus 37% and 41%, p < 0.001). Colorectal cancers were detected at earlier stages in i-FOBT-positive subjects in comparison with non-screening patients; colorectal cancers found at screening had a significantly improved 5-year survival. Copyright © 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Genetic Literacy and Patient Perceptions of IBD Testing Utility and Disease Control: A Randomized Vignette Study of Genetic Testing

PubMed Central

Hooker, Gillian W.; Peay, Holly; Erby, Lori; Bayless, Theodore; Biesecker, Barbara B.; Roter, Debra L.

2014-01-01

Background Findings from inflammatory bowel disease (IBD) genome-wide association studies are being translated clinically into prognostic and diagnostic indicators of disease. Yet, patient perception and understanding of these tests and their applicability to providing risk information is unclear. The goal of this study was to determine, using hypothetical scenarios, whether patients with IBD perceive genetic testing to be useful for risk assessment, whether genetic test results impact perceived control, and whether low genetic literacy may be a barrier to patient understanding of these tests. Methods Two hundred fifty seven patients with IBD from the Johns Hopkins gastroenterology clinics were randomized to receive a vignette depicting either a genetic testing scenario or a standard blood testing scenario. Participants were asked questions about the vignette and responses were compared between groups. Results Perceptions of test utility for risk assessment were higher among participants responding to the genetic vignette (P < 0.001). There were no significant differences in perceptions of control over IBD after hypothetical testing between vignettes (P = 0.24). Participant responses were modified by genetic literacy, measured using a scale developed for this study. Participants randomized to the genetic vignette who scored higher on the genetic literacy scale perceived greater utility of testing for risk assessment (P = 0.008) and more control after testing (P = 0.02). Conclusions Patients with IBD perceive utility in genetic testing for providing information relevant to family members, and this appreciation is promoted by genetic literacy. Low genetic literacy among patients poses a potential threat to effective translation of genetic and genomic tests. PMID:24691112

Colorectal Cancer Screening in Vulnerable Patients: Promoting Informed and Shared Decisions.

PubMed

Brenner, Alison T; Hoffman, Richard; McWilliams, Andrew; Pignone, Michael P; Rhyne, Robert L; Tapp, Hazel; Weaver, Mark A; Callan, Danelle; de Hernandez, Brisa Urquieta; Harbi, Khalil; Reuland, Daniel S

2016-10-01

Low-income, low-literacy, limited English-proficient populations have low colorectal cancer (CRC) screening rates and experience poor patient-provider communication and decision-making processes around screening. The purpose of this study was to test the effect of a CRC screening decision aid on screening-related communication and decision making in primary care visits. RCT with data collected from patients at baseline and immediately after the provider encounter. Patients aged 50-75 years, due for CRC screening, were recruited from two safety net clinics in North Carolina and New Mexico (data collection, January 2014-September 2015; analysis, 2015). Participants viewed a CRC screening decision aid or a food safety (control) video immediately before their provider encounter. CRC screening-related knowledge, discussion, intent, test preferences, and test ordering. The study population (N=262) had a mean age of 58.3 years and was 66% female, 61% Latino, 17% non-Latino black, and 16% non-Latino white. Among Latino participants, 71% preferred Spanish. Compared with controls, intervention participants had greater screening-related knowledge (on average 4.6 vs 2.8 of six knowledge items correct, adjusted difference [AD]=1.8, 95% CI=1.5, 2.1) and were more likely to report screening discussion (71.0% vs 45.0%, AD=26.1%, 95% CI=14.3%, 38.0%) and high screening intent (93.1% vs 84.7%, AD=9.0%, 95% CI=2.0%, 16.0%). Intervention participants were more likely to indicate a specific screening test preference (93.1% vs 68.0%, AD=26.5%, 95% CI=17.2%, 35.8%) and to report having a test ordered (56.5% vs 32.1%, AD=25.8%, 95% CI=14.4%, 37.2%). Viewing a CRC screening decision aid before a primary care encounter improves knowledge and shared decision making around screening in a racially, ethnically, and linguistically diverse safety net clinic population. This study is registered at www.clinicaltrials.gov NCT02054598. Copyright © 2016 American Journal of Preventive Medicine

Predictive features of breast cancer on Mexican screening mammography patients

NASA Astrophysics Data System (ADS)

Rodriguez-Rojas, Juan; Garza-Montemayor, Margarita; Trevino-Alvarado, Victor; Tamez-Pena, José Gerardo

2013-02-01

Breast cancer is the most common type of cancer worldwide. In response, breast cancer screening programs are becoming common around the world and public programs now serve millions of women worldwide. These programs are expensive, requiring many specialized radiologists to examine all images. Nevertheless, there is a lack of trained radiologists in many countries as in Mexico, which is a barrier towards decreasing breast cancer mortality, pointing at the need of a triaging system that prioritizes high risk cases for prompt interpretation. Therefore we explored in an image database of Mexican patients whether high risk cases can be distinguished using image features. We collected a set of 200 digital screening mammography cases from a hospital in Mexico, and assigned low or high risk labels according to its BIRADS score. Breast tissue segmentation was performed using an automatic procedure. Image features were obtained considering only the segmented region on each view and comparing the bilateral di erences of the obtained features. Predictive combinations of features were chosen using a genetic algorithms based feature selection procedure. The best model found was able to classify low-risk and high-risk cases with an area under the ROC curve of 0.88 on a 150-fold cross-validation test. The features selected were associated to the differences of signal distribution and tissue shape on bilateral views. The model found can be used to automatically identify high risk cases and trigger the necessary measures to provide prompt treatment.

Screening for Secondary Endocrine Hypertension in Young Patients

PubMed Central

TRIFANESCU, Raluca; CARSOTE, Mara; CARAGHEORGHEOPOL, Andra; HORTOPAN, Dan; DUMITRASCU, Anda; DOBRESCU, Mariana; POIANA, Catalina

2013-01-01

ABSTRACT Background: Secondary endocrine hypertension accounts for 5-12% of hypertension's causes. In selected patients (type 2 diabetes mellitus, sleep apnea syndrome with resistant hypertension, sudden deterioration in hypertension control), prevalence could be higher. Objectives: To present etiology of endocrine secondary hypertension in a series of patients younger than 40 years at hypertension's onset. Material and methods: Medical records of 80 patients (39M/41F), aged 30.1 ± 8.2 years (range: 12-40 years), with maximum systolic blood pressure=190.4 ± 29.2 mm Hg, range: 145-300 mm Hg, maximum diastolic blood pressure=107.7 ± 16.9 mm Hg, range: 80-170 mm Hg) referred by cardiologists for endocrine hypertension screening were retrospectively reviewed. Cardiac and renal causes of secondary hypertension were previously excluded. In all patients, plasma catecholamines were measured by ELISA and plasma cortisol by immunochemiluminescence. Orthostatic aldosterone (ELISA) and direct renin (chemiluminescence) were measured in 48 patients. Results: Secondary endocrine hypertension was confirmed in 16 out of 80 patients (20%). Primary hyperaldosteronism was diagnosed in 7 (4M/3F) out of 48 screened patients (14.6%). i.e. 8.75% from whole group: 5 patients with adrenal tumors (3 left/2 right), 2 patients with bilateral adrenal hyperplasia; all patients were hypokalemic at diagnostic (average nadir K+ levels = 2.5 ± 0.5 mmol/L); four patients were hypokalaemic on diuretic therapy (indapamidum); other 3 patients were hypokalaemic in the absence of diuretic therapy. Cushing's syndrome was diagnosed in 6 patients (7.5%): subclinical Cushing due to 4 cm right adrenal tumour – n = 1, overt ACTH-independent Cushing's syndrome due to: macronodular adrenal hyperplasia associated with primary hyperparathyroidism – n = 1; due to adrenal carcinoma – n = 1; due to adrenal adenomas – n = 2; Cushing's disease – n = 1). Pheochromocytomas were diagnosed in 3 patients (3

Engaging Patients in Decisions About Cancer Screening: Exploring the Decision Journey Through the Use of a Patient Portal.

PubMed

Woolf, Steven H; Krist, Alex H; Lafata, Jennifer Elston; Jones, Resa M; Lehman, Rebecca R; Hochheimer, Camille J; Sabo, Roy T; Frosch, Dominick L; Zikmund-Fisher, Brian J; Longo, Daniel R

2018-02-01

Engaging patients to make informed choices is paramount but difficult in busy practices. This study sought to engage patients outside the clinical setting to better understand how they approach cancer screening decisions, including their primary concerns and their preferences for finalizing their decision. Twelve primary care practices offering patients an online personal health record invited eligible patients to complete a 17-item online interactive module. Among 11,458 registered users, invitations to complete the module were sent to adults aged 50-74 years who were overdue for colorectal cancer screening and to women aged 40-49 years and men aged 55-69 who had not undergone a recent mammogram or prostate-specific antigen test, respectively. The module was started by 2,355 patients and completed by 903 patients. Most respondents (76.8%) knew they were eligible for screening. Preferred next steps were talking to the clinician (76.6%), reading/research (28.6%), and consulting trusted friends/family (16.4%). Priority topics included how much screening improves life expectancy, comparative test performance, and the prevalence/health risks of the cancer. Leading fears were getting cancer/delayed detection (79.2%), abnormal results (40.5%), and testing complications (39.1%), the last referring to false test results, medical complications, or unnecessary treatments. Men eligible for prostate-specific antigen screening were more likely than women eligible for mammography to express concerns about testing complications and to prioritize weighing pros and cons over gut feelings (p<0.05). Although this sample was predisposed to screening, most patients wanted help in finalizing their decision. Many wanted to weigh the pros and cons and expressed fears of potential harms from screening. Understanding how patients approach decisions may help design more effective engagement strategies. Copyright © 2017 American Journal of Preventive Medicine. Published by Elsevier Inc. All

Genetics Home Reference: short-chain acyl-CoA dehydrogenase deficiency

MedlinePlus

... Orphanet: Short chain acyl-CoA dehydrogenase deficiency Screening, Technology and Research in Genetics Patient Support and Advocacy Resources (5 links) Children Living with Inherited Metabolic Disease (CLIMB) Children's Mitochondrial ...

The Effect of Screen-to-Screen Versus Face-to-Face Consultation on Doctor-Patient Communication: An Experimental Study with Simulated Patients.

PubMed

Tates, Kiek; Antheunis, Marjolijn L; Kanters, Saskia; Nieboer, Theodoor E; Gerritse, Maria Be

2017-12-20

Despite the emergence of Web-based patient-provider contact, it is still unclear how the quality of Web-based doctor-patient interactions differs from face-to-face interactions. This study aimed to examine (1) the impact of a consultation medium on doctors' and patients' communicative behavior in terms of information exchange, interpersonal relationship building, and shared decision making and (2) the mediating role of doctors' and patients' communicative behavior on satisfaction with both types of consultation medium. Doctor-patient consultations on pelvic organ prolapse were simulated, both in a face-to-face and in a screen-to-screen (video) setting. Twelve medical interns and 6 simulated patients prepared 4 different written scenarios and were randomized to perform a total of 48 consultations. Effects of the consultations were measured by questionnaires that participants filled out directly after the consultation. With respect to patient-related outcomes, satisfaction, perceived information exchange, interpersonal relationship building, and perceived shared decision making showed no significant differences between face-to-face and screen-to-screen consultations. Patients' attitude toward Web-based communication (b=-.249, P=.02 and patients' perceived time and attention (b=.271, P=.03) significantly predicted patients' perceived interpersonal relationship building. Patients' perceived shared decision making was positively related to their satisfaction with the consultation (b=.254, P=.005). Overall, patients experienced significantly greater shared decision making with a female doctor (mean 4.21, SD 0.49) than with a male doctor (mean 3.66 [SD 0.73]; b=.401, P=.009). Doctor-related outcomes showed no significant differences in satisfaction, perceived information exchange, interpersonal relationship building, and perceived shared decision making between the conditions. There was a positive relationship between perceived information exchange and doctors

Simulation optimization of PSA-threshold based prostate cancer screening policies

PubMed Central

Zhang, Jingyu; Denton, Brian T.; Shah, Nilay D.; Inman, Brant A.

2013-01-01

We describe a simulation optimization method to design PSA screening policies based on expected quality adjusted life years (QALYs). Our method integrates a simulation model in a genetic algorithm which uses a probabilistic method for selection of the best policy. We present computational results about the efficiency of our algorithm. The best policy generated by our algorithm is compared to previously recommended screening policies. Using the policies determined by our model, we present evidence that patients should be screened more aggressively but for a shorter length of time than previously published guidelines recommend. PMID:22302420

Obstacles to colorectal screening in general practice: a qualitative study of GPs and patients.

PubMed

Aubin-Auger, Isabelle; Mercier, Alain; Lebeau, Jean-Pierre; Baumann, Laurence; Peremans, Lieve; Van Royen, Paul

2011-12-01

The faecal occult blood test (FOBT) has proven efficiency at screening populations for an average risk of colorectal cancer. Mortality related to this cancer decreases by 15-18% among adults, 50-74 years old, tested every 2 years. A participation rate of at least 50% is desirable. This rate has not yet been reached in most French regions. To explore the obstacles to mass colorectal screening in France. In 2009, five focus groups were conducted in different areas to explore physicians' obstacles to FOBT screening. The patients' obstacles were assessed in semi-structured interviews. A purposive sampling had been carried out for both GPs and patients. The focus groups were coded using Nvivo 8(®) software by three researchers; the interviews manually coded by two researchers. GPs reported insufficient training and some doubted the relevance of screening. They expressed concern of having insufficient time for the test during a consultation, as well as practical and administrative obstacles. Some GPs experienced difficulty persuading patients who had no signs of colorectal disease. Obstacles for patients were mainly difficulties in doing screening themselves and a perception of health care that didn't match with screening. Information and organization were also important points to improve. The screening process was considered complex both by GPs and by patients. Numerous obstacles to colorectal screening, from both the physicians' and the patients' perspectives, were found. The major goal to improve mass screening may be to increase awareness and understanding of both physicians and patients regarding this process.

Screening haematology patients for carbapenem-resistant Klebsiella pneumoniae

PubMed Central

Kilgour, Elizabeth; Dunn, Caroline; Thomas, Linda; Fox, Richard; Mitchell, Lindsay; Paterson, Pamela

2013-01-01

Following a cluster of haematology patients with carbapenem-resistant Klebsiella pneumoniae (CRKP) septicaemia, we initiated screening for rectal carriage of CRKP and multidrug-resistant K. pneumoniae (MDRKP) in this patient group. Haematology inpatients submit a rectal swab once weekly. When plated onto chromogenic Brilliance™ UTI Agar (Oxoid), and incubated overnight with a 10 µg ertapenem disc (Oxoid), K. pneumoniae is identified and semi-automated antibiotic susceptibility testing is performed using the Vitek 2 analyser (Biomerieux). When no zone of inhibition occurs, immediate intervention through patient isolation and enhanced environmental cleaning can be instigated to control further spread while empirical antibiotic prescribing is adapted to take account of identified resistances. Over 2 years, six patients with CRKP and 20 patients with MDRKP were identified. These isolates were resistant to first-line empirical treatment choices for neutropenic sepsis and presented a clinical risk of treatment failure for sepsis post cytotoxic chemotherapy. We describe how this rectal screening methodology was developed and how the results influenced appropriate antibiotic prescribing, patient placement in single rooms and the cleaning of the ward environment to prevent person-to-person transmission of MDRKP and CRKP. PMID:28989355

Tuberculosis screening in patients with HIV: An audit against UK national guidelines to assess current practice and the effectiveness of an electronic tuberculosis-screening prompt.

PubMed

Fox-Lewis, A; Brima, N; Muniina, P; Grant, A D; Edwards, S G; Miller, R F; Pett, S L

2016-09-01

A retrospective clinical audit was performed to assess if the British HIV Association 2011 guidelines on routine screening for tuberculosis in HIV are being implemented in a large UK urban clinic, and if a tuberculosis-screening prompt on the electronic patient record for new attendees was effective. Of 4658 patients attending during the inclusion period, 385 were newly diagnosed first-time attendees and routine tuberculosis screening was recommended in 165. Of these, only 6.1% of patients had a completed tuberculosis screening prompt, and 12.1% underwent routine tuberculosis screening. This audit represents the first published UK data on routine screening rates for tuberculosis in HIV and demonstrates low rates of tuberculosis screening despite an electronic screening prompt designed to simplify adherence to the national guideline. Reasons why tuberculosis screening rates were low, and the prompt ineffective, are unclear. A national audit is ongoing, and we await the results to see if our data reflect a lack of routine tuberculosis screening in HIV-infected patients at a national level. © The Author(s) 2016.

Road screening and distribution route multi-objective robust optimization for hazardous materials based on neural network and genetic algorithm.

PubMed

Ma, Changxi; Hao, Wei; Pan, Fuquan; Xiang, Wang

2018-01-01

Route optimization of hazardous materials transportation is one of the basic steps in ensuring the safety of hazardous materials transportation. The optimization scheme may be a security risk if road screening is not completed before the distribution route is optimized. For road screening issues of hazardous materials transportation, a road screening algorithm of hazardous materials transportation is built based on genetic algorithm and Levenberg-Marquardt neural network (GA-LM-NN) by analyzing 15 attributes data of each road network section. A multi-objective robust optimization model with adjustable robustness is constructed for the hazardous materials transportation problem of single distribution center to minimize transportation risk and time. A multi-objective genetic algorithm is designed to solve the problem according to the characteristics of the model. The algorithm uses an improved strategy to complete the selection operation, applies partial matching cross shift and single ortho swap methods to complete the crossover and mutation operation, and employs an exclusive method to construct Pareto optimal solutions. Studies show that the sets of hazardous materials transportation road can be found quickly through the proposed road screening algorithm based on GA-LM-NN, whereas the distribution route Pareto solutions with different levels of robustness can be found rapidly through the proposed multi-objective robust optimization model and algorithm.

AGO Austria recommendation on screening and diagnosis of Lynch syndrome (LS).

PubMed

Zeimet, Alain G; Mori, Harald; Petru, Edgar; Polterauer, Stephan; Reinthaller, Alexander; Schauer, Christian; Scholl-Firon, Tonja; Singer, Christian; Wimmer, Katharina; Zschocke, Johannes; Marth, Christian

2017-07-01

This manuscript reports the consensus recommendations on screening and diagnosis of Lynch syndrome (LS) in patients with endometrial or ovarian cancer as well as on possible preventive measures in effectively LS-diagnosed women. The recommendations are issued by the Austrian Arbeitsgemeinschaft für Gynäkologische Onkologie (AGO) of the Österreichischen Gesellschaft für Gynäkologie und Geburtshilfe (OEGGG) after consultation of the most recent and relevant literature and following deliberation by the Genetic Task-Force convoked May, 2015 by the AGO Council. The Austrian AGO recommends immunohistochemical tissue screening for type-I and type-II endometrial cancers in all patients below the age of 70 years, and for all endometrioid and clear-cell ovarian cancers independently of the patient's age. If needed immunohistochemistry should be complemented by tissue MLH1 promotor hypermethylation testing and/or microsatellite instability (MSI) analysis. The diagnosis LS requires confirmation through identification of a germline mutation by a molecular genetic examination in the mismatch repair genes using the patient's blood. This should be performed without preceding tissue screening when in LS-associated cancer patients the family history fulfills the Amsterdam II or the revised Bethesda criteria. In LS-diagnosed women, the age for prophylactic surgery should be set flexibly based on an informed consent. Regarding the monitoring of these women, chemo-preventive measures as well as screening procedures either to avoid or to early detect LS-related tumors are discussed with a special light on their specific limitations.

Genetics Home Reference: 3-methylcrotonyl-CoA carboxylase deficiency

MedlinePlus

... Targets Orphanet: 3-methylcrotonyl-CoA carboxylase deficiency Screening, Technology, and Research in Genetics Virginia Department of Health (PDF) Patient Support and Advocacy Resources (3 links) Children Living with Inherited Metabolic Diseases (CLIMB) (UK) Organic ...

An Overview of Inflammatory Bowel Disease: General Consideration and Genetic Screening Approach in Diagnosis of Early Onset Subsets

PubMed Central

Nemati, Shahram; Teimourian, Shahram

2017-01-01

Inflammatory bowel disease (IBD) is the consequence of an aberrant hemostasis of the immune cells at the gut mucosal border. Based on clinical manifestation, laboratory tests, radiological studies, endoscopic and histological features, this disease is divided into three main types including Crohn’s disease (CD), Ulcerative colitis (UC), and IBDunclassified (IBD-U). IBD is frequently presented in adults, but about 20% of IBD cases are diagnosed during childhood called pediatric IBD (PIBD). Some patients in the latter group emerge the first symptoms during infancy or under 5 years of age named infantile and very early onset IBD (VEO-IBD), respectively. These subtypes make a small fraction of PIBD, but they have exclusive phenotypic and genetic characteristics such that they are accompanied by severe disease course and resistance to conventional therapy. In this context, understanding the underlying molecular pathology opens a promising field for individualized and effective treatment. Here, we describe current hypotheses on IBD pathophysiology then explain the new idea about genetic screening technology as a good potential approach to identify the causal variants early in the disease manifestation, which is especially important for the fast and accurate treatment of VEO-IBD. PMID:28638582

Genetic and Non-genetic Factors Associated With Constipation in Cancer Patients Receiving Opioids

PubMed Central

Laugsand, Eivor A; Skorpen, Frank; Kaasa, Stein; Sabatowski, Rainer; Strasser, Florian; Fayers, Peter; Klepstad, Pål

2015-01-01

Objectives: To examine whether the inter-individual variation in constipation among patients receiving opioids for cancer pain is associated with genetic or non-genetic factors. Methods: Cancer patients receiving opioids were included from 17 centers in 11 European countries. Intensity of constipation was reported by 1,568 patients on a four-point categorical scale. Non-genetic factors were included as covariates in stratified regression analyses on the association between constipation and 75 single-nucleotide polymorphisms (SNPs) within 15 candidate genes related to opioid- or constipation-signaling pathways (HTR3E, HTR4, HTR2A, TPH1, ADRA2A, CHRM3, TACR1, CCKAR, KIT, ARRB2, GHRL, ABCB1, COMT, OPRM1, and OPRD1). Results: The non-genetic factors significantly associated with constipation were type of laxative, mobility and place of care among patients receiving laxatives (N=806), in addition to Karnofsky performance status and presence of metastases among patients not receiving laxatives (N=762) (P<0.01). Age, gender, body mass index, cancer diagnosis, time on opioids, opioid dose, and type of opioid did not contribute to the inter-individual differences in constipation. Five SNPs, rs1800532 in TPH1, rs1799971 in OPRM1, rs4437575 in ABCB1, rs10802789 in CHRM3, and rs2020917 in COMT were associated with constipation (P<0.01). Only rs2020917 in COMT passed the Benjamini–Hochberg criterion for a 10% false discovery rate. Conclusions: Type of laxative, mobility, hospitalization, Karnofsky performance status, presence of metastases, and five SNPs within TPH1, OPRM1, ABCB1, CHRM3, and COMT may contribute to the variability in constipation among cancer patients treated with opioids. Knowledge of these factors may help to develop new therapies and to identify patients needing a more individualized approach to treatment. PMID:26087058

Genetic and Non-genetic Factors Associated With Constipation in Cancer Patients Receiving Opioids.

PubMed

Laugsand, Eivor A; Skorpen, Frank; Kaasa, Stein; Sabatowski, Rainer; Strasser, Florian; Fayers, Peter; Klepstad, Pål

2015-06-18

To examine whether the inter-individual variation in constipation among patients receiving opioids for cancer pain is associated with genetic or non-genetic factors. Cancer patients receiving opioids were included from 17 centers in 11 European countries. Intensity of constipation was reported by 1,568 patients on a four-point categorical scale. Non-genetic factors were included as covariates in stratified regression analyses on the association between constipation and 75 single-nucleotide polymorphisms (SNPs) within 15 candidate genes related to opioid- or constipation-signaling pathways (HTR3E, HTR4, HTR2A, TPH1, ADRA2A, CHRM3, TACR1, CCKAR, KIT, ARRB2, GHRL, ABCB1, COMT, OPRM1, and OPRD1). The non-genetic factors significantly associated with constipation were type of laxative, mobility and place of care among patients receiving laxatives (N=806), in addition to Karnofsky performance status and presence of metastases among patients not receiving laxatives (N=762) (P<0.01). Age, gender, body mass index, cancer diagnosis, time on opioids, opioid dose, and type of opioid did not contribute to the inter-individual differences in constipation. Five SNPs, rs1800532 in TPH1, rs1799971 in OPRM1, rs4437575 in ABCB1, rs10802789 in CHRM3, and rs2020917 in COMT were associated with constipation (P<0.01). Only rs2020917 in COMT passed the Benjamini-Hochberg criterion for a 10% false discovery rate. Type of laxative, mobility, hospitalization, Karnofsky performance status, presence of metastases, and five SNPs within TPH1, OPRM1, ABCB1, CHRM3, and COMT may contribute to the variability in constipation among cancer patients treated with opioids. Knowledge of these factors may help to develop new therapies and to identify patients needing a more individualized approach to treatment.

Screening Mammography: Patient Perceptions and Preferences Regarding Communication of Estimated Breast Cancer Risk.

PubMed

Amornsiripanitch, Nita; Mangano, Mark; Niell, Bethany L

2017-05-01

Many models exist to estimate a woman's risk of development of breast cancer. At screening mammography, many imaging centers collect data required for these models to identify women who may benefit from supplemental screening and referral for cancer risk assessment. The purpose of this study was to discern perceptions and preferences of screening mammography patients regarding communication of estimated breast cancer risk. An anonymous survey was distributed to screening and surveillance mammography patients between April and June 2015. Survey questions were designed to assess patient preferences regarding the receipt and complexity of risk estimate communication, including hypothetical scenarios with and without > 20% estimated risk of breast cancer. The McNemar test and the Wilcoxon signed rank test were used with p ≤ 0.05 considered statistically significant. The survey was distributed to 1061 screening and surveillance mammography patients, and 503 patients responded (response rate, 47%). Although 86% (431/503) of patients expressed interest in learning their estimated risk, only 8% (38/503) had undergone formal risk assessment. The preferred method (241 respondents [26%]) of communication of risk < 20% was a mailed letter accompanying annual mammogram results. For risk > 20%, patients preferred oral communication and were 10-fold as likely to choose only oral communication (p < 0.000001). For risk < 20% and > 20%, patients preferred to learn their estimated risk in great detail (69% and 85%), although women were significantly more likely to choose greater detail for risk > 20% (p < 0.00001). Screening mammography patients expressed interest in learning their estimated risk of breast cancer regardless of their level of hypothetical risk.

Lung Cancer Screening Guidelines: How Readable Are Internet-Based Patient Education Resources?

PubMed

Hansberry, David Richard; White, Michael D; D'Angelo, Michael; Prabhu, Arpan V; Kamel, Sarah; Lakhani, Paras; Sundaram, Baskaran

2018-04-30

Following the findings of the National Lung Screening Trial, several national societies from multiple disciplines have endorsed the use of low-dose chest CT to screen for lung cancer. Online patient education materials are an important tool to disseminate information to the general public regarding the proven health benefits of lung cancer screening. This study aims to evaluate the reading level at which these materials related to lung cancer screening are written. The four terms "pulmonary nodule," "radiation," "low-dose CT," and "lung cancer screening" were searched on Google, and the first 20 online resources for each term were downloaded, converted into plain text, and analyzed using 10 well-established readability scales. If the websites were not written specifically for patients, they were excluded. The 80 articles were written at a 12.6 ± 2.7 (mean ± SD) grade level, with grade levels ranging from 4.0 to 19.0. Of the 80 articles, 62.5% required a high school education to comprehend, and 22.6% required a college degree or higher (≥ 16th grade) to comprehend. Only 2.5% of the analyzed articles adhered to the recommendations of the National Institutes of Health and American Medical Association that patient education materials be written at a 3rd- to 7th-grade reading level. Commonly visited online lung cancer screening-related patient education materials are written at a level beyond the general patient population's ability to comprehend and may be contributing to a knowledge gap that is inhibiting patients from improving their health literacy.

Effect of Combined Patient Decision Aid and Patient Navigation vs Usual Care for Colorectal Cancer Screening in a Vulnerable Patient Population: A Randomized Clinical Trial.

PubMed

Reuland, Daniel S; Brenner, Alison T; Hoffman, Richard; McWilliams, Andrew; Rhyne, Robert L; Getrich, Christina; Tapp, Hazel; Weaver, Mark A; Callan, Danelle; Cubillos, Laura; Urquieta de Hernandez, Brisa; Pignone, Michael P

2017-07-01

Colorectal cancer (CRC) screening is underused, especially among vulnerable populations. Decision aids and patient navigation are potentially complementary interventions for improving CRC screening rates, but their combined effect on screening completion is unknown. To determine the combined effect of a CRC screening decision aid and patient navigation compared with usual care on CRC screening completion. In this randomized clinical trial, data were collected from January 2014 to March 2016 at 2 community health center practices, 1 in North Carolina and 1 in New Mexico, serving vulnerable populations. Patients ages 50 to 75 years who had average CRC risk, spoke English or Spanish, were not current with recommended CRC screening, and were attending primary care visits were recruited and randomized 1:1 to intervention or control arms. Intervention participants viewed a CRC screening decision aid in English or Spanish immediately before their clinician encounter. The decision aid promoted screening and presented colonoscopy and fecal occult blood testing as screening options. After the clinician encounter, intervention patients received support for screening completion from a bilingual patient navigator. Control participants viewed a food safety video before the encounter and otherwise received usual care. The primary outcome was CRC screening completion within 6 months of the index study visit assessed by blinded medical record review. Characteristics of the 265 participants were as follows: their mean age was 58 years; 173 (65%) were female, 164 (62%) were Latino; 40 (15%) were white non-Latino; 61 (23%) were black or of mixed race; 191 (78%) had a household income of less than $20 000; 101 (38%) had low literacy; 75 (28%) were on Medicaid; and 91 (34%) were uninsured. Intervention participants were more likely to complete CRC screening within 6 months (68% vs 27%); adjusted-difference, 40 percentage points (95% CI, 29-51 percentage points). The intervention was

Lenticular subluxation in a patient with homocystinuria undetected by neonatal screening.

PubMed

Cheng, Kang-Hsiang; Hung, Miao-Chiu; Chen, Shih-Jen; Kao, Chuan-Hong; Niu, Dau-Ming

2007-12-01

A case of homocystinuria with lenticular subluxation was misdiagnosed as Marfan syndrome since the patient had no apparent mental impairment and had had a negative neonatal screen for homocystinuria. The delayed diagnosis of homocystinuria was due to a negative prior neonatal screen which was checked when he was a breastfed healthy newborn. In the absence of an autosomal dominant family history, and because of prior poor school performance, amino acid analysis and mutational analysis of the cystathionine beta-synthase gene were performed, which revealed the presence of homocystinuria. Low methionine diet with vitamin B6, folic acid, betaine, dipyridamole and aspirin was prescribed for emergency ophthalmologic surgery to prevent thromboembolic events. Fortunately, the operation was completed uneventfully. The patient has been followed-up for 4 years without any significant complaints under diet and medical control. Since homocystinuria is easily missed in neonatal screening programs, it should be suspected in patients who present with lenticular subluxation, even after a negative neonatal screen.

Flow Cytometry Enables Multiplexed Measurements of Genetically Encoded Intramolecular FRET Sensors Suitable for Screening.

PubMed

Doucette, Jaimee; Zhao, Ziyan; Geyer, Rory J; Barra, Melanie M; Balunas, Marcy J; Zweifach, Adam

2016-07-01

Genetically encoded sensors based on intramolecular FRET between CFP and YFP are used extensively in cell biology research. Flow cytometry has been shown to offer a means to measure CFP-YFP FRET; we suspected it would provide a unique way to conduct multiplexed measurements from cells expressing different FRET sensors, which is difficult to do with microscopy, and that this could be used for screening. We confirmed that flow cytometry accurately measures FRET signals using cells transiently transfected with an ERK activity reporter, comparing responses measured with imaging and cytometry. We created polyclonal long-term transfectant lines, each expressing a different intramolecular FRET sensor, and devised a way to bar-code four distinct populations of cells. We demonstrated the feasibility of multiplexed measurements and determined that robust multiplexed measurements can be conducted in plate format. To validate the suitability of the method for screening, we measured responses from a plate of bacterial extracts that in unrelated experiments we had determined contained the protein kinase C (PKC)-activating compound teleocidin A-1. The multiplexed assay correctly identifying the teleocidin A-1-containing well. We propose that multiplexed cytometric FRET measurements will be useful for analyzing cellular function and for screening compound collections. © 2016 Society for Laboratory Automation and Screening.

Molecular fragil X screening in normal populations

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

Spence, W.C.; Black, S.H.; Fallon, L.

In December, 1993, we initiated a pilot project in which DNA fragile X (fraX) testing was offered during routine prenatal or genetic counseling to all pregnant women seen at the Genetics & IVF Institute, most of whom were referred for the indication of advanced maternal age. A brochure on fragile X syndrome was sent to each patient prior to her appointment and was reviewed by a counselor or physician during the counseling session. As of June 1995, 3,345 patients were offered testing; 474 women with no identified family history of mental retardation or learning disability and 214 women with amore » positive family history accepted the test on a self-pay basis. The second population screened was 271 potential donors in our anonymous egg donor program. DNA from blood was tested by Southern blot using EcoRI/EagI and StB12.3. If an expansion was detected, CGG repeat number was determined by PCR-based analysis. Among the 474 patients with unremarkable family histories, three fraX carriers were identified (repeat sizes = 60+), whereas none were found in the 214 patients with a positive family history. Among the potential egg donors, two high borderline patients were identified (repeat sizes = between 50 and 59). Our ongoing study indicates that screening of pregnant or preconceptual populations for fraX carrier status using DNA testing is accepted by many patients and is an important addition to current medical practice. 12 refs., 1 tab.« less

Ethical issues in genetic counselling with special reference to haemoglobinopathies.

PubMed

Muthuswamy, Vasantha

2011-10-01

Genetic counselling is provided in places where genetic tests are carried out. The process involves pre-test counselling as well as post-test counselling to enable the individuals to face the situation and take appropriate decisions with the right frame of mind. Major ethical principles which govern the attitudes and actions of counsellors include: respect for patient autonomy, non-maleficence, beneficence, or taking action to help benefit others and prevent harm, both physical and mental, and justice, which requires that services be distributed fairly to those in need. Other moral issues include veracity, the duty to disclose information or to be truthful, and respect for patient confidentiality. Nondirective counselling, a hallmark of this profession, is in accordance with the principle of individual autonomy. High prevalence of haemoglobinopathies with availability of good and sensitive carrier detection tests and prenatal diagnostic techniques makes these good candidates for population screening of carriers along with genetic counselling for primary prevention of the disease. Screening of the extended family members of the affected child, high risk communities and general population screening including antenatal women are the main target groups for planning a Haemoglobinopathy control programme. A critical mass of trained genetic counsellors who have understanding of the ethical issues and its appropriate handling with the required sensitivity is needed in India.

Applying theological developments to bioethical issues such as genetic screening.

PubMed

Mallia, Pierre; ten Have, Henk

2005-01-01

Catholic movements within the centre of Roman Catholic doctrine recently have discussed Trinitarian theology as applied to sciences, arts, economics, health and other social areas. We explore the possibilities Trinitarian theology offers to bioethical debate, concentrating particularly on genetic screening and testing. It is important therefore to analyse the philosophical implications of this approach onto the bioethical world, where much disagreement occurs on fundamental issues. It is Catholic basic teaching to recognize and see God's hand in plurality, not merely as a cliche and then doing what we feel is right, but to recognize how to live in a pluralistic world. We recognize, in agreement with these theologians, that in order for a Trinitarian mode of understanding to be used by those doing bioethical debate, there is a need to depart from fundamentalism.

Screening CT Colonography: Multicenter Survey of Patient Experience, Preference, and Potential Impact on Adherence

PubMed Central

Pooler, B. Dustin; Baumel, Mark J.; Cash, Brooks D.; Moawad, Fouad J.; Riddle, Mark S.; Patrick, Amy M.; Damiano, Mark; Lee, Matthew H.; Kim, David H.; del Rio, Alejandro Muñoz; Pickhardt, Perry J.

2013-01-01

OBJECTIVE Prior research indicates CT colonography (CTC) would be a cost-effective colorectal cancer (CRC) screening test if widespread availability were to increase overall CRC screening adherence rates. The primary aims of this multicenter study were to evaluate patient experience and satisfaction with CTC screening and compare preference against screening colonoscopy. MATERIALS AND METHODS A 12-question survey instrument measuring pretest choice, experience, and satisfaction was given to a consecutive cohort of adults undergoing CTC screening in three disparate screening settings: university academic center, military medical center, and community practice. The study cohort was composed of individuals voluntarily participating in clinical CTC screening programs. RESULTS A total of 1417 patients responded to the survey. The top reasons for choosing CTC for screening included “noninvasiveness” (68.0%), “avoidance of sedation/anesthesia” (63.1%), “ability to drive after the test” (49.2%), “avoidance of optical colonoscopy risks” (46.9%), and “identifying abnormalities outside the colon” (43.3%). Only 7.2% of patients reported pain during the CTC examination and only 2.5% reported greater than moderate discomfort. Of 441 patients who had experienced both CTC and optical colonoscopy, 77.1% preferred CTC and 13.8% preferred optical colonoscopy. Of all patients, 29.6% indicated that they may not have undergone optical colonoscopy screening if CTC were not available. Of all patients, 92.9% labeled their overall experience with CTC as “excellent” or “good,” and 93.0% indicated they would choose CTC for their next screening. CONCLUSION Respondents reported a very high satisfaction level with CTC, and those who had experienced both modalities indicated a preference for CTC over optical colonoscopy. These results suggest that CTC has the potential to increase adherence to CRC screening guidelines if widely available. PMID:22623549

Effectiveness of plasma lyso-Gb3 as a biomarker for selecting high-risk patients with Fabry disease from multispecialty clinics for genetic analysis.

PubMed

Maruyama, Hiroki; Miyata, Kaori; Mikame, Mariko; Taguchi, Atsumi; Guili, Chu; Shimura, Masaru; Murayama, Kei; Inoue, Takeshi; Yamamoto, Saori; Sugimura, Koichiro; Tamita, Koichi; Kawasaki, Toshihiro; Kajihara, Jun; Onishi, Akifumi; Sugiyama, Hitoshi; Sakai, Teiko; Murata, Ichijiro; Oda, Takamasa; Toyoda, Shigeru; Hanawa, Kenichiro; Fujimura, Takeo; Ura, Shigehisa; Matsumura, Mimiko; Takano, Hideki; Yamashita, Satoshi; Matsukura, Gaku; Tazawa, Ryushi; Shiga, Tsuyoshi; Ebato, Mio; Satoh, Hiroshi; Ishii, Satoshi

2018-03-15

PurposePlasma globotriaosylsphingosine (lyso-Gb3) is a promising secondary screening biomarker for Fabry disease. Here, we examined its applicability as a primary screening biomarker for classic and late-onset Fabry disease in males and females.MethodsBetween 1 July 2014 and 31 December 2015, we screened 2,360 patients (1,324 males) referred from 169 Japanese specialty clinics (cardiology, nephrology, neurology, and pediatrics), based on clinical symptoms suggestive of Fabry disease. We used the plasma lyso-Gb3 concentration, α-galactosidase A (α-Gal A) activity, and analysis of the α-Gal A gene (GLA) for primary and secondary screens, respectively.ResultsOf 8 males with elevated lyso-Gb3 levels (≥2.0 ng ml -1 ) and low α-Gal A activity (≤4.0 nmol h -1  ml -1 ), 7 presented a GLA mutation (2 classic and 5 late-onset). Of 15 females with elevated lyso-Gb3, 7 displayed low α-Gal A activity (5 with GLA mutations; 4 classic and 1 late-onset) and 8 exhibited normal α-Gal A activity (1 with a classic GLA mutation and 3 with genetic variants of uncertain significance).ConclusionPlasma lyso-Gb3 is a potential primary screening biomarker for classic and late-onset Fabry disease probands.Genet Med advance online publication, 15 March 2018; doi:10.1038/gim.2018.31.

Patients' and caregivers' beliefs about depression screening and referral in the emergency department.

PubMed

Pailler, Megan E; Cronholm, Peter F; Barg, Frances K; Wintersteen, Matthew B; Diamond, Guy S; Fein, Joel A

2009-11-01

To explore patients' and parents'/caregivers' beliefs about the acceptability of universal depression screening in the emergency department (ED) and their perceptions of the barriers and facilitators to a mental health referral following a positive screen. We conducted semistructured interviews with 60 patients seeking care and 59 caregivers in the ED of an urban children's hospital. Interviews were audiotaped, transcribed, coded, and entered into N6 (version 6.0; QSR, Thousand Oaks, Calif) for coding and content analysis. Patients and caregivers supported the idea of depression screening in the ED, generally viewing screening as a reflection of care and concern. Respondents reported apprehension about stigma, privacy, and provider sensitivity. Introducing the screening concept early in the visit and as part of routine care was believed to reduce stigma. Respondents generally indicated that although they would likely follow through with a referral if given, stigma and denial were viewed as significant barriers. Caregivers also reported that logistical problems such as transportation, insurance, and agency hours created barriers to help seeking, but this could be offset by social supports and information about the agency and the provider. Patients and caregivers generally support depression screening in the pediatric ED but identified several barriers to screening and referral for treatment. Recommendations include introduction of universal screening early in the ED visit, provision of specific information about the meaning of screening results, and support from family and health care providers to help reduce stigma and increase referral acceptability.

An Evolution-Based Screen for Genetic Differentiation between Anopheles Sister Taxa Enriches for Detection of Functional Immune Factors

PubMed Central

Takashima, Eizo; Williams, Marni; Eiglmeier, Karin; Pain, Adrien; Guelbeogo, Wamdaogo M.; Gneme, Awa; Brito-Fravallo, Emma; Holm, Inge; Lavazec, Catherine; Sagnon, N’Fale; Baxter, Richard H.; Riehle, Michelle M.; Vernick, Kenneth D.

2015-01-01

Nucleotide variation patterns across species are shaped by the processes of natural selection, including exposure to environmental pathogens. We examined patterns of genetic variation in two sister species, Anopheles gambiae and Anopheles coluzzii, both efficient natural vectors of human malaria in West Africa. We used the differentiation signature displayed by a known coordinate selective sweep of immune genes APL1 and TEP1 in A. coluzzii to design a population genetic screen trained on the sweep, classified a panel of 26 potential immune genes for concordance with the signature, and functionally tested their immune phenotypes. The screen results were strongly predictive for genes with protective immune phenotypes: genes meeting the screen criteria were significantly more likely to display a functional phenotype against malaria infection than genes not meeting the criteria (p = 0.0005). Thus, an evolution-based screen can efficiently prioritize candidate genes for labor-intensive downstream functional testing, and safely allow the elimination of genes not meeting the screen criteria. The suite of immune genes with characteristics similar to the APL1-TEP1 selective sweep appears to be more widespread in the A. coluzzii genome than previously recognized. The immune gene differentiation may be a consequence of adaptation of A. coluzzii to new pathogens encountered in its niche expansion during the separation from A. gambiae, although the role, if any of natural selection by Plasmodium is unknown. Application of the screen allowed identification of new functional immune factors, and assignment of new functions to known factors. We describe biochemical binding interactions between immune proteins that underlie functional activity for malaria infection, which highlights the interplay between pathogen specificity and the structure of immune complexes. We also find that most malaria-protective immune factors display phenotypes for either human or rodent malaria, with

Screening for sepsis in general hospitalized patients: a systematic review.

PubMed

Alberto, L; Marshall, A P; Walker, R; Aitken, L M

2017-08-01

Sepsis is a condition widely observed outside critical care areas. To examine the application of sepsis screening tools for early recognition of sepsis in general hospitalized patients to: (i) identify the accuracy of these tools; (ii) determine the outcomes associated with their implementation; and (iii) describe the implementation process. A systematic review method was used. PubMed, CINAHL, Cochrane, Scopus, Web of Science, and Embase databases were systematically searched for primary articles, published from January 1990 to June 2016, that investigated screening tools or alert mechanisms for early identification of sepsis in adult general hospitalized patients. The review protocol was registered with PROSPERO (CRD42016042261). More than 8000 citations were screened for eligibility after duplicates had been removed. Six articles met the inclusion criteria testing two types of sepsis screening tools. Electronic tools can capture, recognize abnormal variables, and activate an alert in real time. However, accuracy of these tools was inconsistent across studies with only one demonstrating high specificity and sensitivity. Paper-based, nurse-led screening tools appear to be more sensitive in the identification of septic patients but were only studied in small samples and particular populations. The process of care measures appears to be enhanced; however, demonstrating improved outcomes is more challenging. Implementation details are rarely reported. Heterogeneity of studies prevented meta-analysis. Clinicians, researchers and health decision-makers should consider these findings and limitations when implementing screening tools, research or policy on sepsis recognition in general hospitalized patients. Copyright © 2017 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved.

Culturally targeted patient navigation for increasing african americans' adherence to screening colonoscopy: a randomized clinical trial.

PubMed

Jandorf, Lina; Braschi, Caitlyn; Ernstoff, Elizabeth; Wong, Carrie R; Thelemaque, Linda; Winkel, Gary; Thompson, Hayley S; Redd, William H; Itzkowitz, Steven H

2013-09-01

Patient navigation has been an effective intervention to increase cancer screening rates. This study focuses on predicting outcomes of screening colonoscopy for colorectal cancer among African Americans using different patient navigation formats. In a randomized clinical trial, patients more than 50 years of age without significant comorbidities were randomized into three navigation groups: peer-patient navigation (n = 181), pro-patient navigation (n = 123), and standard (n = 46). Pro-patient navigations were health care professionals who conducted culturally targeted navigation, whereas peer-patient navigations were community members trained in patient navigation who also discussed their personal experiences with screening colonoscopy. Two assessments gathered sociodemographic, medical, and intrapersonal information. Screening colonoscopy completion rate was 75.7% across all groups with no significant differences in completion between the three study arms. Annual income more than $10,000 was an independent predictor of screening colonoscopy adherence. Unexpectedly, low social influence also predicted screening colonoscopy completion. In an urban African American population, patient navigation was effective in increasing screening colonoscopy rates to 15% above the national average, regardless of patient navigation type or content. Because patient navigation successfully increases colonoscopy adherence, cultural targeting may not be necessary in some populations.

Screening of patients with diabetes mellitus for tuberculosis in community health settings in China.

PubMed

Lin, Yan; Innes, Anh; Xu, Lin; Li, Ling; Chen, Jinou; Hou, Jinglong; Mi, Fengling; Kang, Wanli; Harries, Anthony D

2015-08-01

To assess the feasibility and results of screening of patients with DM for TB in routine community health services in China. Agreement on how to screen patients with DM for TB and monitor and record the results was obtained at a stakeholders meeting. Subsequent training was carried out for staff at 10 community health centres, with activities implemented from June 2013 to April 2014. Patients with DM were screened for TB at each clinical visit using a symptom-based enquiry, and those positive to any symptom were referred to the TB clinic for TB investigation. A total of 2942 patients with DM visited these ten clinics. All patients received at least one screening for TB. Two patients were identified as already known to have TB. In total, 278 (9.5% of those screened) who had positive TB symptoms were referred for TB investigations and 209 arrived at the TB centre or underwent a chest radiograph for TB investigation. One patient (0.5% of those investigated) was newly diagnosed with active TB and was started on anti-TB treatment. The TB case notification rate of those screened was 102/100,000. This pilot project shows it is feasible to carry out TB screening among patients with DM in community settings, but further work is needed to better characterise patients with DM at higher risk of TB. This may require a more targeted approach focused on high-risk groups such as those with untreated DM or poorly controlled hyperglycaemia. © 2015 John Wiley & Sons Ltd.