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Sample records for biochemical confounders nfr

  1. Identifying Trustworthiness Deficit in Legacy Systems Using the NFR Approach

    DTIC Science & Technology

    2014-01-01

    this “shortfall” in re-engineered systems. In this project we applied the NFR Approach, as a case study to the middleware system called Phoenix used...The legacy system we used as a case study is the Phoenix middleware system used by the Air Force - we identified the trustworthiness deficit in...engineered systems. In this project we applied the NFR Approach, as a case study to the middleware system called Phoenix used by the Air Force and determined

  2. Evaluation of the Role of the LysM Receptor-Like Kinase, OsNFR5/OsRLK2 for AM Symbiosis in Rice.

    PubMed

    Miyata, Kana; Hayafune, Masahiro; Kobae, Yoshihiro; Kaku, Hanae; Nishizawa, Yoko; Masuda, Yoshiki; Shibuya, Naoto; Nakagawa, Tomomi

    2016-11-01

    In legume-specific rhizobial symbiosis, host plants perceive rhizobial signal molecules, Nod factors, by a pair of LysM receptor-like kinases, NFR1/LYK3 and NFR5/NFP, and activate symbiotic responses through the downstream signaling components also required for arbuscular mycorrhizal (AM) symbiosis. Recently, the rice NFR1/LYK3 ortholog, OsCERK1, was shown to play crucial roles for AM symbiosis. On the other hand, the roles of the NFR5/NFP ortholog in rice have not been elucidated, while it has been shown that NFR5/NFP orthologs, Parasponia PaNFR5 and tomato SlRLK10, engage in AM symbiosis. OsCERK1 also triggers immune responses in combination with a receptor partner, OsCEBiP, against fungal or bacterial infection, thus regulating opposite responses against symbiotic and pathogenic microbes. However, it has not been elucidated how OsCERK1 switches these opposite functions. Here, we analyzed the function of the rice NFR5/NFP ortholog, OsNFR5/OsRLK2, as a possible candidate of the OsCERK1 partner for symbiotic signaling. Inoculation of AM fungi induced the expression of OsNFR5 in the rice root, and the chimeric receptor consisting of the extracellular domain of LjNFR5 and the intracellular domain of OsNFR5 complemented the Ljnfr5 mutant for rhizobial symbiosis, indicating that the intracellular kinase domain of OsNFR5 could activate symbiotic signaling in Lotus japonicus. Although these data suggested the possible involvement of OsNFR5 in AM symbiosis, osnfr5 knockout mutants were colonized by AM fungi similar to the wild-type rice. These observations suggested several possibilities including the presence of functionally redundant genes other than OsNFR5 or involvement of novel ligands, which do not require OsNFR5 for recognition.

  3. Purification and characterization of NF-R1 that regulates the expression of the human multidrug resistance (MDR1) gene.

    PubMed Central

    Ogura, M; Takatori, T; Tsuruo, T

    1992-01-01

    We have purified a protein, NF-R1, that specifically binds to two unrelated motifs--the ATTCAGTCA motif and the GC-box motif--on the MDR1 proximal promoter. Purified NF-R1 has been confirmed by southwestern blotting to be a 110-kDa protein. Methylation interference analysis revealed that the nucleotides were in close contact with purified NF-R1 on the ATTCAGTCA and GC-box motifs. The nucleotides were required for the binding of NF-R1, as seen by competition gel mobility shift assay using point mutated oligonucleotides. In a CAT expression assay using the corresponding point-mutated MDR1 promoter fused to a CAT gene, binding inhibition of NF-R1 to the promoter resulted in 2- to 3-fold increases of CAT activity, as compared to the intact promoter in Adriamycin-resistant K562 cells. Thus NF-R1 has a relation to the negative regulation of the MDR1 gene transcription. Images PMID:1360648

  4. Using multilevel growth curve modeling to examine emotional modulation of temporal summation of pain (TS-pain) and the nociceptive flexion reflex (TS-NFR).

    PubMed

    Rhudy, Jamie L; Martin, Satin L; Terry, Ellen L; Delventura, Jennifer L; Kerr, Kara L; Palit, Shreela

    2012-11-01

    Emotion can modulate pain and spinal nociception, and correlational data suggest that cognitive-emotional processes can facilitate wind-up-like phenomena (ie, temporal summation of pain). However, there have been no experimental studies that manipulated emotion to determine whether within-subject changes in emotion influence temporal summation of pain (TS-pain) and the nociceptive flexion reflex (TS-NFR, a physiological measure of spinal nociception). The present study presented a series of emotionally charged pictures (mutilation, neutral, erotic) during which electric stimuli at 2 Hz were delivered to the sural nerve to evoke TS-pain and TS-NFR. Participants (n=46 healthy; 32 female) were asked to rate their emotional reactions to pictures as a manipulation check. Pain outcomes were analyzed using statistically powerful multilevel growth curve models. Results indicated that emotional state was effectively manipulated. Further, emotion modulated the overall level of pain and NFR; pain and NFR were highest during mutilation and lowest during erotic pictures. Although pain and NFR both summated in response to the 2-Hz stimulation series, the magnitude of pain summation (TS-pain) and NFR summation (TS-NFR) was not modulated by picture-viewing. These results imply that, at least in healthy humans, within-subject changes in emotions do not promote central sensitization via amplification of temporal summation. However, future studies are needed to determine whether these findings generalize to clinical populations (eg, chronic pain).

  5. [Bias in observational research: 'confounding'].

    PubMed

    Groenwold, Rolf H H

    2012-01-01

    Confounding is an important and common issue in observational (non-randomized) research on the effects of pharmaceuticals or exposure to etiologic factors (determinants). Confounding is present when a third factor, related to both the determinant and the outcome, distorts the causal relation between these two. There are different methods to control for confounding. The most commonly used are restriction, stratification, multivariable regression models, and propensity score methods. With these methods it is only possible to control for variables for which data is known: measured confounders. Research in the area of confounding is currently directed at the incorporation of external knowledge on unmeasured confounders, the evaluation of instrumental variables, and the impact of time-dependent confounding.

  6. Identifiability, exchangeability and confounding revisited

    PubMed Central

    Greenland, Sander; Robins, James M

    2009-01-01

    In 1986 the International Journal of Epidemiology published "Identifiability, Exchangeability and Epidemiological Confounding". We review the article from the perspective of a quarter century after it was first drafted and relate it to subsequent developments on confounding, ignorability, and collapsibility. PMID:19732410

  7. Interpretational Confounding or Confounded Interpretations of Causal Indicators?

    PubMed Central

    Bainter, Sierra A.; Bollen, Kenneth A.

    2014-01-01

    In measurement theory causal indicators are controversial and little-understood. Methodological disagreement concerning causal indicators has centered on the question of whether causal indicators are inherently sensitive to interpretational confounding, which occurs when the empirical meaning of a latent construct departs from the meaning intended by a researcher. This article questions the validity of evidence used to claim that causal indicators are inherently susceptible to interpretational confounding. Further, a simulation study demonstrates that causal indicator coefficients are stable across correctly-specified models. Determining the suitability of causal indicators has implications for the way we conceptualize measurement and build and evaluate measurement models. PMID:25530730

  8. Interpretational Confounding or Confounded Interpretations of Causal Indicators?

    ERIC Educational Resources Information Center

    Bainter, Sierra A.; Bollen, Kenneth A.

    2014-01-01

    In measurement theory, causal indicators are controversial and little understood. Methodological disagreement concerning causal indicators has centered on the question of whether causal indicators are inherently sensitive to interpretational confounding, which occurs when the empirical meaning of a latent construct departs from the meaning…

  9. Assessing Sensitivity to Unmeasured Confounding Using a Simulated Potential Confounder

    ERIC Educational Resources Information Center

    Carnegie, Nicole Bohme; Harada, Masataka; Hill, Jennifer L.

    2016-01-01

    A major obstacle to developing evidenced-based policy is the difficulty of implementing randomized experiments to answer all causal questions of interest. When using a nonexperimental study, it is critical to assess how much the results could be affected by unmeasured confounding. We present a set of graphical and numeric tools to explore the…

  10. Introduction to causal diagrams for confounder selection.

    PubMed

    Williamson, Elizabeth J; Aitken, Zoe; Lawrie, Jock; Dharmage, Shyamali C; Burgess, John A; Forbes, Andrew B

    2014-04-01

    In respiratory health research, interest often lies in estimating the effect of an exposure on a health outcome. If randomization of the exposure of interest is not possible, estimating its effect is typically complicated by confounding bias. This can often be dealt with by controlling for the variables causing the confounding, if measured, in the statistical analysis. Common statistical methods used to achieve this include multivariable regression models adjusting for selected confounding variables or stratification on those variables. Therefore, a key question is which measured variables need to be controlled for in order to remove confounding. An approach to confounder-selection based on the use of causal diagrams (often called directed acyclic graphs) is discussed. A causal diagram is a visual representation of the causal relationships believed to exist between the variables of interest, including the exposure, outcome and potential confounding variables. After creating a causal diagram for the research question, an intuitive and easy-to-use set of rules can be applied, based on a foundation of rigorous mathematics, to decide which measured variables must be controlled for in the statistical analysis in order to remove confounding, to the extent that is possible using the available data. This approach is illustrated by constructing a causal diagram for the research question: 'Does personal smoking affect the risk of subsequent asthma?'. Using data taken from the Tasmanian Longitudinal Health Study, the statistical analysis suggested by the causal diagram approach was performed.

  11. Confounding and bias in the attributable fraction.

    PubMed

    Darrow, Lyndsey A; Steenland, N Kyle

    2011-01-01

    Inappropriate methods are frequently used to calculate the population attributable fraction (AF) for a given exposure of interest. This commonly occurs when authors use adjusted relative risks (RRs) reported in the literature (the "source" data), without access to the original data. In this analysis, we examine the relationship between the direction and magnitude of confounding in the source data and resulting bias in the attributable fraction when incorrect methods are used. We assess confounding by the confounding risk ratio, which is the ratio of the crude RR to the adjusted RR. We assess bias in the AF by the ratio of the incorrectly calculated AF to the correctly calculated AF. Using generated data, we examine the relationship between confounding and AF bias under various scenarios of population prevalence of exposure and strength of the exposure-disease association. For confounding risk ratios greater than 1.0 (ie, crude RR >adjusted RR), the AF is underestimated; for confounding risk ratios less than 1.0 (ie, crude RR confounding increases, and is dependent on the prevalence of exposure in the total population, with bias greatest at the lowest prevalence of exposure. Bias in the AF is also higher when the exposure-disease association is weaker. Results of these analyses can assist interpretation of incorrectly calculated attributable fraction estimates commonly reported in the epidemiologic literature.

  12. Assessing the impact of unmeasured confounding for binary outcomes using confounding functions.

    PubMed

    Kasza, Jessica; Wolfe, Rory; Schuster, Tibor

    2017-03-03

    A critical assumption of causal inference is that of no unmeasured confounding: for estimated exposure effects to have valid causal interpretations, a sufficient set of predictors of exposure and outcome must be adequately measured and correctly included in the respective inference model(s). In an observational study setting, this assumption will often be unsatisfied, and the potential impact of unmeasured confounding on effect estimates should be investigated. The confounding function approach allows the impact of unmeasured confounding on estimates to be assessed, where unmeasured confounding may be due to unmeasured confounders and/or biases such as collider bias or information bias. Although this approach is easy to implement and pertains to the sum of all bias, its use has not been widespread, and discussion has typically been limited to continuous outcomes. In this paper, we consider confounding functions for use with binary outcomes and illustrate the approach with an example. We note that confounding function choice encodes assumptions about effect modification: some choices encode the belief that the true causal effect differs across exposure groups, whereas others imply that any difference between the true causal parameter and the estimate is entirely due to imbalanced risks between exposure groups. The confounding function approach is a useful method for assessing the impact of unmeasured confounding, in particular when alternative approaches, e.g. external adjustment or instrumental variable approaches, cannot be applied. We provide Stata and R code for the implementation of this approach when the causal estimand of interest is an odds or risk ratio.

  13. Confounding and control of confounding in nonexperimental studies of medications in patients with CKD.

    PubMed

    Bradbury, Brian D; Gilbertson, David T; Brookhart, M Alan; Kilpatrick, Ryan D

    2012-01-01

    Confounding is an important source of bias in nonexperimental studies, arising when the effect of an exposure on the occurrence of an outcome is distorted by the effect of some other factor. In nonexperimental studies of patients with CKD or who are on chronic dialysis, confounding is a significant concern owing to the high burden of comorbid disease, extent of required clinical management, and high frequency of adverse clinical events in this patient population. Confounding can be addressed in both the design stage (restriction, accurate measurement of confounders) and analysis stage (stratification, multivariable adjustment, propensity scores, marginal structural models, instrumental variable) of a study. Time-dependent confounding and confounding by indication are 2 special cases of confounding that can arise in studies of treatment effects and may require more sophisticated analytic techniques to adequately address. The availability and expanded use of large health care databases have ensured greater precision and have now placed the focus on validity. Addressing the major threats to validity, such as confounding, should be a first-order concern.

  14. Modeling confounding by half-sibling regression

    PubMed Central

    Schölkopf, Bernhard; Hogg, David W.; Wang, Dun; Foreman-Mackey, Daniel; Janzing, Dominik; Simon-Gabriel, Carl-Johann; Peters, Jonas

    2016-01-01

    We describe a method for removing the effect of confounders to reconstruct a latent quantity of interest. The method, referred to as “half-sibling regression,” is inspired by recent work in causal inference using additive noise models. We provide a theoretical justification, discussing both independent and identically distributed as well as time series data, respectively, and illustrate the potential of the method in a challenging astronomy application. PMID:27382154

  15. Modeling confounding by half-sibling regression.

    PubMed

    Schölkopf, Bernhard; Hogg, David W; Wang, Dun; Foreman-Mackey, Daniel; Janzing, Dominik; Simon-Gabriel, Carl-Johann; Peters, Jonas

    2016-07-05

    We describe a method for removing the effect of confounders to reconstruct a latent quantity of interest. The method, referred to as "half-sibling regression," is inspired by recent work in causal inference using additive noise models. We provide a theoretical justification, discussing both independent and identically distributed as well as time series data, respectively, and illustrate the potential of the method in a challenging astronomy application.

  16. A typology of four notions of confounding in epidemiology.

    PubMed

    Suzuki, Etsuji; Mitsuhashi, Toshiharu; Tsuda, Toshihide; Yamamoto, Eiji

    2017-02-01

    Confounding is a major concern in epidemiology. Despite its significance, the different notions of confounding have not been fully appreciated in the literature, leading to confusion of causal concepts in epidemiology. In this article, we aim to highlight the importance of differentiating between the subtly different notions of confounding from the perspective of counterfactual reasoning. By using a simple example, we illustrate the significance of considering the distribution of response types to distinguish causation from association, highlighting that confounding depends not only on the population chosen as the target of inference, but also on the notions of confounding in distribution and confounding in measure. This point has been relatively underappreciated, partly because some literature on the concept of confounding has only used the exposed and unexposed groups as the target populations, while it would be helpful to use the total population as the target population. Moreover, to clarify a further distinction between confounding "in expectation" and "realized" confounding, we illustrate the usefulness of examining the distribution of exposure status in the target population. To grasp the explicit distinction between confounding in expectation and realized confounding, we need to understand the mechanism that generates exposure events, not the product of that mechanism. Finally, we graphically illustrate this point, highlighting the usefulness of directed acyclic graphs in examining the presence of confounding in distribution, in the notion of confounding in expectation.

  17. A typology of four notions of confounding in epidemiology

    PubMed Central

    Suzuki, Etsuji; Mitsuhashi, Toshiharu; Tsuda, Toshihide; Yamamoto, Eiji

    2016-01-01

    Confounding is a major concern in epidemiology. Despite its significance, the different notions of confounding have not been fully appreciated in the literature, leading to confusion of causal concepts in epidemiology. In this article, we aim to highlight the importance of differentiating between the subtly different notions of confounding from the perspective of counterfactual reasoning. By using a simple example, we illustrate the significance of considering the distribution of response types to distinguish causation from association, highlighting that confounding depends not only on the population chosen as the target of inference, but also on the notions of confounding in distribution and confounding in measure. This point has been relatively underappreciated, partly because some literature on the concept of confounding has only used the exposed and unexposed groups as the target populations, while it would be helpful to use the total population as the target population. Moreover, to clarify a further distinction between confounding “in expectation” and “realized” confounding, we illustrate the usefulness of examining the distribution of exposure status in the target population. To grasp the explicit distinction between confounding in expectation and realized confounding, we need to understand the mechanism that generates exposure events, not the product of that mechanism. Finally, we graphically illustrate this point, highlighting the usefulness of directed acyclic graphs in examining the presence of confounding in distribution, in the notion of confounding in expectation. PMID:28142011

  18. Bias Analysis for Uncontrolled Confounding in the Health Sciences.

    PubMed

    Arah, Onyebuchi A

    2017-03-20

    Uncontrolled confounding due to unmeasured confounders biases causal inference in health science studies using observational and imperfect experimental designs. The adoption of methods for analysis of bias due to uncontrolled confounding has been slow, despite the increasing availability of such methods. Bias analysis for such uncontrolled confounding is most useful in big data studies and systematic reviews to gauge the extent to which extraneous preexposure variables that affect the exposure and the outcome can explain some or all of the reported exposure-outcome associations. We review methods that can be applied during or after data analysis to adjust for uncontrolled confounding for different outcomes, confounders, and study settings. We discuss relevant bias formulas and how to obtain the required information for applying them. Finally, we develop a new intuitive generalized bias analysis framework for simulating and adjusting for the amount of uncontrolled confounding due to not measuring and adjusting for one or more confounders.

  19. Infection with parasitic nematodes confounds vaccination efficacy.

    PubMed

    Urban, Joseph F; Steenhard, Nina R; Solano-Aguilar, Gloria I; Dawson, Harry D; Iweala, Onyinye I; Nagler, Cathryn R; Noland, Gregory S; Kumar, Nirbhay; Anthony, Robert M; Shea-Donohue, Terez; Weinstock, Joel; Gause, William C

    2007-08-19

    T helper (Th) cells produce signature cytokine patterns, induced largely by intracellular versus extracellular pathogens that provide the cellular and molecular basis for counter regulatory expression of protective immunity during concurrent infections. The production of IL-12 and IFN-gamma, for example, resulting from exposure to many bacterial, viral, and protozoan pathogens is responsible for Th1-derived protective responses that also can inhibit development of Th2-cells expressing IL-4-dependent immunity to extracellular helminth parasites and vice versa. In a similar manner, concurrent helminth infection alters optimal vaccine-induced responses in humans and livestock; however, the consequences of this condition have not been adequately studied especially in the context of a challenge infection following vaccination. Demands for new and effective vaccines to control chronic and emerging diseases, and the need for rapid deployment of vaccines for bio security concerns requires a systematic evaluation of confounding factors that limit vaccine efficacy. One common albeit overlooked confounder is the presence of gastrointestinal nematode parasites in populations of humans and livestock targeted for vaccination. This is particularly important in areas of the world were helminth infections are prevalent, but the interplay between parasites and emerging diseases that can be transmitted worldwide make this a global issue. In addition, it is not clear if the epidemic in allergic disease in industrialized countries substitutes for geohelminth infection to interfere with effective vaccination regimens. This presentation will focus on recent vaccination studies in mice experimentally infected with Heligmosomoides polygyrus to model the condition of gastrointestinal parasite infestation in mammalian populations targeted for vaccination. In addition, a large animal vaccination and challenge model against Mycoplasma hyopneumonia in swine exposed to Ascaris suum will provide

  20. Methodological issues of confounding in analytical epidemiologic studies.

    PubMed

    Hajian Tilaki, Karimollah

    2012-01-01

    Confounding can be thought of as mixing the effect of exposure on the risk of disease with a third factor which distorts the measure of association such as risk ratio or odds ratio. This bias arises because of complex functional relationship of confounder with both exposure and disease (outcome). In this article, we provided a conceptual framework review of confounding issues in epidemiologic studies, in particular in observational studies and nonrandomized experimental studies. We have shown in 2 by 2 tables with analytical examples how the index of association will be distorted when confounding is present. The criteria, source of confounding and several points in confounding issues have been addressed. The advantages and disadvantages of several strategies for control of confounding have been discussed.

  1. Confounding Effect in Clinical Research of Otolaryngology and Its Control.

    PubMed

    Yu, Yong-qiang; Huang, Dong-yan; Armijo Olivo, Susan; Yang, Huai-an; Bambanini, Yagesh; Sonnenberg, Lyn; Clark, Brenda; Constantinescu, Gabriela; Qian Yu, Jason; Zhang, Ming

    2015-06-01

    Confounding effect is a critical issue in clinical research of otolaryngology because it can distort the research's conclusion. In this review, we introduce the definition of confounding effect, the methods of verifying and controlling the effect. Confounding effect can be prevented by research's design, and adjusted by data analysis. Clinicians would be aware and cautious about confounding effect in their research. They would be able to set up a research's design in which appropriate methods have been applied to prevent this effect.They would know how to adjust confounding effect after data collection. It is important to remember that sometimes it is impossible to eliminate confounding effect completely, and statistical method is not a master key. Solid research knowledge and critical thinking of our brain are the most important in controlling confounding effect.

  2. Transposon Mutagenesis of the Plant-Associated Bacillus amyloliquefaciens ssp. plantarum FZB42 Revealed That the nfrA and RBAM17410 Genes Are Involved in Plant-Microbe-Interactions

    PubMed Central

    Dietel, Kristin; Beator, Barbara; Dolgova, Olga; Fan, Ben; Bleiss, Wilfrid; Ziegler, Jörg; Schmid, Michael; Hartmann, Anton; Borriss, Rainer

    2014-01-01

    Bacillus amyloliquefaciens ssp. plantarum FZB42 represents the prototype of Gram-positive plant growth promoting and biocontrol bacteria. In this study, we applied transposon mutagenesis to generate a transposon library, which was screened for genes involved in multicellular behavior and biofilm formation on roots as a prerequisite of plant growth promoting activity. Transposon insertion sites were determined by rescue-cloning followed by DNA sequencing. As in B. subtilis, the global transcriptional regulator DegU was identified as an activator of genes necessary for swarming and biofilm formation, and the DegU-mutant of FZB42 was found impaired in efficient root colonization. Direct screening of 3,000 transposon insertion mutants for plant-growth-promotion revealed the gene products of nfrA and RBAM_017140 to be essential for beneficial effects exerted by FZB42 on plants. We analyzed the performance of GFP-labeled wild-type and transposon mutants in the colonization of lettuce roots using confocal laser scanning microscopy. While the wild-type strain heavily colonized root surfaces, the nfrA mutant did not colonize lettuce roots, although it was not impaired in growth in laboratory cultures, biofilm formation and swarming motility on agar plates. The RBAM17410 gene, occurring in only a few members of the B. subtilis species complex, was directly involved in plant growth promotion. None of the mutant strains were affected in producing the plant growth hormone auxin. We hypothesize that the nfrA gene product is essential for overcoming the stress caused by plant response towards bacterial root colonization. PMID:24847778

  3. Confounding in longitudinal studies in addiction treatment research

    PubMed Central

    Pierce, Matthias; Dunn, Graham; Millar, Tim

    2017-01-01

    Abstract Background: The effectiveness of treatment for people with substance use disorders is usually examined using longitudinal cohorts. In these studies, treatment is often considered as a time-varying exposure. The aim of this commentary is to examine confounding in this context, when the confounding variable is time-invariant and when it is time-varying. Method: Types of confounding are described with examples and illustrated using path diagrams. Simulations are used to demonstrate the direction of confounding bias and the extent that it is accounted for using standard regression adjustment techniques. Results: When the confounding variable is time invariant or time varying and not influenced by prior treatment, then standard adjustment techniques are adequate to control for confounding bias, provided that in the latter scenario the time-varying form of the variable is used. When the confounder is time varying and affected by prior treatment status (i.e. it is a mediator of treatment), then standard methods of adjustment result in inconsistency. Conclusions: In longitudinal cohorts where treatment exposure is time varying, confounding is an issue which should be considered, even if treatment exposure is initially randomized. In these studies, standard methods of adjustment may result be inadequate, even when all confounders have been identified. This occurs when the confounder is also a mediator of treatment. This is a likely scenario in many studies in addiction.

  4. Confounding in longitudinal studies in addiction treatment research.

    PubMed

    Pierce, Matthias; Dunn, Graham; Millar, Tim

    2017-05-04

    Background: The effectiveness of treatment for people with substance use disorders is usually examined using longitudinal cohorts. In these studies, treatment is often considered as a time-varying exposure. The aim of this commentary is to examine confounding in this context, when the confounding variable is time-invariant and when it is time-varying. Method: Types of confounding are described with examples and illustrated using path diagrams. Simulations are used to demonstrate the direction of confounding bias and the extent that it is accounted for using standard regression adjustment techniques. Results: When the confounding variable is time invariant or time varying and not influenced by prior treatment, then standard adjustment techniques are adequate to control for confounding bias, provided that in the latter scenario the time-varying form of the variable is used. When the confounder is time varying and affected by prior treatment status (i.e. it is a mediator of treatment), then standard methods of adjustment result in inconsistency. Conclusions: In longitudinal cohorts where treatment exposure is time varying, confounding is an issue which should be considered, even if treatment exposure is initially randomized. In these studies, standard methods of adjustment may result be inadequate, even when all confounders have been identified. This occurs when the confounder is also a mediator of treatment. This is a likely scenario in many studies in addiction.

  5. History of the modern epidemiological concept of confounding.

    PubMed

    Morabia, Alfredo

    2011-04-01

    The epidemiological concept of confounding has had a convoluted history. It was first expressed as an issue of group non-comparability, later as an uncontrolled fallacy, then as a controllable fallacy named confounding, and, more recently, as an issue of group non-comparability in the distribution of potential outcome types. This latest development synthesised the apparent disconnect between phases of the history of confounding. Group non-comparability is the essence of confounding, and the statistical fallacy its consequence. This essay discusses how confounding was perceived in the 18th and 19th centuries, reviews how the concept evolved across the 20th century and finally describes the modern definition of confounding.

  6. Distinguishing Selection Bias and Confounding Bias in Comparative Effectiveness Research.

    PubMed

    Haneuse, Sebastien

    2016-04-01

    Comparative effectiveness research (CER) aims to provide patients and physicians with evidence-based guidance on treatment decisions. As researchers conduct CER they face myriad challenges. Although inadequate control of confounding is the most-often cited source of potential bias, selection bias that arises when patients are differentially excluded from analyses is a distinct phenomenon with distinct consequences: confounding bias compromises internal validity, whereas selection bias compromises external validity. Despite this distinction, however, the label "treatment-selection bias" is being used in the CER literature to denote the phenomenon of confounding bias. Motivated by an ongoing study of treatment choice for depression on weight change over time, this paper formally distinguishes selection and confounding bias in CER. By formally distinguishing selection and confounding bias, this paper clarifies important scientific, design, and analysis issues relevant to ensuring validity. First is that the 2 types of biases may arise simultaneously in any given study; even if confounding bias is completely controlled, a study may nevertheless suffer from selection bias so that the results are not generalizable to the patient population of interest. Second is that the statistical methods used to mitigate the 2 biases are themselves distinct; methods developed to control one type of bias should not be expected to address the other. Finally, the control of selection and confounding bias will often require distinct covariate information. Consequently, as researchers plan future studies of comparative effectiveness, care must be taken to ensure that all data elements relevant to both confounding and selection bias are collected.

  7. Graphical presentation of confounding in directed acyclic graphs.

    PubMed

    Suttorp, Marit M; Siegerink, Bob; Jager, Kitty J; Zoccali, Carmine; Dekker, Friedo W

    2015-09-01

    Since confounding obscures the real effect of the exposure, it is important to adequately address confounding for making valid causal inferences from observational data. Directed acyclic graphs (DAGs) are visual representations of causal assumptions that are increasingly used in modern epidemiology. They can help to identify the presence of confounding for the causal question at hand. This structured approach serves as a visual aid in the scientific discussion by making underlying relations explicit. This article explains the basic concepts of DAGs and provides examples in the field of nephrology with and without presence of confounding. Ultimately, these examples will show that DAGs can be preferable to the traditional methods to identify sources of confounding, especially in complex research questions.

  8. The missing cause approach to unmeasured confounding in pharmacoepidemiology.

    PubMed

    Abrahamowicz, Michal; Bjerre, Lise M; Beauchamp, Marie-Eve; LeLorier, Jacques; Burne, Rebecca

    2016-03-30

    Unmeasured confounding is a major threat to the validity of pharmacoepidemiological studies of medication safety and effectiveness. We propose a new method for detecting and reducing the impact of unobserved confounding in large observational database studies. The method uses assumptions similar to the prescribing preference-based instrumental variable (IV) approach. Our method relies on the new 'missing cause' principle, according to which the impact of unmeasured confounding by (contra-)indication may be detected by assessing discrepancies between the following: (i) treatment actually received by individual patients and (ii) treatment that they would be expected to receive based on the observed data. Specifically, we use the treatment-by-discrepancy interaction to test for the presence of unmeasured confounding and correct the treatment effect estimate for the resulting bias. Under standard IV assumptions, we first proved that unmeasured confounding induces a spurious treatment-by-discrepancy interaction in risk difference models for binary outcomes and then simulated large pharmacoepidemiological studies with unmeasured confounding. In simulations, our estimates had four to six times smaller bias than conventional treatment effect estimates, adjusted only for measured confounders, and much smaller variance inflation than unbiased but very unstable IV estimates, resulting in uniformly lowest root mean square errors. The much lower variance of our estimates, relative to IV estimates, was also observed in an application comparing gastrointestinal safety of two classes of anti-inflammatory drugs. In conclusion, our missing cause-based method may complement other methods and enhance accuracy of analyses of large pharmacoepidemiological studies.

  9. Methodological problems with population cancer studies: The forgotten confounding factors.

    PubMed

    Blaylock, Russell L

    2015-01-01

    Among clinical physicians it is the population study that is considered to be the "gold standard" of medical evidence concerning acceptable treatments. As new information comes to light concerning the many variables and confounding factors that can affect such studies, many older studies lose much of their original impact. While newer population studies take into consideration a far greater number of confounding factors many are still omitted and a number of these omitted factors can have profound effects on interpretation and validity of the study. In this editorial, I will discuss some of the omitted confounding factors and demonstrate how they can alter the interpretation of these papers and their clinical application.

  10. Confounding and causation in the epidemiology of lead.

    PubMed

    Wilson, Ian Harold; Wilson, Simon Barton

    2016-01-01

    The National Health and Medical Research Council recently reported that there were not enough high-quality studies to conclude that associations between health effects and blood lead levels <10 μg/dL were caused by lead. It identified uncontrolled confounding, measurement error and other potential causal factors as common weaknesses. This paper supports those findings with evidence of uncontrolled confounding by parental education, intelligence or household management from several papers. It suggests that inappropriate statistical tests and aggregation of data representing different exposure routes partly explain why confounding has been overlooked. Inadequate correction of confounding has contributed to incorrect conclusions regarding causality at low levels of lead. Linear or log-linear regression models have tended to mask any threshold. While the effects of higher levels of lead exposure are not disputed, overestimation of health effects at low lead exposures has significant implications for policy-makers endeavouring to protect public health through cost-effective regulations.

  11. [Application of directed acyclic graphs in control of confounding].

    PubMed

    Xiang, R; Dai, W J; Xiong, Y; Wu, X; Yang, Y F; Wang, L; Dai, Z H; Li, J; Liu, A Z

    2016-07-01

    Observational study is a method most commonly used in the etiology study of epidemiology, but confounders, always distort the true causality between exposure and outcome when local inferencing. In order to eliminate these confounding, the determining of variables which need to be adjusted become a key issue. Directed acyclic graph(DAG)could visualize complex causality, provide a simple and intuitive way to identify the confounding, and convert it into the finding of the minimal sufficient adjustment for the control of confounding. On the one hand, directed acyclic graph can choose less variables, which increase statistical efficiency of the analysis. On the other hand, it could help avoiding variables that is not measured or with missing values. In a word, the directed acyclic graph could facilitate the reveal of the real causality effectively.

  12. The ACCE method: an approach for obtaining quantitative or qualitative estimates of residual confounding that includes unmeasured confounding

    PubMed Central

    Smith, Eric G.

    2015-01-01

    Background:  Nonrandomized studies typically cannot account for confounding from unmeasured factors.  Method:  A method is presented that exploits the recently-identified phenomenon of  “confounding amplification” to produce, in principle, a quantitative estimate of total residual confounding resulting from both measured and unmeasured factors.  Two nested propensity score models are constructed that differ only in the deliberate introduction of an additional variable(s) that substantially predicts treatment exposure.  Residual confounding is then estimated by dividing the change in treatment effect estimate between models by the degree of confounding amplification estimated to occur, adjusting for any association between the additional variable(s) and outcome. Results:  Several hypothetical examples are provided to illustrate how the method produces a quantitative estimate of residual confounding if the method’s requirements and assumptions are met.  Previously published data is used to illustrate that, whether or not the method routinely provides precise quantitative estimates of residual confounding, the method appears to produce a valuable qualitative estimate of the likely direction and general size of residual confounding. Limitations:  Uncertainties exist, including identifying the best approaches for: 1) predicting the amount of confounding amplification, 2) minimizing changes between the nested models unrelated to confounding amplification, 3) adjusting for the association of the introduced variable(s) with outcome, and 4) deriving confidence intervals for the method’s estimates (although bootstrapping is one plausible approach). Conclusions:  To this author’s knowledge, it has not been previously suggested that the phenomenon of confounding amplification, if such amplification is as predictable as suggested by a recent simulation, provides a logical basis for estimating total residual confounding. The method's basic approach is

  13. Using an instrumental variable to test for unmeasured confounding

    PubMed Central

    Guo, Zijian; Cheng, Jing; Lorch, Scott A.; Small, Dylan S.

    2014-01-01

    An important concern in an observational study is whether or not there is unmeasured confounding, that is, unmeasured ways in which the treatment and control groups differ before treatment which affect the outcome. We develop a test of whether there is unmeasured confounding when an instrumental variable (IV) is available. An IV is a variable that is independent of the unmeasured confounding and encourages a subject to take one treatment level versus another, while having no effect on the outcome beyond its encouragement of a certain treatment level. We show what types of unmeasured confounding can be tested for with an IV and develop a test for this type of unmeasured confounding that has correct type I error rate. We show that the widely used Durbin–Wu–Hausman test can have inflated type I error rates when there is treatment effect heterogeneity. Additionally, we show that our test provides more insight into the nature of the unmeasured confounding than the Durbin–Wu–Hausman test. We apply our test to an observational study of the effect of a premature infant being delivered in a high-level neonatal intensive care unit (one with mechanical assisted ventilation and high volume) versus a lower level unit, using the excess travel time a mother lives from the nearest high-level unit to the nearest lower-level unit as an IV. PMID:24930696

  14. Methods to control for unmeasured confounding in pharmacoepidemiology: an overview.

    PubMed

    Uddin, Md Jamal; Groenwold, Rolf H H; Ali, Mohammed Sanni; de Boer, Anthonius; Roes, Kit C B; Chowdhury, Muhammad A B; Klungel, Olaf H

    2016-06-01

    Background Unmeasured confounding is one of the principal problems in pharmacoepidemiologic studies. Several methods have been proposed to detect or control for unmeasured confounding either at the study design phase or the data analysis phase. Aim of the Review To provide an overview of commonly used methods to detect or control for unmeasured confounding and to provide recommendations for proper application in pharmacoepidemiology. Methods/Results Methods to control for unmeasured confounding in the design phase of a study are case only designs (e.g., case-crossover, case-time control, self-controlled case series) and the prior event rate ratio adjustment method. Methods that can be applied in the data analysis phase include, negative control method, perturbation variable method, instrumental variable methods, sensitivity analysis, and ecological analysis. A separate group of methods are those in which additional information on confounders is collected from a substudy. The latter group includes external adjustment, propensity score calibration, two-stage sampling, and multiple imputation. Conclusion As the performance and application of the methods to handle unmeasured confounding may differ across studies and across databases, we stress the importance of using both statistical evidence and substantial clinical knowledge for interpretation of the study results.

  15. Using an instrumental variable to test for unmeasured confounding.

    PubMed

    Guo, Zijian; Cheng, Jing; Lorch, Scott A; Small, Dylan S

    2014-09-10

    An important concern in an observational study is whether or not there is unmeasured confounding, that is, unmeasured ways in which the treatment and control groups differ before treatment, which affect the outcome. We develop a test of whether there is unmeasured confounding when an instrumental variable (IV) is available. An IV is a variable that is independent of the unmeasured confounding and encourages a subject to take one treatment level versus another, while having no effect on the outcome beyond its encouragement of a certain treatment level. We show what types of unmeasured confounding can be tested for with an IV and develop a test for this type of unmeasured confounding that has correct type I error rate. We show that the widely used Durbin-Wu-Hausman test can have inflated type I error rates when there is treatment effect heterogeneity. Additionally, we show that our test provides more insight into the nature of the unmeasured confounding than the Durbin-Wu-Hausman test. We apply our test to an observational study of the effect of a premature infant being delivered in a high-level neonatal intensive care unit (one with mechanical assisted ventilation and high volume) versus a lower level unit, using the excess travel time a mother lives from the nearest high-level unit to the nearest lower-level unit as an IV.

  16. Environmental confounding in gene-environment interaction studies.

    PubMed

    Vanderweele, Tyler J; Ko, Yi-An; Mukherjee, Bhramar

    2013-07-01

    We show that, in the presence of uncontrolled environmental confounding, joint tests for the presence of a main genetic effect and gene-environment interaction will be biased if the genetic and environmental factors are correlated, even if there is no effect of either the genetic factor or the environmental factor on the disease. When environmental confounding is ignored, such tests will in fact reject the joint null of no genetic effect with a probability that tends to 1 as the sample size increases. This problem with the joint test vanishes under gene-environment independence, but it still persists if estimating the gene-environment interaction parameter itself is of interest. Uncontrolled environmental confounding will bias estimates of gene-environment interaction parameters even under gene-environment independence, but it will not do so if the unmeasured confounding variable itself does not interact with the genetic factor. Under gene-environment independence, if the interaction parameter without controlling for the environmental confounder is nonzero, then there is gene-environment interaction either between the genetic factor and the environmental factor of interest or between the genetic factor and the unmeasured environmental confounder. We evaluate several recently proposed joint tests in a simulation study and discuss the implications of these results for the conduct of gene-environment interaction studies.

  17. Opportunities for minimization of confounding in observational research.

    PubMed

    Quartey, George; Feudjo-Tepie, Maurille; Wang, Jixian; Kim, Joseph

    2011-01-01

    Observational epidemiological studies are increasingly used in pharmaceutical research to evaluate the safety and effectiveness of medicines. Such studies can complement findings from randomized clinical trials by involving larger and more generalizable patient populations by accruing greater durations of follow-up and by representing what happens more typically in the clinical setting. However, the interpretation of exposure effects in observational studies is almost always complicated by non-random exposure allocation, which can result in confounding and potentially lead to misleading conclusions. Confounding occurs when an extraneous factor, related to both the exposure and the outcome of interest, partly or entirely explains the relationship observed between the study exposure and the outcome. Although randomization can eliminate confounding by distributing all such extraneous factors equally across the levels of a given exposure, methods for dealing with confounding in observational studies include a careful choice of study design and the possible use of advanced analytical methods. The aim of this paper is to introduce some of the approaches that can be used to help minimize the impact of confounding in observational research to the reader working in the pharmaceutical industry.

  18. Literature-Based Discovery of Confounding in Observational Clinical Data

    PubMed Central

    Malec, Scott A.; Wei, Peng; Xu, Hua; Bernstam, Elmer V.; Myneni, Sahiti; Cohen, Trevor

    2016-01-01

    Observational data recorded in the Electronic Health Record (EHR) can help us better understand the effects of therapeutic agents in routine clinical practice. As such data were not collected for research purposes, their reuse for research must compensate for additional information that may bias analyses and lead to faulty conclusions. Confounding is present when factors aside from the given predictor(s) affect the response of interest. However, these additional factors may not be known at the outset. In this paper, we present a scalable literature-based confounding variable discovery method for biomedical research applications with pharmacovigilance as our use case. We hypothesized that statistical models, adjusted with literature-derived confounders, will more accurately identify causative drug-adverse drug event (ADE) relationships. We evaluated our method with a curated reference standard, and found a pattern of improved performance ~ 5% in two out of three models for gastrointestinal bleeding (pre-adjusted Area Under Curve ≥ 0.6). PMID:28269951

  19. Methodological problems with population cancer studies: The forgotten confounding factors

    PubMed Central

    Blaylock, Russell L.

    2015-01-01

    Among clinical physicians it is the population study that is considered to be the “gold standard” of medical evidence concerning acceptable treatments. As new information comes to light concerning the many variables and confounding factors that can affect such studies, many older studies lose much of their original impact. While newer population studies take into consideration a far greater number of confounding factors many are still omitted and a number of these omitted factors can have profound effects on interpretation and validity of the study. In this editorial, I will discuss some of the omitted confounding factors and demonstrate how they can alter the interpretation of these papers and their clinical application. PMID:26097772

  20. Air Pollution and Autism Spectrum Disorders: Causal or Confounded?

    PubMed

    Weisskopf, Marc G; Kioumourtzoglou, Marianthi-Anna; Roberts, Andrea L

    2015-12-01

    In the last decade, several studies have examined the association between perinatal exposure to ambient air pollution and risk of autism spectrum disorder (ASD). These studies have largely been consistent, with associations seen with different aspects of air pollution, including hazardous air toxics, ozone, particulate, and traffic-related pollution. Confounding by socioeconomic status (SES) and place of residence are of particular concern, as these can be related to ASD case ascertainment and other potential causal risk factors for ASD. While all studies take steps to address this concern, residual confounding is difficult to rule out. Two recent studies of air pollution and ASD, however, present findings that strongly argue against residual confounding, especially for factors that do not vary over relatively short time intervals. These two studies, conducted in communities around the USA, found a specific association with air pollution exposure during the 3rd, but not the 1st, trimester, when both trimesters were modeled simultaneously. In this review, we discuss confounding possibilities and then explain-with the aid of directed acyclic graphs (DAGs)-why an association that is specific to a particular time window, when multiple exposure windows are simultaneously assessed, argues against residual confounding by (even unmeasured) non-time-varying factors. In addition, we discuss why examining ambient air pollution concentration as a proxy for personal exposure helps avoid confounding by personal behavior differences, and the implications of measurement error in using ambient concentrations as a proxy for personal exposures. Given the general consistency of findings across studies and the exposure-window-specific associations recently reported, the overall evidence for a causal association between air pollution and ASD is increasingly compelling.

  1. Confounding and exposure measurement error in air pollution epidemiology.

    PubMed

    Sheppard, Lianne; Burnett, Richard T; Szpiro, Adam A; Kim, Sun-Young; Jerrett, Michael; Pope, C Arden; Brunekreef, Bert

    2012-06-01

    Studies in air pollution epidemiology may suffer from some specific forms of confounding and exposure measurement error. This contribution discusses these, mostly in the framework of cohort studies. Evaluation of potential confounding is critical in studies of the health effects of air pollution. The association between long-term exposure to ambient air pollution and mortality has been investigated using cohort studies in which subjects are followed over time with respect to their vital status. In such studies, control for individual-level confounders such as smoking is important, as is control for area-level confounders such as neighborhood socio-economic status. In addition, there may be spatial dependencies in the survival data that need to be addressed. These issues are illustrated using the American Cancer Society Cancer Prevention II cohort. Exposure measurement error is a challenge in epidemiology because inference about health effects can be incorrect when the measured or predicted exposure used in the analysis is different from the underlying true exposure. Air pollution epidemiology rarely if ever uses personal measurements of exposure for reasons of cost and feasibility. Exposure measurement error in air pollution epidemiology comes in various dominant forms, which are different for time-series and cohort studies. The challenges are reviewed and a number of suggested solutions are discussed for both study domains.

  2. The Threshold of Embedded M Collider Bias and Confounding Bias

    ERIC Educational Resources Information Center

    Kelcey, Benjamin; Carlisle, Joanne

    2011-01-01

    Of particular import to this study, is collider bias originating from stratification on retreatment variables forming an embedded M or bowtie structural design. That is, rather than assume an M structural design which suggests that "X" is a collider but not a confounder, the authors adopt what they consider to be a more reasonable…

  3. The relation of collapsibility and confounding to faithfulness and stability.

    PubMed

    Mansournia, Mohammad Ali; Greenland, Sander

    2015-07-01

    A probability distribution may have some properties that are stable under a structure (e.g., a causal graph) and other properties that are unstable. Stable properties are implied by the structure and thus will be shared by populations following the structure. In contrast, unstable properties correspond to special circumstances that are unlikely to be replicated across those populations. A probability distribution is faithful to the structure if all independencies in the distribution are logical consequences of the structure. We explore the distinction between confounding and noncollapsibility in relation to the concepts of faithfulness and stability. Simple collapsibility of an odds ratio over a risk factor is unstable and thus unlikely if the exposure affects the outcome, whether or not the risk factor is associated with exposure. For a binary exposure with no effect, collapsibility over a confounder also requires unfaithfulness. Nonetheless, if present, simple collapsibility of the odds ratio limits the degree of confounding by the covariate. Collapsibility of effect measures is stable if the covariate is independent of the outcome given exposure, but it is unstable if the covariate is an instrumental variable. Understanding stable and unstable properties of distributions under causal structures, and the distinction between stability and faithfulness, yields important insights into the correspondence between noncollapsibility and confounding.

  4. Causal diagrams and multivariate analysis III: confound it!

    PubMed

    Jupiter, Daniel C

    2015-01-01

    This commentary concludes my series concerning inclusion of variables in multivariate analyses. We take up the issues of confounding and effect modification and summarize the work we have thus far done. Finally, we provide a rough algorithm to help guide us through the maze of possibilities that we have outlined.

  5. Simultaneous dimension reduction and adjustment for confounding variation.

    PubMed

    Lin, Zhixiang; Yang, Can; Zhu, Ying; Duchi, John; Fu, Yao; Wang, Yong; Jiang, Bai; Zamanighomi, Mahdi; Xu, Xuming; Li, Mingfeng; Sestan, Nenad; Zhao, Hongyu; Wong, Wing Hung

    2016-12-20

    Dimension reduction methods are commonly applied to high-throughput biological datasets. However, the results can be hindered by confounding factors, either biological or technical in origin. In this study, we extend principal component analysis (PCA) to propose AC-PCA for simultaneous dimension reduction and adjustment for confounding (AC) variation. We show that AC-PCA can adjust for (i) variations across individual donors present in a human brain exon array dataset and (ii) variations of different species in a model organism ENCODE RNA sequencing dataset. Our approach is able to recover the anatomical structure of neocortical regions and to capture the shared variation among species during embryonic development. For gene selection purposes, we extend AC-PCA with sparsity constraints and propose and implement an efficient algorithm. The methods developed in this paper can also be applied to more general settings. The R package and MATLAB source code are available at https://github.com/linzx06/AC-PCA.

  6. Gaseous pollutants in particulate matter epidemiology: confounders or surrogates?

    PubMed Central

    Sarnat, J A; Schwartz, J; Catalano, P J; Suh, H H

    2001-01-01

    Air pollution epidemiologic studies use ambient pollutant concentrations as surrogates of personal exposure. Strong correlations among numerous ambient pollutant concentrations, however, have made it difficult to determine the relative contribution of each pollutant to a given health outcome and have led to criticism that health effect estimates for particulate matter may be biased due to confounding. In the current study we used data collected from a multipollutant exposure study conducted in Baltimore, Maryland, during both the summer and winter to address the potential for confounding further. Twenty-four-hour personal exposures and corresponding ambient concentrations to fine particulate matter (PM(2.5)), ozone, nitrogen dioxide, sulfur dioxide, and carbon monoxide were measured for 56 subjects. Results from correlation and regression analyses showed that personal PM(2.5) and gaseous air pollutant exposures were generally not correlated, as only 9 of the 178 individual-specific pairwise correlations were significant. Similarly, ambient concentrations were not associated with their corresponding personal exposures for any of the pollutants, except for PM(2.5), which had significant associations during both seasons (p < 0.0001). Ambient gaseous concentrations were, however, strongly associated with personal PM(2.5) exposures. The strongest associations were shown between ambient O(3) and personal PM(2.5) (p < 0.0001 during both seasons). These results indicate that ambient PM(2.5) concentrations are suitable surrogates for personal PM(2.5) exposures and that ambient gaseous concentrations are surrogates, as opposed to confounders, of PM(2.5). These findings suggest that the use of multiple pollutant models in epidemiologic studies of PM(2.5) may not be suitable and that health effects attributed to the ambient gases may actually be a result of exposures to PM(2.5). PMID:11675271

  7. Carotta: Revealing Hidden Confounder Markers in Metabolic Breath Profiles

    PubMed Central

    Hauschild, Anne-Christin; Frisch, Tobias; Baumbach, Jörg Ingo; Baumbach, Jan

    2015-01-01

    Computational breath analysis is a growing research area aiming at identifying volatile organic compounds (VOCs) in human breath to assist medical diagnostics of the next generation. While inexpensive and non-invasive bioanalytical technologies for metabolite detection in exhaled air and bacterial/fungal vapor exist and the first studies on the power of supervised machine learning methods for profiling of the resulting data were conducted, we lack methods to extract hidden data features emerging from confounding factors. Here, we present Carotta, a new cluster analysis framework dedicated to uncovering such hidden substructures by sophisticated unsupervised statistical learning methods. We study the power of transitivity clustering and hierarchical clustering to identify groups of VOCs with similar expression behavior over most patient breath samples and/or groups of patients with a similar VOC intensity pattern. This enables the discovery of dependencies between metabolites. On the one hand, this allows us to eliminate the effect of potential confounding factors hindering disease classification, such as smoking. On the other hand, we may also identify VOCs associated with disease subtypes or concomitant diseases. Carotta is an open source software with an intuitive graphical user interface promoting data handling, analysis and visualization. The back-end is designed to be modular, allowing for easy extensions with plugins in the future, such as new clustering methods and statistics. It does not require much prior knowledge or technical skills to operate. We demonstrate its power and applicability by means of one artificial dataset. We also apply Carotta exemplarily to a real-world example dataset on chronic obstructive pulmonary disease (COPD). While the artificial data are utilized as a proof of concept, we will demonstrate how Carotta finds candidate markers in our real dataset associated with confounders rather than the primary disease (COPD) and bronchial

  8. Saccade-confounded image statistics explain visual crowding.

    PubMed

    Nandy, Anirvan S; Tjan, Bosco S

    2012-01-08

    Processing of shape information in human peripheral visual fields is impeded beyond what can be expected by poor spatial resolution. Visual crowding, the inability to identify objects in clutter, has been shown to be the primary factor limiting shape perception in peripheral vision. Despite the well-documented effects of crowding, its underlying causes remain poorly understood. Given that spatial attention both facilitates learning of image statistics and directs saccadic eye movements, we propose that the acquisition of image statistics in peripheral visual fields is confounded by eye-movement artifacts. Specifically, the image statistics acquired under a peripherally deployed spotlight of attention are systematically biased by saccade-induced image displacements. These erroneously represented image statistics lead to inappropriate contextual interactions in the periphery and cause crowding.

  9. Negative Confounding by Essential Fatty Acids in Methylmercury Neurotoxicity Associations

    PubMed Central

    Choi, Anna L; Mogensen, Ulla B.; Bjerve, Kristian S.; Debes, Frodi; Weihe, Pal; Grandjean, Philippe; Budtz-Jørgensen, Esben

    2014-01-01

    Background Methylmercury, a worldwide contaminant of fish and seafood, can cause adverse effects on the developing nervous system. However, long-chain n-3 polyunsaturated fatty acids in seafood provide beneficial effects on brain development. Negative confounding will likely result in underestimation of both mercury toxicity and nutrient benefits unless mutual adjustment is included in the analysis. Methods We examined these associations in 176 Faroese children, in whom prenatal methylmercury exposure was assessed from mercury concentrations in cord blood and maternal hair. The relative concentrations of fatty acids were determined in cord serum phospholipids. Neuropsychological performance in verbal, motor, attention, spatial, and memory functions was assessed at 7 years of age. Multiple regression and structural equation models (SEMs) were carried out to determine the confounder-adjusted associations with methylmercury exposure. Results A short delay recall (in percent change) in the California Verbal Learning Test (CVLT) was associated with a doubling of cord blood methylmercury (−18.9, 95% confidence interval [CI] = −36.3, −1.51). The association became stronger after the inclusion of fatty acid concentrations in the analysis (−22.0, 95% confidence interval [CI] = −39.4, −4.62). In structural equation models, poorer memory function (corresponding to a lower score in the learning trials and short delay recall in CVLT) was associated with a doubling of prenatal exposure to methylmercury after the inclusion of fatty acid concentrations in the analysis (−1.94, 95% CI = −3.39, −0.49). Conclusions Associations between prenatal exposure to methylmercury and neurobehavioral deficits in memory function at school age were strengthened after fatty acid adjustment, thus suggesting that n-3 fatty acids need to be included in analysis of similar studies to avoid underestimation of the associations with methylmercury exposure. PMID:24561639

  10. NFR TRIGA package design review report

    SciTech Connect

    Clements, M.D.

    1994-08-26

    The purpose of this document is to compile, present and document the formal design review of the NRF TRIGA packaging. The contents of this document include: the briefing meeting presentations, package description, design calculations, package review drawings, meeting minutes, action item lists, review comment records, final resolutions, and released drawings. This design review required more than two meeting to resolve comments. Therefore, there are three meeting minutes and two action item lists.

  11. Heterogeneity Confounds Establishment of "a" Model Microbial Strain.

    PubMed

    Keller, Nancy P

    2017-02-21

    Aspergillus fumigatus is a ubiquitous environmental mold and the leading cause of diverse human diseases ranging from allergenic bronchopulmonary aspergillosis (ABPA) to invasive pulmonary aspergillosis (IPA). Experimental investigations of the biology and virulence of this opportunistic pathogen have historically used a few type strains; however, it is increasingly observed with this fungus that heterogeneity among isolates potentially confounds the use of these reference isolates. Illustrating this point, Kowalski et al. (mBio 7:e01515-16, 2016, https://doi.org/10.1128/mBio.01515-16) demonstrated that variation in 16 environmental and clinical isolates of A. fumigatus correlated virulence with fitness in low oxygen, whereas Fuller et al. (mBio 7:e01517-16, 2016, https://doi.org/10.1128/mBio.01517-16) showed wide variation in light responses at a physiological and protein functionality level in 15 A. fumigatus isolates. In both studies, two commonly used type strains, Af293 and CEA10, displayed significant differences in physiological responses to abiotic stimuli and virulence in a murine model of IPA.

  12. Smoking and hormesis as confounding factors in radiation pulmonary carcinogenesis.

    PubMed

    Sanders, Charles L; Scott, Bobby R

    2006-12-06

    Confounding factors in radiation pulmonary carcinogenesis are passive and active cigarette smoke exposures and radiation hormesis. Significantly increased lung cancer risk from ionizing radiation at lung doses < 1 Gy is not observed in never smokers exposed to ionizing radiations. Residential radon is not a cause of lung cancer in never smokers and may protect against lung cancer in smokers. The risk of lung cancer found in many epidemiological studies was less than the expected risk (hormetic effect) for nuclear weapons and power plant workers, shipyard workers, fluoroscopy patients, and inhabitants of high-dose background radiation. The protective effect was noted for low- and mixed high- and low-linear energy transfer (LET) radiations in both genders. Many studies showed a protection factor (PROFAC) > 0.40 (40% avoided) against the occurrence of lung cancer. The ubiquitous nature of the radiation hormesis response in cellular, animal, and epidemio-logical studies negates the healthy worker effect as an explanation for radiation hormesis. Low-dose radiation may stimulate DNA repair/apoptosis and immunity to suppress and eliminate cigarette-smoke-induced transformed cells in the lung, reducing lung cancer occurrence in smokers.

  13. Distribution-free mediation analysis for nonlinear models with confounding.

    PubMed

    Albert, Jeffrey M

    2012-11-01

    Recently, researchers have used a potential-outcome framework to estimate causally interpretable direct and indirect effects of an intervention or exposure on an outcome. One approach to causal-mediation analysis uses the so-called mediation formula to estimate the natural direct and indirect effects. This approach generalizes the classical mediation estimators and allows for arbitrary distributions for the outcome variable and mediator. A limitation of the standard (parametric) mediation formula approach is that it requires a specified mediator regression model and distribution; such a model may be difficult to construct and may not be of primary interest. To address this limitation, we propose a new method for causal-mediation analysis that uses the empirical distribution function, thereby avoiding parametric distribution assumptions for the mediator. To adjust for confounders of the exposure-mediator and exposure-outcome relationships, inverse-probability weighting is incorporated based on a supplementary model of the probability of exposure. This method, which yields the estimates of the natural direct and indirect effects for a specified reference group, is applied to data from a cohort study of dental caries in very-low-birth-weight adolescents to investigate the oral-hygiene index as a possible mediator. Simulation studies show low bias in the estimation of direct and indirect effects in a variety of distribution scenarios, whereas the standard mediation formula approach can be considerably biased when the distribution of the mediator is incorrectly specified.

  14. Heterogeneity Confounds Establishment of “a” Model Microbial Strain

    PubMed Central

    2017-01-01

    ABSTRACT Aspergillus fumigatus is a ubiquitous environmental mold and the leading cause of diverse human diseases ranging from allergenic bronchopulmonary aspergillosis (ABPA) to invasive pulmonary aspergillosis (IPA). Experimental investigations of the biology and virulence of this opportunistic pathogen have historically used a few type strains; however, it is increasingly observed with this fungus that heterogeneity among isolates potentially confounds the use of these reference isolates. Illustrating this point, Kowalski et al. (mBio 7:e01515-16, 2016, https://doi.org/10.1128/mBio.01515-16) demonstrated that variation in 16 environmental and clinical isolates of A. fumigatus correlated virulence with fitness in low oxygen, whereas Fuller et al. (mBio 7:e01517-16, 2016, https://doi.org/10.1128/mBio.01517-16) showed wide variation in light responses at a physiological and protein functionality level in 15 A. fumigatus isolates. In both studies, two commonly used type strains, Af293 and CEA10, displayed significant differences in physiological responses to abiotic stimuli and virulence in a murine model of IPA. PMID:28223452

  15. Diagnostic and therapeutic strategy for confounding radiation myelitis.

    PubMed

    Higashida, Tetsuhiro; Colen, Chaim B; Guthikonda, Murali

    2010-05-01

    We report a case of confounding radiation myelitis to demonstrate the usefulness of surgical biopsy in ensuring the correct diagnosis and to avoid unnecessary treatment. The patient was a 40-year-old man with a history of epiglottis carcinoma and sarcoidosis. Six months after radiation therapy and chemotherapy for epiglottis carcinoma, he noticed paresthesia and dysesthesia in the left arm and leg. Two months after that, he complained of severe neck pain and rapidly progressing weakness in all extremities. MRI showed an enhanced intramedullary lesion with extensive edema in the cervical spinal cord. Radiation myelitis, intramedullary spinal tumor, and neurosarcoidosis were considered as differential diagnoses. Spinal cord biopsy with laminectomy was performed and radiation myelitis was diagnosed. After the surgery, the lesion was significantly decreased in size even though corticosteroid therapy was rapidly tapered. We emphasize that a spinal cord biopsy is indicated to obtain a pathological diagnosis and to make a clear treatment strategy for patients with associated diseases causing lesions of the spinal cord.

  16. Packet Randomized Experiments for Eliminating Classes of Confounders

    PubMed Central

    Pavela, Greg; Wiener, Howard; Fontaine, Kevin R.; Fields, David A.; Voss, Jameson D.; Allison, David B.

    2014-01-01

    Background Although randomization is considered essential for causal inference, it is often not possible to randomize in nutrition and obesity research. To address this, we develop a framework for an experimental design—packet randomized experiments (PREs), which improves causal inferences when randomization on a single treatment variable is not possible. This situation arises when subjects are randomly assigned to a condition (such as a new roommate) which varies in one characteristic of interest (such as weight), but also varies across many others. There has been no general discussion of this experimental design, including its strengths, limitations, and statistical properties. As such, researchers are left to develop and apply PREs on an ad hoc basis, limiting its potential to improve causal inferences among nutrition and obesity researchers. Methods We introduce PREs as an intermediary design between randomized controlled trials and observational studies. We review previous research that used the PRE design and describe its application in obesity-related research, including random roommate assignments, heterochronic parabiosis, and the quasi-random assignment of subjects to geographic areas. We then provide a statistical framework to control for potential packet-level confounders not accounted for by randomization. Results PREs have successfully been used to improve causal estimates of the effect of roommates, altitude, and breastfeeding on weight outcomes. When certain assumptions are met, PREs can asymptotically control for packet-level characteristics. This has the potential to statistically estimate the effect of a single treatment even when randomization to a single treatment did not occur. Conclusions Applying PREs to obesity-related research will improve decisions about clinical, public health, and policy actions insofar as it offers researchers new insight into cause and effect relationships among variables. PMID:25444088

  17. HIV-1: the confounding variables of virus neutralization.

    PubMed

    Nara, Peter L; Lin, George

    2005-06-01

    The development of an effective vaccine against HIV-1 would be greatly facilitated by the ability to elicit potent, high affinity antibodies that are capable of broad neutralization, viral inactivation and protection against infection and/or disease. New insights into the structure and function of the HIV-1 envelope glycoprotein (Env) that mediates viral fusion and entry may ultimately lead to strategies successful in eliciting these protective antibody responses. Insights have been gained regarding HIV-1 Env attachment and receptor engagement, the fusion process and kinetics, and the structural/functional attributes of Env that allow humoral immune evasion. In addition, studies of a limited number of broadly neutralizing human monoclonal antibodies have shed some light as to how antibodies may penetrate the immune evading armor that HIV-1 has evolved. As the elusive goal of generating these types of antibodies emerge and are developed in the context of generating new candidate HIV-1 vaccines, a relevant in vitro measurement of neutralization by these types of antibodies becomes a complex task. This is in part due to a list of confounding variables which include: the physical and genomic nature (amino acid variation) of the infecting virion, the type of target cells, the concentration and clonality of the reactants, assay format and design, the affinity and kinetics of the reaction, receptors/coreceptors and attachment factors, and soluble host factors. This review will focus on the past, current, and future knowledge required to advance the field of HIV-1 humoral immunity as it impacts future HIV-1 vaccine development.

  18. Handling stress may confound murine gut microbiota studies

    PubMed Central

    Allen-Blevins, Cary R.; You, Xiaomeng; Hinde, Katie

    2017-01-01

    Background Accumulating evidence indicates interactions between human milk composition, particularly sugars (human milk oligosaccharides or HMO), the gut microbiota of human infants, and behavioral effects. Some HMO secreted in human milk are unable to be endogenously digested by the human infant but are able to be metabolized by certain species of gut microbiota, including Bifidobacterium longum subsp. infantis (B. infantis), a species sensitive to host stress (Bailey & Coe, 2004). Exposure to gut bacteria like B. infantisduring critical neurodevelopment windows in early life appears to have behavioral consequences; however, environmental, physical, and social stress during this period can also have behavioral and microbial consequences. While rodent models are a useful method for determining causal relationships between HMO, gut microbiota, and behavior, murine studies of gut microbiota usually employ oral gavage, a technique stressful to the mouse. Our aim was to develop a less-invasive technique for HMO administration to remove the potential confound of gavage stress. Under the hypothesis that stress affects gut microbiota, particularly B. infantis, we predicted the pups receiving a prebiotic solution in a less-invasive manner would have the highest amount of Bifidobacteria in their gut. Methods This study was designed to test two methods, active and passive, of solution administration to mice and the effects on their gut microbiome. Neonatal C57BL/6J mice housed in a specific-pathogen free facility received increasing doses of fructooligosaccharide (FOS) solution or deionized, distilled water. Gastrointestinal (GI) tracts were collected from five dams, six sires, and 41 pups over four time points. Seven fecal pellets from unhandled pups and two pellets from unhandled dams were also collected. Qualitative real-time polymerase chain reaction (qRT-PCR) was used to quantify and compare the amount of Bifidobacterium, Bacteroides, Bacteroidetes, and Firmicutes

  19. Determining confounding sensitivities in eddy current thin film measurements

    NASA Astrophysics Data System (ADS)

    Gros, Ethan; Udpa, Lalita; Smith, James A.; Wachs, Katelyn

    2017-02-01

    Eddy current (EC) techniques are widely used in industry to measure the thickness of non-conductive films on a metal substrate. This is done by using a system whereby a coil carrying a high-frequency alternating current is used to create an alternating magnetic field at the surface of the instrument's probe. When the probe is brought near a conductive surface, the alternating magnetic field will induce ECs in the conductor. The substrate characteristics and the distance of the probe from the substrate (the coating thickness) affect the magnitude of the ECs. The induced currents load the probe coil affecting the terminal impedance of the coil. The measured probe impedance is related to the lift off between coil and conductor as well as conductivity of the test sample. For a known conductivity sample, the probe impedance can be converted into an equivalent film thickness value. The EC measurement can be confounded by a number of measurement parameters. It was the goal of this research to determine which physical properties of the measurement set-up and sample can adversely affect the thickness measurement. The eddy-current testing was performed using a commercially available, hand-held eddy-current probe (ETA3.3H spring-loaded eddy probe running at 8 MHz) that comes with a stand to hold the probe. The stand holds the probe and adjusts the probe on the z-axis to help position the probe in the correct area as well as make precise measurements. The signal from the probe was sent to a hand-held readout, where the results are recorded directly in terms of liftoff or film thickness. Understanding the effect of certain factors on the measurements of film thickness, will help to evaluate how accurate the ETA3.3H spring-loaded eddy probe was at measuring film thickness under varying experimental conditions. This research studied the effects of a number of factors such as i) conductivity, ii) edge effect, iii) surface finish of base material and iv) cable condition.

  20. Control of confounding in the analysis phase – an overview for clinicians

    PubMed Central

    Kahlert, Johnny; Gribsholt, Sigrid Bjerge; Gammelager, Henrik; Dekkers, Olaf M; Luta, George

    2017-01-01

    In observational studies, control of confounding can be done in the design and analysis phases. Using examples from large health care database studies, this article provides the clinicians with an overview of standard methods in the analysis phase, such as stratification, standardization, multivariable regression analysis and propensity score (PS) methods, together with the more advanced high-dimensional propensity score (HD-PS) method. We describe the progression from simple stratification confined to the inclusion of a few potential confounders to complex modeling procedures such as the HD-PS approach by which hundreds of potential confounders are extracted from large health care databases. Stratification and standardization assist in the understanding of the data at a detailed level, while accounting for potential confounders. Incorporating several potential confounders in the analysis typically implies the choice between multivariable analysis and PS methods. Although PS methods have gained remarkable popularity in recent years, there is an ongoing discussion on the advantages and disadvantages of PS methods as compared to those of multivariable analysis. Furthermore, the HD-PS method, despite its generous inclusion of potential confounders, is also associated with potential pitfalls. All methods are dependent on the assumption of no unknown, unmeasured and residual confounding and suffer from the difficulty of identifying true confounders. Even in large health care databases, insufficient or poor data may contribute to these challenges. The trend in data collection is to compile more fine-grained data on lifestyle and severity of diseases, based on self-reporting and modern technologies. This will surely improve our ability to incorporate relevant confounders or their proxies. However, despite a remarkable development of methods that account for confounding and new data opportunities, confounding will remain a serious issue. Considering the advantages and

  1. Confounding by dietary pattern of the inverse association between alcohol consumption and type 2 diabetes risk

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Epidemiology of dietary components and disease risk limits interpretability due to potential residual confounding by correlated dietary components. Dietary pattern analyses by factor analysis or partial least squares may overcome the limitation. To examine confounding by dietary pattern as well as ...

  2. Bed Sharing, SIDS Research, and the Concept of Confounding: A Review for Public Health Nurses.

    PubMed

    Keys, Elizabeth M; Rankin, James A

    2015-01-01

    Confounding is an important concept for public health nurses (PHNs) to understand when considering the results of epidemiological research. The term confounding is derived from Latin, confundere, which means to "mix-up" or "mix together". Epidemiologists attempt to derive a cause and effect relationship between two variables traditionally known as the exposure and disease (e.g., smoking and lung cancer). Confounding occurs when a third factor, known as a confounder, leads to an over- or underestimate of the magnitude of the association between the exposure and disease. An understanding of confounding will facilitate critical appraisal of epidemiological research findings. This knowledge will enable PHNs to strengthen their evidence-based practice and better prepare them for policy development and implementation. In recent years, researchers and clinicians have examined the relationship between bed sharing and sudden infant death syndrome (SIDS). The discussion regarding the risk of bed sharing and SIDS provides ample opportunity to discuss the various aspects of confounding. The purpose of this article is to use the bed sharing and SIDS literature to assist PHNs to understand confounding and to apply this knowledge when appraising epidemiological research. In addition, strategies that are used to control confounding are discussed.

  3. Structural confounding of area-level deprivation and segreation: an empirical example

    EPA Science Inventory

    The neighborhood effects literature has grown, but its utility is limited by the lack of attention paid to non-random selection into neighborhoods. Confounding occurs when an exposure and an outcome share an underlying common cause. Confounding resulting from differential allocat...

  4. Confounding by dietary patterns of the inverse association between alcohol consumption and type 2 diabetes risk

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Epidemiology of dietary components and disease risk limits interpretability due to potential residual confounding by correlated dietary components. Dietary pattern analyses by factor analysis or partial least squares may overcome this limitation. To examine confounding by dietary pattern as well as ...

  5. Bayesian modeling of cost-effectiveness studies with unmeasured confounding: a simulation study.

    PubMed

    Stamey, James D; Beavers, Daniel P; Faries, Douglas; Price, Karen L; Seaman, John W

    2014-01-01

    Unmeasured confounding is a common problem in observational studies. Failing to account for unmeasured confounding can result in biased point estimators and poor performance of hypothesis tests and interval estimators. We provide examples of the impacts of unmeasured confounding on cost-effectiveness analyses using observational data along with a Bayesian approach to correct estimation. Assuming validation data are available, we propose a Bayesian approach to correct cost-effectiveness studies for unmeasured confounding. We consider the cases where both cost and effectiveness are assumed to have a normal distribution and when costs are gamma distributed and effectiveness is normally distributed. Simulation studies were conducted to determine the impact of ignoring the unmeasured confounder and to determine the size of the validation data required to obtain valid inferences.

  6. Biochemical transformation of coals

    DOEpatents

    Lin, Mow S.; Premuzic, Eugene T.

    1999-03-23

    A method of biochemically transforming macromolecular compounds found in solid carbonaceous materials, such as coal is provided. The preparation of new microorganisms, metabolically weaned through challenge growth processes to biochemically transform solid carbonaceous materials at extreme temperatures, pressures, pH, salt and toxic metal concentrations is also disclosed.

  7. Biochemical transformation of coals

    DOEpatents

    Lin, M.S.; Premuzic, E.T.

    1999-03-23

    A method of biochemically transforming macromolecular compounds found in solid carbonaceous materials, such as coal is provided. The preparation of new microorganisms, metabolically weaned through challenge growth processes to biochemically transform solid carbonaceous materials at extreme temperatures, pressures, pH, salt and toxic metal concentrations is also disclosed. 7 figs.

  8. The control outcome calibration approach for causal inference with unobserved confounding.

    PubMed

    Tchetgen Tchetgen, Eric

    2014-03-01

    Unobserved confounding can seldom be ruled out with certainty in nonexperimental studies. Negative controls are sometimes used in epidemiologic practice to detect the presence of unobserved confounding. An outcome is said to be a valid negative control variable to the extent that it is influenced by unobserved confounders of the exposure effects on the outcome in view, although not directly influenced by the exposure. Thus, a negative control outcome found to be empirically associated with the exposure after adjustment for observed confounders indicates that unobserved confounding may be present. In this paper, we go beyond the use of control outcomes to detect possible unobserved confounding and propose to use control outcomes in a simple but formal counterfactual-based approach to correct causal effect estimates for bias due to unobserved confounding. The proposed control outcome calibration approach is developed in the context of a continuous or binary outcome, and the control outcome and the exposure can be discrete or continuous. A sensitivity analysis technique is also developed, which can be used to assess the degree to which a violation of the main identifying assumption of the control outcome calibration approach might impact inference about the effect of the exposure on the outcome in view.

  9. Does exposure prediction bias health-effect estimation?: The relationship between confounding adjustment and exposure prediction.

    PubMed

    Cefalu, Matthew; Dominici, Francesca

    2014-07-01

    In environmental epidemiology, we are often faced with 2 challenges. First, an exposure prediction model is needed to estimate the exposure to an agent of interest, ideally at the individual level. Second, when estimating the health effect associated with the exposure, confounding adjustment is needed in the health-effects regression model. The current literature addresses these 2 challenges separately. That is, methods that account for measurement error in the predicted exposure often fail to acknowledge the possibility of confounding, whereas methods designed to control confounding often fail to acknowledge that the exposure has been predicted. In this article, we consider exposure prediction and confounding adjustment in a health-effects regression model simultaneously. Using theoretical arguments and simulation studies, we show that the bias of a health-effect estimate is influenced by the exposure prediction model, the type of confounding adjustment used in the health-effects regression model, and the relationship between these 2. Moreover, we argue that even with a health-effects regression model that properly adjusts for confounding, the use of a predicted exposure can bias the health-effect estimate unless all confounders included in the health-effects regression model are also included in the exposure prediction model. While these results of this article were motivated by studies of environmental contaminants, they apply more broadly to any context where an exposure needs to be predicted.

  10. Breast milk and cognitive development—the role of confounders: a systematic review

    PubMed Central

    Walfisch, Asnat; Sermer, Corey; Cressman, Alex; Koren, Gideon

    2013-01-01

    Objectives The association between breastfeeding and child cognitive development is conflicted by studies reporting positive and null effects. This relationship may be confounded by factors associated with breastfeeding, specifically maternal socioeconomic class and IQ. Design Systematic review of the literature. Setting and participants Any prospective or retrospective study, in any language, evaluating the association between breastfeeding and cognitive development using a validated method in healthy term infants, children or adults, was included. Primary and secondary outcome measures Extracted data included the study design, target population and sample size, breastfeeding exposure, cognitive development assessment tool used and participants’ age, summary of the results prior to, and following, adjustment for confounders, and all confounders adjusted for. Study quality was assessed as well. Results 84 studies met our inclusion criteria (34 rated as high quality, 26 moderate and 24 low quality). Critical assessment of accepted studies revealed the following associations: 21 null, 28 positive, 18 null after adjusting for confounders and 17 positive—diminished after adjusting for confounders. Directionality of effect did not correlate with study quality; however, studies showing a decreased effect after multivariate analysis were of superior quality compared with other study groupings (14/17 high quality, 82%). Further, studies that showed null or diminished effect after multivariate analysis corrected for significantly more confounders (7.7±3.4) as compared with those that found no change following adjustment (5.6±4.5, p=0.04). The majority of included studies were carried out during childhood (75%) and set in high-income countries (85.5%). Conclusions Much of the reported effect of breastfeeding on child neurodevelopment is due to confounding. It is unlikely that additional work will change the current synthesis. Future studies should attempt to rigorously

  11. From bad to worse: collider stratification amplifies confounding bias in the "obesity paradox".

    PubMed

    Banack, Hailey R; Kaufman, Jay S

    2015-10-01

    Smoking is often identified as a confounder of the obesity-mortality relationship. Selection bias can amplify the magnitude of an existing confounding bias. The objective of the present report is to demonstrate how confounding bias due to cigarette smoking is increased in the presence of collider stratification bias using an empirical example and directed acyclic graphs. The empirical example uses data from the Atherosclerosis Risk in Communities (ARIC) study, a prospective cohort study of 15,792 men and women in the United States. Poisson regression models were used to examine the confounding effect of smoking. In the total ARIC study population, smoking produced a confounding bias of <3 percentage points. This result was obtained by comparing the incidence rate ratio (IRR) for obesity from a model adjusted for smoking was 1.07 (95 % CI 1.00, 1.15) with one that did not adjust for smoking was 1.10 (95 % CI 1.03, 1.18). However, among smokers with CVD, the obesity IRR was 0.89 (95 % CI 0.81, 0.99), while among non-smokers with CVD the obesity IRR was 1.20 (95 % CI 1.03, 1.41). The empirical and graphical explanations presented suggest that the magnitude of the confounding bias induced by smoking is greater in the presence of collider stratification bias.

  12. Structural equation modeling versus marginal structural modeling for assessing mediation in the presence of posttreatment confounding.

    PubMed

    Moerkerke, Beatrijs; Loeys, Tom; Vansteelandt, Stijn

    2015-06-01

    Inverse probability weighting for marginal structural models has been suggested as a strategy to estimate the direct effect of a treatment or exposure on an outcome in studies where the effect of mediator on outcome is subject to posttreatment confounding. This type of confounding, whereby confounders of the effect of mediator on outcome are themselves affected by the exposure, complicates mediation analyses and necessitates apt analysis strategies. In this article, we contrast the inverse probability weighting approach with the traditional path analysis approach to mediation analysis. We show that in a particular class of linear models, adjustment for posttreatment confounding can be realized via a fairly standard modification of the traditional path analysis approach. The resulting approach is simpler; by avoiding inverse probability weighting, it moreover results in direct effect estimators with smaller finite sample bias and greater precision. We further show that a particular variant of the G-estimation approach from the causal inference literature is equivalent with the path analysis approach in simple linear settings but is more generally applicable in settings with interactions and/or noncontinuous mediators and confounders. We conclude that the use of inverse probability weighting for marginal structural models to adjust for posttreatment confounding in mediation analysis is primarily indicated in nonlinear models for the outcome.

  13. Regularized Regression Versus the High-Dimensional Propensity Score for Confounding Adjustment in Secondary Database Analyses.

    PubMed

    Franklin, Jessica M; Eddings, Wesley; Glynn, Robert J; Schneeweiss, Sebastian

    2015-10-01

    Selection and measurement of confounders is critical for successful adjustment in nonrandomized studies. Although the principles behind confounder selection are now well established, variable selection for confounder adjustment remains a difficult problem in practice, particularly in secondary analyses of databases. We present a simulation study that compares the high-dimensional propensity score algorithm for variable selection with approaches that utilize direct adjustment for all potential confounders via regularized regression, including ridge regression and lasso regression. Simulations were based on 2 previously published pharmacoepidemiologic cohorts and used the plasmode simulation framework to create realistic simulated data sets with thousands of potential confounders. Performance of methods was evaluated with respect to bias and mean squared error of the estimated effects of a binary treatment. Simulation scenarios varied the true underlying outcome model, treatment effect, prevalence of exposure and outcome, and presence of unmeasured confounding. Across scenarios, high-dimensional propensity score approaches generally performed better than regularized regression approaches. However, including the variables selected by lasso regression in a regular propensity score model also performed well and may provide a promising alternative variable selection method.

  14. Adjustments for Unmeasured Confounders in Pharmacoepidemiologic Database Studies Using External Information

    PubMed Central

    Stürmer, Til; Glynn, Robert J; Rothman, Kenneth J; Avorn, Jerry; Schneeweiss, Sebastian

    2008-01-01

    Background Non-experimental studies of drug effects in large automated databases can provide timely assessment of real-life drug use, but are prone to confounding by variables that are not contained in these databases and thus cannot be controlled. Objectives To describe how information on additional confounders from validation studies can help address the problem of unmeasured confounding in the main study. Research Design Review types of validation studies that allow adjustment for unmeasured confounding and illustrate these with an example. Subjects: Main study New Jersey residents 65 years or older hospitalized between 1995 and 1997, who filled prescriptions within Medicaid or a pharmaceutical assistance program. Validation study: representative sample of Medicare beneficiaries. Measures Association between nonsteroidal anti-inflammatory drugs (NSAIDs) and mortality. Results Validation studies are categorized as internal (ie, additional information is collected on participants of the main study) or external. Availability of information on disease outcome will affect choice of analytic strategies. Using an external validation study without data on disease outcome to adjust for unmeasured confounding, propensity score calibration (PSC) leads to a plausible estimate of the association between NSAIDs and mortality in the elderly, if the biases caused by measured and unmeasured confounders go in the same direction. Conclusions Estimates of drug effects can be adjusted for confounders that are not available in the main but can be measured in a validation study. PSC uses validation data without information on disease outcome under a strong assumption. The collection and integration of validation data in pharmacoepidemiology should be encouraged. PMID:17909375

  15. On a preference-based instrumental variable approach in reducing unmeasured confounding-by-indication.

    PubMed

    Li, Yun; Lee, Yoonseok; Wolfe, Robert A; Morgenstern, Hal; Zhang, Jinyao; Port, Friedrich K; Robinson, Bruce M

    2015-03-30

    Treatment preferences of groups (e.g., clinical centers) have often been proposed as instruments to control for unmeasured confounding-by-indication in instrumental variable (IV) analyses. However, formal evaluations of these group-preference-based instruments are lacking. Unique challenges include the following: (i) correlations between outcomes within groups; (ii) the multi-value nature of the instruments; (iii) unmeasured confounding occurring between and within groups. We introduce the framework of between-group and within-group confounding to assess assumptions required for the group-preference-based IV analyses. Our work illustrates that, when unmeasured confounding effects exist only within groups but not between groups, preference-based IVs can satisfy assumptions required for valid instruments. We then derive a closed-form expression of asymptotic bias of the two-stage generalized ordinary least squares estimator when the IVs are valid. Simulations demonstrate that the asymptotic bias formula approximates bias in finite samples quite well, particularly when the number of groups is moderate to large. The bias formula shows that when the cluster size is finite, the IV estimator is asymptotically biased; only when both the number of groups and cluster size go to infinity, the bias disappears. However, the IV estimator remains advantageous in reducing bias from confounding-by-indication. The bias assessment provides practical guidance for preference-based IV analyses. To increase their performance, one should adjust for as many measured confounders as possible, consider groups that have the most random variation in treatment assignment and increase cluster size. To minimize the likelihood for these IVs to be invalid, one should minimize unmeasured between-group confounding.

  16. ADDRESSING CONFOUNDING WHEN ESTIMATING THE EFFECTS OF LATENT CLASSES ON A DISTAL OUTCOME.

    PubMed

    Schuler, Megan S; Leoutsakos, Jeannie-Marie S; Stuart, Elizabeth A

    2014-12-01

    Confounding is widely recognized in settings where all variables are fully observed, yet recognition of and statistical methods to address confounding in the context of latent class regression are slowly emerging. In this study we focus on confounding when regressing a distal outcome on latent class; extending standard confounding methods is not straightforward when the treatment of interest is a latent variable. We describe a recent 1-step method, as well as two 3-step methods (modal and pseudoclass assignment) that incorporate propensity score weighting. Using simulated data, we compare the performance of these three adjusted methods to an unadjusted 1-step and unadjusted 3-step method. We also present an applied example regarding adolescent substance use treatment that examines the effect of treatment service class on subsequent substance use problems. Our simulations indicated that the adjusted 1-step method and both adjusted 3-step methods significantly reduced bias arising from confounding relative to the unadjusted 1-step and 3-step approaches. However, the adjusted 1-step method performed better than the adjusted 3-step methods with regard to bias and 95% CI coverage, particularly when class separation was poor. Our applied example also highlighted the importance of addressing confounding - both unadjusted methods indicated significant differences across treatment classes with respect to the outcome, yet these class differences were not significant when using any of the three adjusted methods. Potential confounding should be carefully considered when conducting latent class regression with a distal outcome; failure to do so may results in significantly biased effect estimates or incorrect inferences.

  17. Comparison of statistical approaches dealing with time-dependent confounding in drug effectiveness studies.

    PubMed

    Karim, Mohammad Ehsanul; Petkau, John; Gustafson, Paul; Platt, Robert W; Tremlett, Helen

    2016-09-21

    In longitudinal studies, if the time-dependent covariates are affected by the past treatment, time-dependent confounding may be present. For a time-to-event response, marginal structural Cox models are frequently used to deal with such confounding. To avoid some of the problems of fitting marginal structural Cox model, the sequential Cox approach has been suggested as an alternative. Although the estimation mechanisms are different, both approaches claim to estimate the causal effect of treatment by appropriately adjusting for time-dependent confounding. We carry out simulation studies to assess the suitability of the sequential Cox approach for analyzing time-to-event data in the presence of a time-dependent covariate that may or may not be a time-dependent confounder. Results from these simulations revealed that the sequential Cox approach is not as effective as marginal structural Cox model in addressing the time-dependent confounding. The sequential Cox approach was also found to be inadequate in the presence of a time-dependent covariate. We propose a modified version of the sequential Cox approach that correctly estimates the treatment effect in both of the above scenarios. All approaches are applied to investigate the impact of beta-interferon treatment in delaying disability progression in the British Columbia Multiple Sclerosis cohort (1995-2008).

  18. A case study on the identification of confounding factors for gene disease association analysis.

    PubMed

    Han, Bin; Xie, Ruifei; Wu, Shixiu; Li, Lihua; Zhu, Lei

    2015-01-01

    Variation in the expression of genes arises from a variety of sources. It is important to remove sources of variation between arrays of non-biological origin. Non-biological variation, caused by lurking confounding factors, usually attracts little attention, although it may substantially influence the expression profile of genes. In this study, we proposed a method which is able to identify the potential confounding factors and highlight the non-biological variations. We also developed methods and statistical tests to study the confounding factors and their influence on the homogeneity of microarray data, gene selection, and disease classification. We explored an ovarian cancer gene expression profile and showed that data batches and arraying conditions are two confounding factors. Their influence on the homogeneity of data, gene selection, and disease classification are statistically analyzed. Experiments showed that after normalization, their influences were removed. Comparative studies further showed that the data became more homogeneous and the classification quality was improved. This research demonstrated that identifying and reducing the impact of confounding factors is paramount in making sense of gene-disease association analysis.

  19. Assessment and indirect adjustment for confounding by smoking in cohort studies using relative hazards models.

    PubMed

    Richardson, David B; Laurier, Dominique; Schubauer-Berigan, Mary K; Tchetgen Tchetgen, Eric; Cole, Stephen R

    2014-11-01

    Workers' smoking histories are not measured in many occupational cohort studies. Here we discuss the use of negative control outcomes to detect and adjust for confounding in analyses that lack information on smoking. We clarify the assumptions necessary to detect confounding by smoking and the additional assumptions necessary to indirectly adjust for such bias. We illustrate these methods using data from 2 studies of radiation and lung cancer: the Colorado Plateau cohort study (1950-2005) of underground uranium miners (in which smoking was measured) and a French cohort study (1950-2004) of nuclear industry workers (in which smoking was unmeasured). A cause-specific relative hazards model is proposed for estimation of indirectly adjusted associations. Among the miners, the proposed method suggests no confounding by smoking of the association between radon and lung cancer--a conclusion supported by adjustment for measured smoking. Among the nuclear workers, the proposed method suggests substantial confounding by smoking of the association between radiation and lung cancer. Indirect adjustment for confounding by smoking resulted in an 18% decrease in the adjusted estimated hazard ratio, yet this cannot be verified because smoking was unmeasured. Assumptions underlying this method are described, and a cause-specific proportional hazards model that allows easy implementation using standard software is presented.

  20. The "Dry-Run" Analysis: A Method for Evaluating Risk Scores for Confounding Control.

    PubMed

    Wyss, Richard; Hansen, Ben B; Ellis, Alan R; Gagne, Joshua J; Desai, Rishi J; Glynn, Robert J; Stürmer, Til

    2017-03-06

    A propensity score (PS) model's ability to control confounding can be assessed by evaluating covariate balance across exposure groups after PS adjustment. The optimal strategy for evaluating a disease risk score (DRS) model's ability to control confounding is less clear. DRS models cannot be evaluated through balance checks within the full population, and they are usually assessed through prediction diagnostics and goodness-of-fit tests. A proposed alternative is the "dry-run" analysis, which divides the unexposed population into "pseudo-exposed" and "pseudo-unexposed" groups so that differences on observed covariates resemble differences between the actual exposed and unexposed populations. With no exposure effect separating the pseudo-exposed and pseudo-unexposed groups, a DRS model is evaluated by its ability to retrieve an unconfounded null estimate after adjustment in this pseudo-population. We used simulations and an empirical example to compare traditional DRS performance metrics with the dry-run validation. In simulations, the dry run often improved assessment of confounding control, compared with the C statistic and goodness-of-fit tests. In the empirical example, PS and DRS matching gave similar results and showed good performance in terms of covariate balance (PS matching) and controlling confounding in the dry-run analysis (DRS matching). The dry-run analysis may prove useful in evaluating confounding control through DRS models.

  1. "Toward a clearer definition of confounding" revisited with directed acyclic graphs.

    PubMed

    Howards, Penelope P; Schisterman, Enrique F; Poole, Charles; Kaufman, Jay S; Weinberg, Clarice R

    2012-09-15

    In a 1993 paper (Am J Epidemiol. 1993;137(1):1-8), Weinberg considered whether a variable that is associated with the outcome and is affected by exposure but is not an intermediate variable between exposure and outcome should be considered a confounder in etiologic studies. As an example, she examined the common practice of adjusting for history of spontaneous abortion when estimating the effect of an exposure on the risk of spontaneous abortion. She showed algebraically that such an adjustment could substantially bias the results even though history of spontaneous abortion would meet some definitions of a confounder. Directed acyclic graphs (DAGs) were introduced into epidemiology several years later as a tool with which to identify confounders. The authors now revisit Weinberg's paper using DAGs to represent scenarios that arise from her original assumptions. DAG theory is consistent with Weinberg's finding that adjusting for history of spontaneous abortion introduces bias in her original scenario. In the authors' examples, treating history of spontaneous abortion as a confounder introduces bias if it is a descendant of the exposure and is associated with the outcome conditional on exposure or is a child of a collider on a relevant undirected path. Thoughtful DAG analyses require clear research questions but are easily modified for examining different causal assumptions that may affect confounder assessment.

  2. Biochemical upgrading of oils

    DOEpatents

    Premuzic, E.T.; Lin, M.S.

    1999-01-12

    A process for biochemical conversion of heavy crude oils is provided. The process includes contacting heavy crude oils with adapted biocatalysts. The resulting upgraded oil shows, a relative increase in saturated hydrocarbons, emulsions and oxygenates and a decrease in compounds containing organic sulfur, organic nitrogen and trace metals. Adapted microorganisms which have been modified under challenged growth processes are also disclosed. 121 figs.

  3. Biochemical upgrading of oils

    DOEpatents

    Premuzic, Eugene T.; Lin, Mow S.

    1999-01-12

    A process for biochemical conversion of heavy crude oils is provided. The process includes contacting heavy crude oils with adapted biocatalysts. The resulting upgraded oil shows, a relative increase in saturated hydrocarbons, emulsions and oxygenates and a decrease in compounds containing in organic sulfur, organic nitrogen and trace metals. Adapted microorganisms which have been modified under challenged growth processes are also disclosed.

  4. Biochemical Education in Brazil.

    ERIC Educational Resources Information Center

    Vella, F.

    1988-01-01

    Described are discussions held concerning the problems of biochemical education in Brazil at a meeting of the Sociedade Brazileira de Bioquimica in April 1988. Also discussed are other visits that were made to universities in Brazil. Three major recommendations to improve the state of biochemistry education in Brazil are presented. (CW)

  5. Measures of Biochemical Sociology

    ERIC Educational Resources Information Center

    Snell, Joel; Marsh, Mitchell

    2008-01-01

    In a previous article, the authors introduced a new sub field in sociology that we labeled "biochemical sociology." We introduced the definition of a sociology that encompasses sociological measures, psychological measures, and biological indicators Snell & Marsh (2003). In this article, we want to demonstrate a research strategy that would assess…

  6. Nanoparticles as biochemical sensors

    PubMed Central

    El-Ansary, Afaf; Faddah, Layla M

    2010-01-01

    There is little doubt that nanoparticles offer real and new opportunities in many fields, such as biomedicine and materials science. Such particles are small enough to enter almost all areas of the body, including cells and organelles, potentially leading to new approaches in nanomedicine. Sensors for small molecules of biochemical interest are of critical importance. This review is an attempt to trace the use of nanomaterials in biochemical sensor design. The possibility of using nanoparticles functionalized with antibodies as markers for proteins will be elucidated. Moreover, capabilities and applications for nanoparticles based on gold, silver, magnetic, and semiconductor materials (quantum dots), used in optical (absorbance, luminescence, surface enhanced Raman spectroscopy, surface plasmon resonance), electrochemical, and mass-sensitive sensors will be highlighted. The unique ability of nanosensors to improve the analysis of biochemical fluids is discussed either through considering the use of nanoparticles for in vitro molecular diagnosis, or in the biological/biochemical analysis for in vivo interaction with the human body. PMID:24198472

  7. Restricted spatial regression in practice: Geostatistical models, confounding, and robustness under model misspecification

    USGS Publications Warehouse

    Hanks, Ephraim M.; Schliep, Erin M.; Hooten, Mevin B.; Hoeting, Jennifer A.

    2015-01-01

    In spatial generalized linear mixed models (SGLMMs), covariates that are spatially smooth are often collinear with spatially smooth random effects. This phenomenon is known as spatial confounding and has been studied primarily in the case where the spatial support of the process being studied is discrete (e.g., areal spatial data). In this case, the most common approach suggested is restricted spatial regression (RSR) in which the spatial random effects are constrained to be orthogonal to the fixed effects. We consider spatial confounding and RSR in the geostatistical (continuous spatial support) setting. We show that RSR provides computational benefits relative to the confounded SGLMM, but that Bayesian credible intervals under RSR can be inappropriately narrow under model misspecification. We propose a posterior predictive approach to alleviating this potential problem and discuss the appropriateness of RSR in a variety of situations. We illustrate RSR and SGLMM approaches through simulation studies and an analysis of malaria frequencies in The Gambia, Africa.

  8. EVALUATING COSTS WITH UNMEASURED CONFOUNDING: A SENSITIVITY ANALYSIS FOR THE TREATMENT EFFECT

    PubMed Central

    Handorf, Elizabeth A.; Bekelman, Justin E.; Heitjan, Daniel F.; Mitra, Nandita

    2014-01-01

    Estimates of the effects of treatment on cost from observational studies are subject to bias if there are unmeasured confounders. It is therefore advisable in practice to assess the potential magnitude of such biases. We derive a general adjustment formula for loglinear models of mean cost and explore special cases under plausible assumptions about the distribution of the unmeasured confounder. We assess the performance of the adjustment by simulation, in particular, examining robustness to a key assumption of conditional independence between the unmeasured and measured covariates given the treatment indicator. We apply our method to SEER-Medicare cost data for a stage II/III muscle-invasive bladder cancer cohort. We evaluate the costs for radical cystectomy vs. combined radiation/chemotherapy, and find that the significance of the treatment effect is sensitive to plausible unmeasured Bernoulli, Poisson and Gamma confounders. PMID:24587844

  9. Distinguishing prostate cancer from benign confounders via a cascaded classifier on multi-parametric MRI

    NASA Astrophysics Data System (ADS)

    Litjens, G. J. S.; Elliott, R.; Shih, N.; Feldman, M.; Barentsz, J. O.; Hulsbergen-van de Kaa, C. A.; Kovacs, I.; Huisman, H. J.; Madabhushi, A.

    2014-03-01

    Learning how to separate benign confounders from prostate cancer is important because the imaging characteristics of these confounders are poorly understood. Furthermore, the typical representations of the MRI parameters might not be enough to allow discrimination. The diagnostic uncertainty this causes leads to a lower diagnostic accuracy. In this paper a new cascaded classifier is introduced to separate prostate cancer and benign confounders on MRI in conjunction with specific computer-extracted features to distinguish each of the benign classes (benign prostatic hyperplasia (BPH), inflammation, atrophy or prostatic intra-epithelial neoplasia (PIN). In this study we tried to (1) calculate different mathematical representations of the MRI parameters which more clearly express subtle differences between different classes, (2) learn which of the MRI image features will allow to distinguish specific benign confounders from prostate cancer, and (2) find the combination of computer-extracted MRI features to best discriminate cancer from the confounding classes using a cascaded classifier. One of the most important requirements for identifying MRI signatures for adenocarcinoma, BPH, atrophy, inflammation, and PIN is accurate mapping of the location and spatial extent of the confounder and cancer categories from ex vivo histopathology to MRI. Towards this end we employed an annotated prostatectomy data set of 31 patients, all of whom underwent a multi-parametric 3 Tesla MRI prior to radical prostatectomy. The prostatectomy slides were carefully co-registered to the corresponding MRI slices using an elastic registration technique. We extracted texture features from the T2-weighted imaging, pharmacokinetic features from the dynamic contrast enhanced imaging and diffusion features from the diffusion-weighted imaging for each of the confounder classes and prostate cancer. These features were selected because they form the mainstay of clinical diagnosis. Relevant features for

  10. On negative outcome control of unobserved confounding as a generalization of difference-in-differences

    PubMed Central

    Sofer, Tamar; Richardson, David B.; Colicino, Elena; Schwartz, Joel; Tchetgen Tchetgen, Eric J.

    2016-01-01

    The difference-in-differences (DID) approach is a well known strategy for estimating the effect of an exposure in the presence of unobserved confounding. The approach is most commonly used when pre-and post-exposure outcome measurements are available, and one can assume that the association of the unobserved confounder with the outcome is equal in the two exposure groups, and constant over time. Then, one recovers the treatment effect by regressing the change in outcome over time on the exposure. In this paper, we interpret the difference-in-differences as a negative outcome control (NOC) approach. We show that the pre-exposure outcome is a negative control outcome, as it cannot be influenced by the subsequent exposure, and it is affected by both observed and unobserved confounders of the exposure-outcome association of interest. The relation between DID and NOC provides simple conditions under which negative control outcomes can be used to detect and correct for confounding bias. However, for general negative control outcomes, the DID-like assumption may be overly restrictive and rarely credible, because it requires that both the outcome of interest and the control outcome are measured on the same scale. Thus, we present a scale-invariant generalization of the DID that may be used in broader NOC contexts. The proposed approach is demonstrated in simulations and on a Normative Aging Study data set, in which Body Mass Index is used for NOC of the relationship between air pollution and inflammatory outcomes. PMID:28239233

  11. Combating Unmeasured Confounding in Cross-Sectional Studies: Evaluating Instrumental-Variable and Heckman Selection Models

    PubMed Central

    DeMaris, Alfred

    2014-01-01

    Unmeasured confounding is the principal threat to unbiased estimation of treatment “effects” (i.e., regression parameters for binary regressors) in nonexperimental research. It refers to unmeasured characteristics of individuals that lead them both to be in a particular “treatment” category and to register higher or lower values than others on a response variable. In this article, I introduce readers to 2 econometric techniques designed to control the problem, with a particular emphasis on the Heckman selection model (HSM). Both techniques can be used with only cross-sectional data. Using a Monte Carlo experiment, I compare the performance of instrumental-variable regression (IVR) and HSM to that of ordinary least squares (OLS) under conditions with treatment and unmeasured confounding both present and absent. I find HSM generally to outperform IVR with respect to mean-square-error of treatment estimates, as well as power for detecting either a treatment effect or unobserved confounding. However, both HSM and IVR require a large sample to be fully effective. The use of HSM and IVR in tandem with OLS to untangle unobserved confounding bias in cross-sectional data is further demonstrated with an empirical application. Using data from the 2006–2010 General Social Survey (National Opinion Research Center, 2014), I examine the association between being married and subjective well-being. PMID:25110904

  12. An Introduction to Sensitivity Analysis for Unobserved Confounding in Non-Experimental Prevention Research

    PubMed Central

    Kuramoto, S. Janet; Stuart, Elizabeth A.

    2013-01-01

    Despite that randomization is the gold standard for estimating causal relationships, many questions in prevention science are left to be answered through non-experimental studies often because randomization is either infeasible or unethical. While methods such as propensity score matching can adjust for observed confounding, unobserved confounding is the Achilles heel of most non-experimental studies. This paper describes and illustrates seven sensitivity analysis techniques that assess the sensitivity of study results to an unobserved confounder. These methods were categorized into two groups to reflect differences in their conceptualization of sensitivity analysis, as well as their targets of interest. As a motivating example we examine the sensitivity of the association between maternal suicide and offspring’s risk for suicide attempt hospitalization. While inferences differed slightly depending on the type of sensitivity analysis conducted, overall the association between maternal suicide and offspring’s hospitalization for suicide attempt was found to be relatively robust to an unobserved confounder. The ease of implementation and the insight these analyses provide underscores sensitivity analysis techniques as an important tool for non-experimental studies. The implementation of sensitivity analysis can help increase confidence in results from non-experimental studies and better inform prevention researchers and policymakers regarding potential intervention targets. PMID:23408282

  13. Guided Bayesian imputation to adjust for confounding when combining heterogeneous data sources in comparative effectiveness research.

    PubMed

    Antonelli, Joseph; Zigler, Corwin; Dominici, Francesca

    2017-03-03

    In comparative effectiveness research, we are often interested in the estimation of an average causal effect from large observational data (the main study). Often this data does not measure all the necessary confounders. In many occasions, an extensive set of additional covariates is measured for a smaller and non-representative population (the validation study). In this setting, standard approaches for missing data imputation might not be adequate due to the large number of missing covariates in the main data relative to the smaller sample size of the validation data. We propose a Bayesian approach to estimate the average causal effect in the main study that borrows information from the validation study to improve confounding adjustment. Our approach combines ideas of Bayesian model averaging, confounder selection, and missing data imputation into a single framework. It allows for different treatment effects in the main study and in the validation study, and propagates the uncertainty due to the missing data imputation and confounder selection when estimating the average causal effect (ACE) in the main study. We compare our method to several existing approaches via simulation. We apply our method to a study examining the effect of surgical resection on survival among 10 396 Medicare beneficiaries with a brain tumor when additional covariate information is available on 2220 patients in SEER-Medicare. We find that the estimated ACE decreases by 30% when incorporating additional information from SEER-Medicare.

  14. Controlling Time-Dependent Confounding by Health Status and Frailty: Restriction Versus Statistical Adjustment.

    PubMed

    McGrath, Leah J; Ellis, Alan R; Brookhart, M Alan

    2015-07-01

    Nonexperimental studies of preventive interventions are often biased because of the healthy-user effect and, in frail populations, because of confounding by functional status. Bias is evident when estimating influenza vaccine effectiveness, even after adjustment for claims-based indicators of illness. We explored bias reduction methods while estimating vaccine effectiveness in a cohort of adult hemodialysis patients. Using the United States Renal Data System and linked data from a commercial dialysis provider, we estimated vaccine effectiveness using a Cox proportional hazards marginal structural model of all-cause mortality before and during 3 influenza seasons in 2005/2006 through 2007/2008. To improve confounding control, we added frailty indicators to the model, measured time-varying confounders at different time intervals, and restricted the sample in multiple ways. Crude and baseline-adjusted marginal structural models remained strongly biased. Restricting to a healthier population removed some unmeasured confounding; however, this reduced the sample size, resulting in wide confidence intervals. We estimated an influenza vaccine effectiveness of 9% (hazard ratio = 0.91, 95% confidence interval: 0.72, 1.15) when bias was minimized through cohort restriction. In this study, the healthy-user bias could not be controlled through statistical adjustment; however, sample restriction reduced much of the bias.

  15. Combating unmeasured confounding in cross-sectional studies: evaluating instrumental-variable and Heckman selection models.

    PubMed

    DeMaris, Alfred

    2014-09-01

    Unmeasured confounding is the principal threat to unbiased estimation of treatment "effects" (i.e., regression parameters for binary regressors) in nonexperimental research. It refers to unmeasured characteristics of individuals that lead them both to be in a particular "treatment" category and to register higher or lower values than others on a response variable. In this article, I introduce readers to 2 econometric techniques designed to control the problem, with a particular emphasis on the Heckman selection model (HSM). Both techniques can be used with only cross-sectional data. Using a Monte Carlo experiment, I compare the performance of instrumental-variable regression (IVR) and HSM to that of ordinary least squares (OLS) under conditions with treatment and unmeasured confounding both present and absent. I find HSM generally to outperform IVR with respect to mean-square-error of treatment estimates, as well as power for detecting either a treatment effect or unobserved confounding. However, both HSM and IVR require a large sample to be fully effective. The use of HSM and IVR in tandem with OLS to untangle unobserved confounding bias in cross-sectional data is further demonstrated with an empirical application. Using data from the 2006-2010 General Social Survey (National Opinion Research Center, 2014), I examine the association between being married and subjective well-being.

  16. Assessing Mediation Using Marginal Structural Models in the Presence of Confounding and Moderation

    ERIC Educational Resources Information Center

    Coffman, Donna L.; Zhong, Wei

    2012-01-01

    This article presents marginal structural models with inverse propensity weighting (IPW) for assessing mediation. Generally, individuals are not randomly assigned to levels of the mediator. Therefore, confounders of the mediator and outcome may exist that limit causal inferences, a goal of mediation analysis. Either regression adjustment or IPW…

  17. Adjusting for unmeasured confounding due to either of two crossed factors with a logistic regression model.

    PubMed

    Li, Li; Brumback, Babette A; Weppelmann, Thomas A; Morris, J Glenn; Ali, Afsar

    2016-08-15

    Motivated by an investigation of the effect of surface water temperature on the presence of Vibrio cholerae in water samples collected from different fixed surface water monitoring sites in Haiti in different months, we investigated methods to adjust for unmeasured confounding due to either of the two crossed factors site and month. In the process, we extended previous methods that adjust for unmeasured confounding due to one nesting factor (such as site, which nests the water samples from different months) to the case of two crossed factors. First, we developed a conditional pseudolikelihood estimator that eliminates fixed effects for the levels of each of the crossed factors from the estimating equation. Using the theory of U-Statistics for independent but non-identically distributed vectors, we show that our estimator is consistent and asymptotically normal, but that its variance depends on the nuisance parameters and thus cannot be easily estimated. Consequently, we apply our estimator in conjunction with a permutation test, and we investigate use of the pigeonhole bootstrap and the jackknife for constructing confidence intervals. We also incorporate our estimator into a diagnostic test for a logistic mixed model with crossed random effects and no unmeasured confounding. For comparison, we investigate between-within models extended to two crossed factors. These generalized linear mixed models include covariate means for each level of each factor in order to adjust for the unmeasured confounding. We conduct simulation studies, and we apply the methods to the Haitian data. Copyright © 2016 John Wiley & Sons, Ltd.

  18. Multi-locus Test and Correction for Confounding Effects in Genome-Wide Association Studies.

    PubMed

    Chen, Donglai; Liu, Chuanhai; Xie, Jun

    2016-11-01

    Genome-wide association studies (GWAS) examine a large number of genetic variants, e. g., single nucleotide polymorphisms (SNP), and associate them with a disease of interest. Traditional statistical methods for GWASs can produce spurious associations, due to limited information from individual SNPs and confounding effects. This paper develops two statistical methods to enhance data analysis of GWASs. The first is a multiple-SNP association test, which is a weighted chi-square test derived for big contingency tables. The test assesses combinatorial effects of multiple SNPs and improves conventional methods of single SNP analysis. The second is a method that corrects for confounding effects, which may come from population stratification as well as other ambiguous (unknown) factors. The proposed method identifies a latent confounding factor, using a profile of whole genome SNPs, and eliminates confounding effects through matching or stratified statistical analysis. Simulations and a GWAS of rheumatoid arthritis demonstrate that the proposed methods dramatically remove the number of significant tests, or false positives, and outperforms other available methods.

  19. Counselor Confounds in Evaluations of Vocational Rehabilitation Methods in Substance Dependency Treatment

    ERIC Educational Resources Information Center

    Staines, Graham L.; Cleland, Charles M.; Blankertz, Laura

    2006-01-01

    Evaluation research on vocational counseling in substance dependency treatment should distinguish between the effects of counselors and counseling methods on clients' employment outcomes. Three experimental designs permit investigation of possible confounds between these types of effects: (a) nested designs (each counselor delivers one counseling…

  20. Multi-locus Test and Correction for Confounding Effects in Genome-Wide Association Studies

    PubMed Central

    Chen, Donglai; Liu, Chuanhai; Xie, Jun

    2016-01-01

    Genome-wide association studies (GWAS) examine a large number of genetic variants, e.g., single nucleotide polymorphisms (SNP), and associate them with a disease of interest. Traditional statistical methods for GWASs can produce spurious associations, due to limited information from individual SNPs and confounding effects. This paper develops two statistical methods to enhance data analysis of GWASs. The first is a multiple-SNP association test, which is a weighted chi-square test derived for big contingency tables. The test assesses combinatorial effects of multiple SNPs and improves conventional methods of single SNP analysis. The second is a method that corrects for confounding effects, which may come from population stratification as well as other ambiguous (unknown) factors. The proposed method identifies a latent confounding factor, using a profile of whole genome SNPs, and eliminates confounding effects through matching or stratified statistical analysis. Simulations and a GWAS of rheumatoid arthritis demonstrate that the proposed methods dramatically remove the number of significant tests, or false positives, and outperforms other available methods. PMID:27232635

  1. Race and Socioeconomic Status as Confounding Variables in the Accurate Diagnosis of Alcoholism.

    ERIC Educational Resources Information Center

    Luepnitz, Roy R.; And Others

    1982-01-01

    Studied the incidence of bias related to race and socioeconomic status which could confound the diagnosis of alcoholism. Graduate psychology students made a diagnosis based on videotapes. Results indicated lower socioeconomic class individuals were more often diagnosed correctly for alcoholism, and Blacks were diagnosed alcoholic more often than…

  2. Adjusting for Confounding Factors in Quasi-Experiments: Another Reanalysis of the Westinghouse Head Start Evaluation.

    ERIC Educational Resources Information Center

    Magidson, Jay; Sorbom, Dag

    Evaluations of social programs based upon quasi-experimental designs are typically plagued by problems of nonequivalence between the experimental and comparison group prior to the experiment. In such settings it is extremely difficult, if not impossible, to isolate the effects of the program from the confounding effects associated with the…

  3. An education gradient in health, a health gradient in education, or a confounded gradient in both?

    PubMed

    Lynch, Jamie L; von Hippel, Paul T

    2016-04-01

    There is a positive gradient associating educational attainment with health, yet the explanation for this gradient is not clear. Does higher education improve health (causation)? Do the healthy become highly educated (selection)? Or do good health and high educational attainment both result from advantages established early in the life course (confounding)? This study evaluates these competing explanations by tracking changes in educational attainment and Self-rated Health (SRH) from age 15 to age 31 in the National Longitudinal Study of Youth, 1997 cohort. Ordinal logistic regression confirms that high-SRH adolescents are more likely to become highly educated. This is partly because adolescent SRH is associated with early advantages including adolescents' academic performance, college plans, and family background (confounding); however, net of these confounders adolescent SRH still predicts adult educational attainment (selection). Fixed-effects longitudinal regression shows that educational attainment has little causal effect on SRH at age 31. Completion of a high school diploma or associate's degree has no effect on SRH, while completion of a bachelor's or graduate degree have effects that, though significant, are quite small (less than 0.1 points on a 5-point scale). While it is possible that educational attainment would have greater effect on health at older ages, at age 31 what we see is a health gradient in education, shaped primarily by selection and confounding rather than by a causal effect of education on health.

  4. Confounding in observational studies based on large health care databases: problems and potential solutions - a primer for the clinician.

    PubMed

    Nørgaard, Mette; Ehrenstein, Vera; Vandenbroucke, Jan P

    2017-01-01

    Population-based health care databases are a valuable tool for observational studies as they reflect daily medical practice for large and representative populations. A constant challenge in observational designs is, however, to rule out confounding, and the value of these databases for a given study question accordingly depends on completeness and validity of the information on confounding factors. In this article, we describe the types of potential confounding factors typically lacking in large health care databases and suggest strategies for confounding control when data on important confounders are unavailable. Using Danish health care databases as examples, we present the use of proxy measures for important confounders and the use of external adjustment. We also briefly discuss the potential value of active comparators, high-dimensional propensity scores, self-controlled designs, pseudorandomization, and the use of positive or negative controls.

  5. Confounding in observational studies based on large health care databases: problems and potential solutions – a primer for the clinician

    PubMed Central

    Nørgaard, Mette; Ehrenstein, Vera; Vandenbroucke, Jan P

    2017-01-01

    Population-based health care databases are a valuable tool for observational studies as they reflect daily medical practice for large and representative populations. A constant challenge in observational designs is, however, to rule out confounding, and the value of these databases for a given study question accordingly depends on completeness and validity of the information on confounding factors. In this article, we describe the types of potential confounding factors typically lacking in large health care databases and suggest strategies for confounding control when data on important confounders are unavailable. Using Danish health care databases as examples, we present the use of proxy measures for important confounders and the use of external adjustment. We also briefly discuss the potential value of active comparators, high-dimensional propensity scores, self-controlled designs, pseudorandomization, and the use of positive or negative controls.

  6. Should we adjust for a confounder if empirical and theoretical criteria yield contradictory results? A simulation study

    PubMed Central

    Lee, Paul H.

    2014-01-01

    Confounders can be identified by one of two main strategies: empirical or theoretical. Although confounder identification strategies that combine empirical and theoretical strategies have been proposed, the need for adjustment remains unclear if the empirical and theoretical criteria yield contradictory results due to random error. We simulated several scenarios to mimic either the presence or the absence of a confounding effect and tested the accuracy of the exposure-outcome association estimates with and without adjustment. Various criteria (significance criterion, Change-in-estimate(CIE) criterion with a 10% cutoff and with a simulated cutoff) were imposed, and a range of sample sizes were trialed. In the presence of a true confounding effect, unbiased estimates were obtained only by using the CIE criterion with a simulated cutoff. In the absence of a confounding effect, all criteria performed well regardless of adjustment. When the confounding factor was affected by both exposure and outcome, all criteria yielded accurate estimates without adjustment, but the adjusted estimates were biased. To conclude, theoretical confounders should be adjusted for regardless of the empirical evidence found. The adjustment for factors that do not have a confounding effect minimally effects. Potential confounders affected by both exposure and outcome should not be adjusted for. PMID:25124526

  7. Comparing High-dimensional Confounder Control Methods for Rapid Cohort Studies From Electronic Health Records

    PubMed Central

    Low, Yen Sia; Gallego, Blanca; Shah, Nigam Haresh

    2016-01-01

    Aims Electronic health records (EHR), containing rich clinical histories of large patient populations, can provide evidence for clinical decisions when evidence from trials and literature is absent. To enable such observational studies from EHR in real time, particularly in emergencies, rapid confounder control methods that can handle numerous variables and adjust for biases are imperative. This study compares the performance of 19 automatic confounder control methods. Methods Methods include propensity scores, direct adjustment by machine learning, similarity matching and resampling in two simulated and one real-world EHR datasets. Results and conclusions Direct adjustment by lasso regression and ensemble models involving multiple resamples have performance comparable to expert-based propensity scores and thus, may help provide real-time EHR-based evidence for timely clinical decisions. PMID:26634383

  8. Syphilis may be a confounding factor, not a causative agent, in syphilitic ALS.

    PubMed

    Tuk, Bert

    2016-01-01

    Based upon a review of published clinical observations regarding syphilitic amyotrophic lateral sclerosis (ALS), I hypothesize that syphilis is actually a confounding factor, not a causative factor, in syphilitic ALS. Moreover, I propose that the successful treatment of ALS symptoms in patients with syphilitic ALS using penicillin G and hydrocortisone is an indirect consequence of the treatment regimen and is not due to the treatment of syphilis. Specifically, I propose that the observed effect is due to the various pharmacological activities of penicillin G ( e.g., a GABA receptor antagonist) and/or the multifaceted pharmacological activity of hydrocortisone. The notion that syphilis may be a confounding factor in syphilitic ALS is highly relevant, as it suggests that treating ALS patients with penicillin G and hydrocortisone-regardless of whether they present with syphilitic ALS or non-syphilitic ALS-may be effective at treating this rapidly progressive, highly devastating disease.

  9. In vivo measurement of 241Am in the lungs confounded by activity deposited in other organs.

    PubMed

    Lobaugh, Megan L; Spitz, Henry B; Glover, Samuel E

    2015-01-01

    Radioactive material deposited in multiple organs of the body is likely to confound a result of an in vivo measurement performed over the lungs, the most frequently monitored organ for occupational exposure. The significance of this interference was evaluated by measuring anthropometric torso phantoms containing lungs, liver, skeleton, and axillary lymph nodes, each with a precisely known quantity of 241Am uniformly distributed in the organs. Arrays of multiple high-resolution germanium detectors were positioned over organs within the torso phantom containing 241Am or over proximal organs without activity to determine the degree of measurement confounding due to photons emitted from other source organs. A set of four mathematical response functions describes the measured count rate with detectors positioned over each of the relevant organs and 241Am contained in the measured organ or one of the other organs selected as a confounder. Simultaneous solution of these equations by matrix algebra, where the diagonal terms of the matrix are calibration factors for a direct measurement of activity in an organ and the off-diagonal terms reflect the contribution (i.e., interference or cross-talk) produced by 241Am in a confounding organ, yields the activity deposited in each of the relevant organs. The matrix solution described in this paper represents a method for adjusting a result of 241Am measured directly in one organ for interferences that may arise from 241Am deposited elsewhere and represents a technically valid procedure to aid in evaluating internal dose based upon in vivo measurements for those radioactive materials known to deposit in multiple organs.

  10. Diagnostics for Confounding of Time-varying and Other Joint Exposures.

    PubMed

    Jackson, John W

    2016-11-01

    The effects of joint exposures (or exposure regimes) include those of adhering to assigned treatment versus placebo in a randomized controlled trial, duration of exposure in a cohort study, interactions between exposures, and direct effects of exposure, among others. Unlike the setting of a single point exposure (e.g., propensity score matching), there are few tools to describe confounding for joint exposures or how well a method resolves it. Investigators need tools that describe confounding in ways that are conceptually grounded and intuitive for those who read, review, and use applied research to guide policy. We revisit the implications of exchangeability conditions that hold in sequentially randomized trials, and the bias structure that motivates the use of g-methods, such as marginal structural models. From these, we develop covariate balance diagnostics for joint exposures that can (1) describe time-varying confounding, (2) assess whether covariates are predicted by prior exposures given their past, the indication for g-methods, and (3) describe residual confounding after inverse probability weighting. For each diagnostic, we present time-specific metrics that encompass a wide class of joint exposures, including regimes of multivariate time-varying exposures in censored data, with multivariate point exposures as a special case. We outline how to estimate these directly or with regression and how to average them over person-time. Using a simulated example, we show how these metrics can be presented graphically. This conceptually grounded framework can potentially aid the transparent design, analysis, and reporting of studies that examine joint exposures. We provide easy-to-use tools to implement it.

  11. Wind turbines and idiopathic symptoms: The confounding effect of concurrent environmental exposures.

    PubMed

    Blanes-Vidal, Victoria; Schwartz, Joel

    2016-01-01

    Whether or not wind turbines pose a risk to human health is a matter of heated debate. Personal reactions to other environmental exposures occurring in the same settings as wind turbines may be responsible of the reported symptoms. However, these have not been accounted for in previous studies. We investigated whether there is an association between residential proximity to wind turbines and idiopathic symptoms, after controlling for personal reactions to other environmental co-exposures. We assessed wind turbine exposures in 454 residences as the distance to the closest wind turbine (Dw) and number of wind turbines <1000m (Nw1000). Information on symptoms, demographics and personal reactions to exposures was obtained by a blind questionnaire. We identified confounders using confounders' selection criteria and used adjusted logistic regression models to estimate associations. When controlling only for socio-demographic characteristics, log10Dw was associated with "unnatural fatigue" (ORadj=0.38, 95%CI=0.15-1.00) and "difficulty concentrating" (ORadj=0.26, 95%CI=0.08-0.83) and Nw1000 was associated with "unnatural fatigue" (ORadj=1.35, 95%CI=1.07-1.70) and "headache" (ORadj=1.26, 95%CI=1.00-1.58). After controlling for personal reactions to noise from sources different from wind turbines and agricultural odor exposure, we did not observe a significant relationship between residential proximity to wind turbines and symptoms and the parameter estimates were attenuated toward zero. Wind turbines-health associations can be confounded by personal reactions to other environmental co-exposures. Isolated associations reported in the literature may be due to confounding bias.

  12. Misleading biochemical laboratory test results

    PubMed Central

    Nanji, Amin A.

    1984-01-01

    This article reviews the general and specific factors that interfere with the performance of common biochemical laboratory tests and the interpretation of their results. The clinical status of the patient, drug interactions, and in-vivo and in-vitro biochemical interactions and changes may alter the results obtained from biochemical analysis of blood constituents. Failure to recognize invalid laboratory test results may lead to injudicious and dangerous management of patients. PMID:6375845

  13. Efforts to adjust for confounding by neighborhood using complex survey data.

    PubMed

    Brumback, Babette A; Dailey, Amy B; He, Zhulin; Brumback, Lyndia C; Livingston, Melvin D

    2010-08-15

    In social epidemiology, one often considers neighborhood or contextual effects on health outcomes, in addition to effects of individual exposures. This paper is concerned with the estimation of an individual exposure effect in the presence of confounding by neighborhood effects, motivated by an analysis of National Health Interview Survey (NHIS) data. In the analysis, we operationalize neighborhood as the secondary sampling unit of the survey, which consists of small groups of neighboring census blocks. Thus the neighborhoods are sampled with unequal probabilities, as are individuals within neighborhoods. We develop and compare several approaches for the analysis of the effect of dichotomized individual-level education on the receipt of adequate mammography screening. In the analysis, neighborhood effects are likely to confound the individual effects, due to such factors as differential availability of health services and differential neighborhood culture. The approaches can be grouped into three broad classes: ordinary logistic regression for survey data, with either no effect or a fixed effect for each cluster; conditional logistic regression extended for survey data; and generalized linear mixed model (GLMM) regression for survey data. Standard use of GLMMs with small clusters fails to adjust for confounding by cluster (e.g. neighborhood); this motivated us to develop an adaptation. We use theory, simulation, and analyses of the NHIS data to compare and contrast all of these methods. One conclusion is that all of the methods perform poorly when the sampling bias is strong; more research and new methods are clearly needed.

  14. Threats to internal validity in exercise science: a review of overlooked confounding variables.

    PubMed

    Halperin, Israel; Pyne, David B; Martin, David T

    2015-10-01

    Internal validity refers to the degree of control exerted over potential confounding variables to reduce alternative explanations for the effects of various treatments. In exercise and sports-science research and routine testing, internal validity is commonly achieved by controlling variables such as exercise and warm-up protocols, prior training, nutritional intake before testing, ambient temperature, time of testing, hours of sleep, age, and gender. However, a number of other potential confounding variables often do not receive adequate attention in sports physiology and performance research. These confounding variables include instructions on how to perform the test, volume and frequency of verbal encouragement, knowledge of exercise endpoint, number and gender of observers in the room, influence of music played before and during testing, and the effects of mental fatigue on performance. In this review the authors discuss these variables in relation to common testing environments in exercise and sports science and present some recommendations with the goal of reducing possible threats to internal validity.

  15. Assessing moderated mediation in linear models requires fewer confounding assumptions than assessing mediation.

    PubMed

    Loeys, Tom; Talloen, Wouter; Goubert, Liesbet; Moerkerke, Beatrijs; Vansteelandt, Stijn

    2016-11-01

    It is well known from the mediation analysis literature that the identification of direct and indirect effects relies on strong no unmeasured confounding assumptions of no unmeasured confounding. Even in randomized studies the mediator may still be correlated with unobserved prognostic variables that affect the outcome, in which case the mediator's role in the causal process may not be inferred without bias. In the behavioural and social science literature very little attention has been given so far to the causal assumptions required for moderated mediation analysis. In this paper we focus on the index for moderated mediation, which measures by how much the mediated effect is larger or smaller for varying levels of the moderator. We show that in linear models this index can be estimated without bias in the presence of unmeasured common causes of the moderator, mediator and outcome under certain conditions. Importantly, one can thus use the test for moderated mediation to support evidence for mediation under less stringent confounding conditions. We illustrate our findings with data from a randomized experiment assessing the impact of being primed with social deception upon observer responses to others' pain, and from an observational study of individuals who ended a romantic relationship assessing the effect of attachment anxiety during the relationship on mental distress 2 years after the break-up.

  16. Multiple imputation for handling systematically missing confounders in meta-analysis of individual participant data.

    PubMed

    Resche-Rigon, Matthieu; White, Ian R; Bartlett, Jonathan W; Peters, Sanne A E; Thompson, Simon G

    2013-12-10

    A variable is 'systematically missing' if it is missing for all individuals within particular studies in an individual participant data meta-analysis. When a systematically missing variable is a potential confounder in observational epidemiology, standard methods either fail to adjust the exposure-disease association for the potential confounder or exclude studies where it is missing. We propose a new approach to adjust for systematically missing confounders based on multiple imputation by chained equations. Systematically missing data are imputed via multilevel regression models that allow for heterogeneity between studies. A simulation study compares various choices of imputation model. An illustration is given using data from eight studies estimating the association between carotid intima media thickness and subsequent risk of cardiovascular events. Results are compared with standard methods and also with an extension of a published method that exploits the relationship between fully adjusted and partially adjusted estimated effects through a multivariate random effects meta-analysis model. We conclude that multiple imputation provides a practicable approach that can handle arbitrary patterns of systematic missingness. Bias is reduced by including sufficient between-study random effects in the imputation model.

  17. Mediation Analysis With Intermediate Confounding: Structural Equation Modeling Viewed Through the Causal Inference Lens

    PubMed Central

    De Stavola, Bianca L.; Daniel, Rhian M.; Ploubidis, George B.; Micali, Nadia

    2015-01-01

    The study of mediation has a long tradition in the social sciences and a relatively more recent one in epidemiology. The first school is linked to path analysis and structural equation models (SEMs), while the second is related mostly to methods developed within the potential outcomes approach to causal inference. By giving model-free definitions of direct and indirect effects and clear assumptions for their identification, the latter school has formalized notions intuitively developed in the former and has greatly increased the flexibility of the models involved. However, through its predominant focus on nonparametric identification, the causal inference approach to effect decomposition via natural effects is limited to settings that exclude intermediate confounders. Such confounders are naturally dealt with (albeit with the caveats of informality and modeling inflexibility) in the SEM framework. Therefore, it seems pertinent to revisit SEMs with intermediate confounders, armed with the formal definitions and (parametric) identification assumptions from causal inference. Here we investigate: 1) how identification assumptions affect the specification of SEMs, 2) whether the more restrictive SEM assumptions can be relaxed, and 3) whether existing sensitivity analyses can be extended to this setting. Data from the Avon Longitudinal Study of Parents and Children (1990–2005) are used for illustration. PMID:25504026

  18. Mediation analysis with intermediate confounding: structural equation modeling viewed through the causal inference lens.

    PubMed

    De Stavola, Bianca L; Daniel, Rhian M; Ploubidis, George B; Micali, Nadia

    2015-01-01

    The study of mediation has a long tradition in the social sciences and a relatively more recent one in epidemiology. The first school is linked to path analysis and structural equation models (SEMs), while the second is related mostly to methods developed within the potential outcomes approach to causal inference. By giving model-free definitions of direct and indirect effects and clear assumptions for their identification, the latter school has formalized notions intuitively developed in the former and has greatly increased the flexibility of the models involved. However, through its predominant focus on nonparametric identification, the causal inference approach to effect decomposition via natural effects is limited to settings that exclude intermediate confounders. Such confounders are naturally dealt with (albeit with the caveats of informality and modeling inflexibility) in the SEM framework. Therefore, it seems pertinent to revisit SEMs with intermediate confounders, armed with the formal definitions and (parametric) identification assumptions from causal inference. Here we investigate: 1) how identification assumptions affect the specification of SEMs, 2) whether the more restrictive SEM assumptions can be relaxed, and 3) whether existing sensitivity analyses can be extended to this setting. Data from the Avon Longitudinal Study of Parents and Children (1990-2005) are used for illustration.

  19. Biochemical Reversal of Aging

    NASA Astrophysics Data System (ADS)

    Ely, John T. A.

    2006-03-01

    We cite our progress on biochemical reversal of aging. However, it may be circa 2 years before we have necessary substances at low cost. Meanwhile, without them, a number of measures can be adopted providing marked improvement for the problems of aging in modern societies. For example, enzymes are needed to excrete toxins that accelerate aging; Hg is the ultimate toxin that disables all enzymes (including those needed to excrete Hg itself). Low Hg level in the urine, due to loss of excretory ability, causes the diagnosis of Hg toxicity to almost always be missed. Hg sources must be removed from the body! Another example is excess sugar; hyperglycemia decreases intracellular ascorbic acid (AA) by competitively inhibiting the insulin- mediated active transport of AA into cells. Thus, immunity is impaired by low leucocyte AA. AA is needed for new proteins in aging tissues. Humans must supplement AA; their need same as in AA-synthesizing mammals.

  20. Sensitivity analysis for direct and indirect effects in the presence of exposure-induced mediator-outcome confounders

    PubMed Central

    Chiba, Yasutaka

    2014-01-01

    Questions of mediation are often of interest in reasoning about mechanisms, and methods have been developed to address these questions. However, these methods make strong assumptions about the absence of confounding. Even if exposure is randomized, there may be mediator-outcome confounding variables. Inference about direct and indirect effects is particularly challenging if these mediator-outcome confounders are affected by the exposure because in this case these effects are not identified irrespective of whether data is available on these exposure-induced mediator-outcome confounders. In this paper, we provide a sensitivity analysis technique for natural direct and indirect effects that is applicable even if there are mediator-outcome confounders affected by the exposure. We give techniques for both the difference and risk ratio scales and compare the technique to other possible approaches. PMID:25580387

  1. Quantification of confounding factors in MRI-based dose calculations as applied to prostate IMRT

    NASA Astrophysics Data System (ADS)

    Maspero, Matteo; Seevinck, Peter R.; Schubert, Gerald; Hoesl, Michaela A. U.; van Asselen, Bram; Viergever, Max A.; Lagendijk, Jan J. W.; Meijer, Gert J.; van den Berg, Cornelis A. T.

    2017-02-01

    Magnetic resonance (MR)-only radiotherapy treatment planning requires pseudo-CT (pCT) images to enable MR-based dose calculations. To verify the accuracy of MR-based dose calculations, institutions interested in introducing MR-only planning will have to compare pCT-based and computer tomography (CT)-based dose calculations. However, interpreting such comparison studies may be challenging, since potential differences arise from a range of confounding factors which are not necessarily specific to MR-only planning. Therefore, the aim of this study is to identify and quantify the contribution of factors confounding dosimetric accuracy estimation in comparison studies between CT and pCT. The following factors were distinguished: set-up and positioning differences between imaging sessions, MR-related geometric inaccuracy, pCT generation, use of specific calibration curves to convert pCT into electron density information, and registration errors. The study comprised fourteen prostate cancer patients who underwent CT/MRI-based treatment planning. To enable pCT generation, a commercial solution (MRCAT, Philips Healthcare, Vantaa, Finland) was adopted. IMRT plans were calculated on CT (gold standard) and pCTs. Dose difference maps in a high dose region (CTV) and in the body volume were evaluated, and the contribution to dose errors of possible confounding factors was individually quantified. We found that the largest confounding factor leading to dose difference was the use of different calibration curves to convert pCT and CT into electron density (0.7%). The second largest factor was the pCT generation which resulted in pCT stratified into a fixed number of tissue classes (0.16%). Inter-scan differences due to patient repositioning, MR-related geometric inaccuracy, and registration errors did not significantly contribute to dose differences (0.01%). The proposed approach successfully identified and quantified the factors confounding accurate MRI-based dose calculation in

  2. Quantification of confounding factors in MRI-based dose calculations as applied to prostate IMRT.

    PubMed

    Maspero, Matteo; Seevinck, Peter R; Schubert, Gerald; Hoesl, Michaela A U; van Asselen, Bram; Viergever, Max A; Lagendijk, Jan J W; Meijer, Gert J; van den Berg, Cornelis A T

    2017-02-07

    Magnetic resonance (MR)-only radiotherapy treatment planning requires pseudo-CT (pCT) images to enable MR-based dose calculations. To verify the accuracy of MR-based dose calculations, institutions interested in introducing MR-only planning will have to compare pCT-based and computer tomography (CT)-based dose calculations. However, interpreting such comparison studies may be challenging, since potential differences arise from a range of confounding factors which are not necessarily specific to MR-only planning. Therefore, the aim of this study is to identify and quantify the contribution of factors confounding dosimetric accuracy estimation in comparison studies between CT and pCT. The following factors were distinguished: set-up and positioning differences between imaging sessions, MR-related geometric inaccuracy, pCT generation, use of specific calibration curves to convert pCT into electron density information, and registration errors. The study comprised fourteen prostate cancer patients who underwent CT/MRI-based treatment planning. To enable pCT generation, a commercial solution (MRCAT, Philips Healthcare, Vantaa, Finland) was adopted. IMRT plans were calculated on CT (gold standard) and pCTs. Dose difference maps in a high dose region (CTV) and in the body volume were evaluated, and the contribution to dose errors of possible confounding factors was individually quantified. We found that the largest confounding factor leading to dose difference was the use of different calibration curves to convert pCT and CT into electron density (0.7%). The second largest factor was the pCT generation which resulted in pCT stratified into a fixed number of tissue classes (0.16%). Inter-scan differences due to patient repositioning, MR-related geometric inaccuracy, and registration errors did not significantly contribute to dose differences (0.01%). The proposed approach successfully identified and quantified the factors confounding accurate MRI-based dose calculation in

  3. Rapamycin regulates biochemical metabolites

    PubMed Central

    Tucci, Paola; Porta, Giovanni; Agostini, Massimiliano; Antonov, Alexey; Garabadgiu, Alexander Vasilievich; Melino, Gerry; Willis, Anne E

    2013-01-01

    The mammalian target of rapamycin (mTOR) kinase is a master regulator of protein synthesis that couples nutrient sensing to cell growth, and deregulation of this pathway is associated with tumorigenesis. p53, and its less investigated family member p73, have been shown to interact closely with mTOR pathways through the transcriptional regulation of different target genes. To investigate the metabolic changes that occur upon inhibition of the mTOR pathway and the role of p73 in this response primary mouse embryonic fibroblast from control and TAp73−/− were treated with the macrocyclic lactone rapamycin. Extensive gas chromatography/mass spectrometry (GC/MS) and liquid chromatography/mass spectrometry (LC/MS/MS) analysis were used to obtain a rapamycin-dependent global metabolome profile from control or TAp73−/− cells. In total 289 metabolites involved in selective pathways were identified; 39 biochemical metabolites were found to be significantly altered, many of which are known to be associated with the cellular stress response. PMID:23839040

  4. Removal of Potentially Confounding Phenotypes from a Siamese-Derived Feline Glaucoma Breeding Colony

    PubMed Central

    Rutz-Mendicino, Michelle M; Snella, Elizabeth M; Jens, Jackie K; Gandolfi, Barbara; Carlson, Steven A; Kuehn, Markus H; McLellan, Gillian J; Ellinwood, N Matthew

    2011-01-01

    Feline breeding colonies face genetic constraints involving founder effects. A Siamese-founded colony used to study primary congenital glaucoma displayed coat colors additional to the Siamese coat. Genes affecting pigment can exhibit pleiotropy on ocular development and function. To remove potentially confounding phenotypes from our colony, we documented the source and frequency of the Siamese allele at the gene for tyrosinase (TYR), the dilution allele at melanophilin (MLPH), and the brown allele at tyrosinase-related protein 1 (TYRP1). We used PCR–RFLP diagnostics to genotype cats in our colony for the published alleles. A commercially acquired phenotypically normal tom was the source of the dilute allele. A founding Siamese queen was the source of the brown allele. Founders also were blood-typed and screened for disease-associated alleles segregating in Siamese cats at 3 loci (ASB, GLB1, and CEP290). Siamese founders were normal at all loci except ASB, at which both animals carried the hypomorphic allele. Current stock is being managed to limit production of glaucomatous cats with brown, dilute, or Siamese phenotypes or homozygosity for the ASB hypomorphic allele. Genotyping will aid in the elimination of these alleles. The clinical effect of these phenotypes and alleles on the glaucoma phenotype is uncertain, but their elimination will remove potentially confounding effects. In conclusion, when founding a colony, stock should be selected or screened to limit potentially confounding phenotypes. When studying the immune, nervous, and visual systems, screening stock for alleles known to be associated with coat color may be warranted. PMID:21819695

  5. The Effect of Clozapine on Premature Mortality: An Assessment of Clinical Monitoring and Other Potential Confounders

    PubMed Central

    Hayes, Richard D.; Downs, Johnny; Chang, Chin-Kuo; Jackson, Richard G.; Shetty, Hitesh; Broadbent, Matthew; Hotopf, Matthew; Stewart, Robert

    2015-01-01

    Clozapine can cause severe adverse effects yet it is associated with reduced mortality risk. We test the hypothesis this association is due to increased clinical monitoring and investigate risk of premature mortality from natural causes. We identified 14 754 individuals (879 deaths) with serious mental illness (SMI) including schizophrenia, schizoaffective and bipolar disorders aged ≥ 15 years in a large specialist mental healthcare case register linked to national mortality tracing. In this cohort study we modeled the effect of clozapine on mortality over a 5-year period (2007–2011) using Cox regression. Individuals prescribed clozapine had more severe psychopathology and poorer functional status. Many of the exposures associated with clozapine use were themselves risk factors for increased mortality. However, we identified a strong association between being prescribed clozapine and lower mortality which persisted after controlling for a broad range of potential confounders including clinical monitoring and markers of disease severity (adjusted hazard ratio 0.4; 95% CI 0.2–0.7; p = .001). This association remained after restricting the sample to those with a diagnosis of schizophrenia or those taking antipsychotics and after using propensity scores to reduce the impact of confounding by indication. Among individuals with SMI, those prescribed clozapine had a reduced risk of mortality due to both natural and unnatural causes. We found no evidence to indicate that lower mortality associated with clozapine in SMI was due to increased clinical monitoring or confounding factors. This is the first study to report an association between clozapine and reduced risk of mortality from natural causes. PMID:25154620

  6. Role of Environmental Confounding in the Association between FKBP5 and First-Episode Psychosis

    PubMed Central

    Ajnakina, Olesya; Borges, Susana; Di Forti, Marta; Patel, Yogen; Xu, Xiaohui; Green, Priscilla; Stilo, Simona A.; Kolliakou, Anna; Sood, Poonam; Marques, Tiago Reis; David, Anthony S.; Prata, Diana; Dazzan, Paola; Powell, John; Pariante, Carmine; Mondelli, Valeria; Morgan, Craig; Murray, Robin M.; Fisher, Helen L.; Iyegbe, Conrad

    2014-01-01

    Background: Failure to account for the etiological diversity that typically occurs in psychiatric cohorts may increase the potential for confounding as a proportion of genetic variance will be specific to exposures that have varying distributions in cases. This study investigated whether minimizing the potential for such confounding strengthened the evidence for a genetic candidate currently unsupported at the genome-wide level. Methods: Two hundred and ninety-one first-episode psychosis cases from South London, UK and 218 unaffected controls were evaluated for a functional polymorphism at the rs1360780 locus in FKBP5. The relationship between FKBP5 and psychosis was modeled using logistic regression. Cannabis use (Cannabis Experiences Questionnaire) and parental separation (Childhood Experience of Care and Abuse Questionnaire) were included as confounders in the analysis. Results: Association at rs1360780 was not detected until the effects of the two environmental factors had been adjusted for in the model (OR = 2.81, 95% CI 1.23–6.43, p = 0.02). A statistical interaction between rs1360780 and parental separation was confirmed by stratified tests (OR = 2.8, p = 0.02 vs. OR = 0.89, p = 0.80). The genetic main effect was directionally consistent with findings in other (stress-related) clinical phenotypes. Moreover, the variation in effect magnitude was explained by the level of power associated with different cannabis constructs used in the model (r = 0.95). Conclusion: Our results suggest that the extent to which genetic variants in FKBP5 can influence susceptibility to psychosis may depend on other etiological factors. This finding requires further validation in large independent cohorts. Potentially this work could have translational implications; the ability to discriminate between genetic etiologies based on a case-by-case understanding of previous environmental exposures would confer an important clinical advantage that would

  7. A comparison of confounding adjustment methods with an application to early life determinants of childhood obesity.

    PubMed

    Li, L; Kleinman, K; Gillman, M W

    2014-12-01

    We implemented six confounding adjustment methods: (1) covariate-adjusted regression, (2) propensity score (PS) regression, (3) PS stratification, (4) PS matching with two calipers, (5) inverse probability weighting and (6) doubly robust estimation to examine the associations between the body mass index (BMI) z-score at 3 years and two separate dichotomous exposure measures: exclusive breastfeeding v. formula only (n=437) and cesarean section v. vaginal delivery (n=1236). Data were drawn from a prospective pre-birth cohort study, Project Viva. The goal is to demonstrate the necessity and usefulness, and approaches for multiple confounding adjustment methods to analyze observational data. Unadjusted (univariate) and covariate-adjusted linear regression associations of breastfeeding with BMI z-score were -0.33 (95% CI -0.53, -0.13) and -0.24 (-0.46, -0.02), respectively. The other approaches resulted in smaller n (204-276) because of poor overlap of covariates, but CIs were of similar width except for inverse probability weighting (75% wider) and PS matching with a wider caliper (76% wider). Point estimates ranged widely, however, from -0.01 to -0.38. For cesarean section, because of better covariate overlap, the covariate-adjusted regression estimate (0.20) was remarkably robust to all adjustment methods, and the widths of the 95% CIs differed less than in the breastfeeding example. Choice of covariate adjustment method can matter. Lack of overlap in covariate structure between exposed and unexposed participants in observational studies can lead to erroneous covariate-adjusted estimates and confidence intervals. We recommend inspecting covariate overlap and using multiple confounding adjustment methods. Similar results bring reassurance. Contradictory results suggest issues with either the data or the analytic method.

  8. Evaluation in medical education: A topical review of target parameters, data collection tools and confounding factors

    PubMed Central

    Schiekirka, Sarah; Feufel, Markus A.; Herrmann-Lingen, Christoph; Raupach, Tobias

    2015-01-01

    Background and objective: Evaluation is an integral part of education in German medical schools. According to the quality standards set by the German Society for Evaluation, evaluation tools must provide an accurate and fair appraisal of teaching quality. Thus, data collection tools must be highly reliable and valid. This review summarises the current literature on evaluation of medical education with regard to the possible dimensions of teaching quality, the psychometric properties of survey instruments and potential confounding factors. Methods: We searched Pubmed, PsycINFO and PSYNDEX for literature on evaluation in medical education and included studies published up until June 30, 2011 as well as articles identified in the “grey literature”. Results are presented as a narrative review. Results: We identified four dimensions of teaching quality: structure, process, teacher characteristics, and outcome. Student ratings are predominantly used to address the first three dimensions, and a number of reliable tools are available for this purpose. However, potential confounders of student ratings pose a threat to the validity of these instruments. Outcome is usually operationalised in terms of student performance on examinations, but methodological problems may limit the usability of these data for evaluation purposes. In addition, not all examinations at German medical schools meet current quality standards. Conclusion: The choice of tools for evaluating medical education should be guided by the dimension that is targeted by the evaluation. Likewise, evaluation results can only be interpreted within the context of the construct addressed by the data collection tool that was used as well as its specific confounding factors. PMID:26421003

  9. Is the Inverse Association Between Selenium and Bladder Cancer Due to Confounding by Smoking?

    PubMed Central

    Beane Freeman, Laura E.; Karagas, Margaret R.; Baris, Dalsu; Schwenn, Molly; Johnson, Alison T.; Colt, Joanne S.; Jackson, Brian; Hosain, G. M. Monawar; Cantor, Kenneth P.; Silverman, Debra T.

    2015-01-01

    Selenium has been linked to a reduced risk of bladder cancer in some studies. Smoking, a well-established risk factor for bladder cancer, has been associated with lower selenium levels in the body. We investigated the selenium-bladder cancer association in subjects from Maine, New Hampshire, and Vermont in the New England Bladder Cancer Case-Control Study. At interview (2001–2005), participants provided information on a variety of factors, including a comprehensive smoking history, and submitted toenail samples, from which we measured selenium levels. We estimated odds ratios and 95% confidence intervals among 1,058 cases and 1,271 controls using logistic regression. After controlling for smoking, we saw no evidence of an association between selenium levels and bladder cancer (for fourth quartile vs. first quartile, odds ratio (OR) = 0.98, 95% confidence interval (CI): 0.77, 1.25). When results were restricted to regular smokers, there appeared to be an inverse association (OR = 0.76, 95% CI: 0.58, 0.99); however, when pack-years of smoking were considered, this association was attenuated (OR = 0.91, 95% CI: 0.68, 1.20), indicating potential confounding by smoking. Despite some reports of an inverse association between selenium and bladder cancer overall, our results, combined with an in-depth evaluation of other studies, suggested that confounding from smoking intensity or duration could explain this association. Our study highlights the need to carefully evaluate the confounding association of smoking in the selenium-bladder cancer association. PMID:25776013

  10. Is the inverse association between selenium and bladder cancer due to confounding by smoking?

    PubMed

    Beane Freeman, Laura E; Karagas, Margaret R; Baris, Dalsu; Schwenn, Molly; Johnson, Alison T; Colt, Joanne S; Jackson, Brian; Hosain, G M Monawar; Cantor, Kenneth P; Silverman, Debra T

    2015-04-01

    Selenium has been linked to a reduced risk of bladder cancer in some studies. Smoking, a well-established risk factor for bladder cancer, has been associated with lower selenium levels in the body. We investigated the selenium-bladder cancer association in subjects from Maine, New Hampshire, and Vermont in the New England Bladder Cancer Case-Control Study. At interview (2001-2005), participants provided information on a variety of factors, including a comprehensive smoking history, and submitted toenail samples, from which we measured selenium levels. We estimated odds ratios and 95% confidence intervals among 1,058 cases and 1,271 controls using logistic regression. After controlling for smoking, we saw no evidence of an association between selenium levels and bladder cancer (for fourth quartile vs. first quartile, odds ratio (OR) = 0.98, 95% confidence interval (CI): 0.77, 1.25). When results were restricted to regular smokers, there appeared to be an inverse association (OR = 0.76, 95% CI: 0.58, 0.99); however, when pack-years of smoking were considered, this association was attenuated (OR = 0.91, 95% CI: 0.68, 1.20), indicating potential confounding by smoking. Despite some reports of an inverse association between selenium and bladder cancer overall, our results, combined with an in-depth evaluation of other studies, suggested that confounding from smoking intensity or duration could explain this association. Our study highlights the need to carefully evaluate the confounding association of smoking in the selenium-bladder cancer association.

  11. A comparison of Bayesian and Monte Carlo sensitivity analysis for unmeasured confounding.

    PubMed

    McCandless, Lawrence C; Gustafson, Paul

    2017-04-06

    Bias from unmeasured confounding is a persistent concern in observational studies, and sensitivity analysis has been proposed as a solution. In the recent years, probabilistic sensitivity analysis using either Monte Carlo sensitivity analysis (MCSA) or Bayesian sensitivity analysis (BSA) has emerged as a practical analytic strategy when there are multiple bias parameters inputs. BSA uses Bayes theorem to formally combine evidence from the prior distribution and the data. In contrast, MCSA samples bias parameters directly from the prior distribution. Intuitively, one would think that BSA and MCSA ought to give similar results. Both methods use similar models and the same (prior) probability distributions for the bias parameters. In this paper, we illustrate the surprising finding that BSA and MCSA can give very different results. Specifically, we demonstrate that MCSA can give inaccurate uncertainty assessments (e.g. 95% intervals) that do not reflect the data's influence on uncertainty about unmeasured confounding. Using a data example from epidemiology and simulation studies, we show that certain combinations of data and prior distributions can result in dramatic prior-to-posterior changes in uncertainty about the bias parameters. This occurs because the application of Bayes theorem in a non-identifiable model can sometimes rule out certain patterns of unmeasured confounding that are not compatible with the data. Consequently, the MCSA approach may give 95% intervals that are either too wide or too narrow and that do not have 95% frequentist coverage probability. Based on our findings, we recommend that analysts use BSA for probabilistic sensitivity analysis. Copyright © 2017 John Wiley & Sons, Ltd.

  12. A comparison of confounding adjustment methods with an application to early life determinants of childhood obesity

    PubMed Central

    Kleinman, Ken; Gillman, Matthew W.

    2014-01-01

    We implemented 6 confounding adjustment methods: 1) covariate-adjusted regression, 2) propensity score (PS) regression, 3) PS stratification, 4) PS matching with two calipers, 5) inverse-probability-weighting, and 6) doubly-robust estimation to examine the associations between the BMI z-score at 3 years and two separate dichotomous exposure measures: exclusive breastfeeding versus formula only (N = 437) and cesarean section versus vaginal delivery (N = 1236). Data were drawn from a prospective pre-birth cohort study, Project Viva. The goal is to demonstrate the necessity and usefulness, and approaches for multiple confounding adjustment methods to analyze observational data. Unadjusted (univariate) and covariate-adjusted linear regression associations of breastfeeding with BMI z-score were −0.33 (95% CI −0.53, −0.13) and −0.24 (−0.46, −0.02), respectively. The other approaches resulted in smaller N (204 to 276) because of poor overlap of covariates, but CIs were of similar width except for inverse-probability-weighting (75% wider) and PS matching with a wider caliper (76% wider). Point estimates ranged widely, however, from −0.01 to −0.38. For cesarean section, because of better covariate overlap, the covariate-adjusted regression estimate (0.20) was remarkably robust to all adjustment methods, and the widths of the 95% CIs differed less than in the breastfeeding example. Choice of covariate adjustment method can matter. Lack of overlap in covariate structure between exposed and unexposed participants in observational studies can lead to erroneous covariate-adjusted estimates and confidence intervals. We recommend inspecting covariate overlap and using multiple confounding adjustment methods. Similar results bring reassurance. Contradictory results suggest issues with either the data or the analytic method. PMID:25171142

  13. Cellular GFP Toxicity and Immunogenicity: Potential Confounders in in Vivo Cell Tracking Experiments.

    PubMed

    Ansari, Amir Mehdi; Ahmed, A Karim; Matsangos, Aerielle E; Lay, Frank; Born, Louis J; Marti, Guy; Harmon, John W; Sun, Zhaoli

    2016-10-01

    Green Fluorescent protein (GFP), used as a cellular tag, provides researchers with a valuable method of measuring gene expression and cell tracking. However, there is evidence to suggest that the immunogenicity and cytotoxicity of GFP potentially confounds the interpretation of in vivo experimental data. Studies have shown that GFP expression can deteriorate over time as GFP tagged cells are prone to death. Therefore, the cells that were originally marked with GFP do not survive and cannot be accurately traced over time. This review will present current evidence for the immunogenicity and cytotoxicity of GFP in in vivo studies by characterizing these responses.

  14. Subliminal psychodynamic activation: an experiment controlling for major possible confounding influences outlined by Fudin.

    PubMed

    Gustafson, R; Källmén, H

    1991-08-01

    40 and 48 subjects participated in two separate experiments aimed at reproducing the subliminal psychodynamic activation (SPA) phenomenon and taking into account the major methodological critique by Fudin (1986, 1990). Subjects were first exposed either to a full or one of all possible partial symbiotic messages and then to their anagram equivalents. Confounding and irrelevant influences were controlled; the results indicate that only the full symbiotic message improved motor performance. This strongly suggests that subjects encode the meaning of the full message and supports an interpretation in terms of an alleviation of an internal symbiotic conflict leading to a state of calmness conducive to improved motor performance.

  15. Lung cancer gene associated with COPD: triple whammy or possible confounding effect?

    PubMed

    Young, R P; Hopkins, R J; Hay, B A; Epton, M J; Black, P N; Gamble, G D

    2008-11-01

    Recently, several large genome-wide association studies have identified a putative "lung cancer" locus in the nicotinic acetylcholine receptor subunit genes (nAChR) on 15q25. However, these findings may be confounded by the presence of chronic obstructive pulmonary disease (COPD), which is also strongly associated with smoking exposure and lung cancer. This is likely as the prevalence of COPD in lung cancer cohorts is as much as two-fold greater than that reported in smoking control populations (50 versus 20%). The present authors compared the genotype frequencies of the most strongly associated single nucleotide polymorphism (rs16969968) in the alpha5 subunit of the nAChR gene cluster between three matched smoking cohorts. The AA genotype was found to be more frequent and was seen in 437 (16%) lung cancer cases and 445 (14%) COPD cases compared with 475 (9%) healthy smoking controls. More importantly, when 429 lung cancer cases were divided according to spirometry results (performed within 3 months of diagnosis, prior to surgery and in the absence of effusions or collapse), the AA genotype was present in 19 and 11% of cases with and without COPD, respectively. These findings suggest that the association between the alpha5 subunit nicotinic acetylcholine receptor single nucleotide polymorphism and lung cancer may, in part, be confounded by chronic obstructive pulmonary disease.

  16. Hamilton study: distribution of factors confounding the relationship between air quality and respiratory health

    SciTech Connect

    Pengelly, L.D.; Kerigan, A.T.; Goldsmith, C.H.; Inman, E.M.

    1984-10-01

    Hamilton, Ontario is an industrial city with a population of 300,000 which is situated at the western end of Lake Ontario. Canada's two largest iron and steel mills are located here; the city historically has had relatively poor air quality, which has improved markedly in the last 25 years. Concern about the health effects of current air quality recently led us to carry out an epidemiological study of the effects of air pollution on the respiratory health of over 3500 school children. Respiratory health was measured by pulmonary function testing of each child, and by an assessment of each child's respiratory symptoms via a questionnaire administered to the parents. Previous studies had shown that other environmental factors (e.g. parental smoking, parental cough, socioeconomic level, housing, and gas cooking) might also affect respiratory health, and thus confound any potential relationships between health and air pollution. The questionnaire also collected information on many of these confounding factors. For the purposes of initial analysis, the city was divided into five areas in which differences in air quality were expected. In general, factors which have been associated with poor respiratory health were observed to be more prevalent in areas of poorer air quality.

  17. Overcoming confounding plate effects in differential expression analyses of single-cell RNA-seq data.

    PubMed

    Lun, Aaron T L; Marioni, John C

    2017-02-06

    An increasing number of studies are using single-cell RNA-sequencing (scRNA-seq) to characterize the gene expression profiles of individual cells. One common analysis applied to scRNA-seq data involves detecting differentially expressed (DE) genes between cells in different biological groups. However, many experiments are designed such that the cells to be compared are processed in separate plates or chips, meaning that the groupings are confounded with systematic plate effects. This confounding aspect is frequently ignored in DE analyses of scRNA-seq data. In this article, we demonstrate that failing to consider plate effects in the statistical model results in loss of type I error control. A solution is proposed whereby counts are summed from all cells in each plate and the count sums for all plates are used in the DE analysis. This restores type I error control in the presence of plate effects without compromising detection power in simulated data. Summation is also robust to varying numbers and library sizes of cells on each plate. Similar results are observed in DE analyses of real data where the use of count sums instead of single-cell counts improves specificity and the ranking of relevant genes. This suggests that summation can assist in maintaining statistical rigour in DE analyses of scRNA-seq data with plate effects.

  18. The assessment of cortisol in human hair: associations with sociodemographic variables and potential confounders.

    PubMed

    Dettenborn, L; Tietze, A; Kirschbaum, C; Stalder, T

    2012-11-01

    To inform the future use of hair cortisol measurement, we have investigated influences of potential confounding variables (natural hair colour, frequency of hair washes, age, sex, oral contraceptive (OC) use and smoking status) on hair cortisol levels. The main study sample comprised 360 participants (172 women) covering a wide range of ages (1-91 years; mean = 25.95). In addition, to more closely examine influences of natural hair colour and young age on hair cortisol levels, two additional samples comprising 69 participants with natural blond or dark brown hair (hair colour sample) as well as 28 young children and 34 adults (young age sample) were recruited. Results revealed a lack of an effect for natural hair colour, OC use, and smoking status on hair cortisol levels (all p's >0.10). No influence of frequency of hair washes was seen for proximal hair segments (p = 0.335) but for the third hair segment indicating lower cortisol content (p = 0.008). We found elevated hair cortisol levels in young children and older adults (p < 0.001). Finally, men showed higher hair cortisol levels than women (p = 0.002). The present data indicate that hair cortisol measurement provides a useful tool in stress-related psychobiological research when applied with the consideration of possible confounders including age and sex.

  19. Child welfare clients have higher risks for teenage childbirths: which are the major confounders?

    PubMed Central

    Vinnerljung, Bo; Hjern, Anders

    2016-01-01

    Background: Aiming to support effective social intervention strategies targeting high-risk groups for teenage motherhood, this study examined to what extent the elevated crude risks of teenage childbirth among child welfare groups were attributable to the uneven distribution of adverse individual and family background factors. Methods: Comprehensive longitudinal register data for more than 700 000 Swedish females born 1973–1989 (including around 29 000 child welfare clients) were analysed by means of binary logistic regression. The Karlson/Holm/Breen-method was used to decompose each confounding factor’s relative contribution to the difference between crude and adjusted odds ratios (ORs). Results: Elevated crude risks for teenage childbirth are to a large extent attributable to selection on observables. Girls’ school failure was the most potent confounder, accounting for 28–35% of the difference between crude and adjusted ORs. Conclusion: As in majority populations, girls’ school failure was a strong risk factor for teenage childbirth among former child welfare children. At least among pre-adolescents, promoting school performance among children in the child welfare system seems to be a viable intervention path. PMID:27085195

  20. Limitations of individual causal models, causal graphs, and ignorability assumptions, as illustrated by random confounding and design unfaithfulness.

    PubMed

    Greenland, Sander; Mansournia, Mohammad Ali

    2015-10-01

    We describe how ordinary interpretations of causal models and causal graphs fail to capture important distinctions among ignorable allocation mechanisms for subject selection or allocation. We illustrate these limitations in the case of random confounding and designs that prevent such confounding. In many experimental designs individual treatment allocations are dependent, and explicit population models are needed to show this dependency. In particular, certain designs impose unfaithful covariate-treatment distributions to prevent random confounding, yet ordinary causal graphs cannot discriminate between these unconfounded designs and confounded studies. Causal models for populations are better suited for displaying these phenomena than are individual-level models, because they allow representation of allocation dependencies as well as outcome dependencies across individuals. Nonetheless, even with this extension, ordinary graphical models still fail to capture distinctions between hypothetical superpopulations (sampling distributions) and observed populations (actual distributions), although potential-outcome models can be adapted to show these distinctions and their consequences.

  1. A two-stage strategy to accommodate general patterns of confounding in the design of observational studies.

    PubMed

    Haneuse, Sebastien; Schildcrout, Jonathan; Gillen, Daniel

    2012-04-01

    Accommodating general patterns of confounding in sample size/power calculations for observational studies is extremely challenging, both technically and scientifically. While employing previously implemented sample size/power tools is appealing, they typically ignore important aspects of the design/data structure. In this paper, we show that sample size/power calculations that ignore confounding can be much more unreliable than is conventionally thought; using real data from the US state of North Carolina, naive calculations yield sample size estimates that are half those obtained when confounding is appropriately acknowledged. Unfortunately, eliciting realistic design parameters for confounding mechanisms is difficult. To overcome this, we propose a novel two-stage strategy for observational study design that can accommodate arbitrary patterns of confounding. At the first stage, researchers establish bounds for power that facilitate the decision of whether or not to initiate the study. At the second stage, internal pilot data are used to estimate key scientific inputs that can be used to obtain realistic sample size/power. Our results indicate that the strategy is effective at replicating gold standard calculations based on knowing the true confounding mechanism. Finally, we show that consideration of the nature of confounding is a crucial aspect of the elicitation process; depending on whether the confounder is positively or negatively associated with the exposure of interest and outcome, naive power calculations can either under or overestimate the required sample size. Throughout, simulation is advocated as the only general means to obtain realistic estimates of statistical power; we describe, and provide in an R package, a simple algorithm for estimating power for a case-control study.

  2. Evaluating the impact of unmeasured confounding with internal validation data: an example cost evaluation in type 2 diabetes.

    PubMed

    Faries, Douglas; Peng, Xiaomei; Pawaskar, Manjiri; Price, Karen; Stamey, James D; Seaman, John W

    2013-01-01

    The quantitative assessment of the potential influence of unmeasured confounders in the analysis of observational data is rare, despite reliance on the "no unmeasured confounders" assumption. In a recent comparison of costs of care between two treatments for type 2 diabetes using a health care claims database, propensity score matching was implemented to adjust for selection bias though it was noted that information on baseline glycemic control was not available for the propensity model. Using data from a linked laboratory file, data on this potential "unmeasured confounder" were obtained for a small subset of the original sample. By using this information, we demonstrate how Bayesian modeling, propensity score calibration, and multiple imputation can utilize this additional information to perform sensitivity analyses to quantitatively assess the potential impact of unmeasured confounding. Bayesian regression models were developed to utilize the internal validation data as informative prior distributions for all parameters, retaining information on the correlation between the confounder and other covariates. While assumptions supporting the use of propensity score calibration were not met in this sample, the use of Bayesian modeling and multiple imputation provided consistent results, suggesting that the lack of data on the unmeasured confounder did not have a strong impact on the original analysis, due to the lack of strong correlation between the confounder and the cost outcome variable. Bayesian modeling with informative priors and multiple imputation may be useful tools for unmeasured confounding sensitivity analysis in these situations. Further research to understand the operating characteristics of these methods in a variety of situations, however, remains.

  3. Biochemical Engineering and Industrial Biotechnology.

    ERIC Educational Resources Information Center

    Moo-Young, Murray

    1986-01-01

    Describes the biochemical engineering and industrial biotechnology programs of the University of Waterloo (Ontario, Canada). Provides descriptions of graduate courses, along with a sample of current research activities. Includes a discussion of the programs' mechanisms for technology transfer. (TW)

  4. A Course in... Biochemical Engineering.

    ERIC Educational Resources Information Center

    Ng, Terry K-L.; And Others

    1988-01-01

    Describes a chemical engineering course for senior undergraduates and first year graduate students in biochemical engineering. Discusses five experiments used in the course: aseptic techniques, dissolved oxygen measurement, oxygen uptake by yeast, continuous sterilization, and cultivation of microorganisms. (MVL)

  5. Non-Chemical Distant Cellular Interactions as a potential confounder of cell biology experiments

    PubMed Central

    Farhadi, Ashkan

    2014-01-01

    Distant cells can communicate with each other through a variety of methods. Two such methods involve electrical and/or chemical mechanisms. Non-chemical, distant cellular interactions may be another method of communication that cells can use to modify the behavior of other cells that are mechanically separated. Moreover, non-chemical, distant cellular interactions may explain some cases of confounding effects in Cell Biology experiments. In this article, we review non-chemical, distant cellular interactions studies to try to shed light on the mechanisms in this highly unconventional field of cell biology. Despite the existence of several theories that try to explain the mechanism of non-chemical, distant cellular interactions, this phenomenon is still speculative. Among candidate mechanisms, electromagnetic waves appear to have the most experimental support. In this brief article, we try to answer a few key questions that may further clarify this mechanism. PMID:25368582

  6. Microsatellite instability confounds engraftment analysis of hematopoietic stem-cell transplantation.

    PubMed

    Tseng, Li-Hui; Tang, Jih-Luh; Haley, Lisa; Beierl, Katie; Gocke, Christopher D; Eshleman, James R; Lin, Ming-Tseh

    2014-07-01

    Polymorphic short tandem-repeat, or microsatellite, loci have been widely used to analyze chimerism status after allogeneic hematopoietic stem-cell transplantation. In molecular diagnostic laboratories, it is recommended to calculate mixed chimerism for at least 2 informative loci and to avoid microsatellite loci on chromosomes with copy number changes. In this report, we show that microsatellite instability observed in 2 patients with acute leukemia may confound chimerism analysis. Interpretation errors may occur even if 2 to 3 loci are analyzed because of length variation in multiple microsatellite loci. Although microsatellite loci with length variation should not be selected for chimerism analysis, the presence of microsatellite instability, like copy number alteration because of aberrant chromosomes, provides evidence of recurrent or residual cancer cells after hematopoietic stem-cell transplantation.

  7. Can jurors recognize missing control groups, confounds, and experimenter bias in psychological science?

    PubMed

    McAuliff, Bradley D; Kovera, Margaret Bull; Nunez, Gabriel

    2009-06-01

    This study examined the ability of jury-eligible community members (N = 248) to detect internal validity threats in psychological science presented during a trial. Participants read a case summary in which an expert testified about a study that varied in internal validity (valid, missing control group, confound, and experimenter bias) and ecological validity (high, low). Ratings of expert evidence quality and expert credibility were higher for the valid versus missing control group versions only. Internal validity did not influence verdict or ratings of plaintiff credibility and no differences emerged as a function of ecological validity. Expert evidence quality, expert credibility, and plaintiff credibility were positively correlated with verdict. Implications for the scientific reasoning literature and for trials containing psychological science are discussed.

  8. Parasitism can be a confounding factor in assessing the response of zebra mussels to water contamination.

    PubMed

    Minguez, Laëtitia; Buronfosse, Thierry; Beisel, Jean-Nicolas; Giambérini, Laure

    2012-03-01

    Biological responses measured in aquatic organisms to monitor environmental pollution could be also affected by different biotic and abiotic factors. Among these environmental factors, parasitism has often been neglected even if infection by parasites is very frequent. In the present field investigation, the parasite infra-communities and zebra mussel biological responses were studied up- and downstream a waste water treatment plant in northeast France. In both sites, mussels were infected by ciliates and/or intracellular bacteria, but prevalence rates and infection intensities were different according to the habitat. Concerning the biological responses differences were observed related to the site quality and the infection status. Parasitism affects both systems but seemed to depend mainly on environmental conditions. The influence of parasites is not constant, but remains important to consider it as a potential confounding factor in ecotoxicological studies. This study also emphasizes the interesting use of integrative indexes to synthesize data set.

  9. Recommendations to standardize preanalytical confounding factors in Alzheimer's and Parkinson's disease cerebrospinal fluid biomarkers: an update.

    PubMed

    del Campo, Marta; Mollenhauer, Brit; Bertolotto, Antonio; Engelborghs, Sebastiaan; Hampel, Harald; Simonsen, Anja Hviid; Kapaki, Elisabeth; Kruse, Niels; Le Bastard, Nathalie; Lehmann, Sylvain; Molinuevo, Jose L; Parnetti, Lucilla; Perret-Liaudet, Armand; Sáez-Valero, Javier; Saka, Esen; Urbani, Andrea; Vanmechelen, Eugeen; Verbeek, Marcel; Visser, Pieter Jelle; Teunissen, Charlotte

    2012-08-01

    Early diagnosis of neurodegenerative disorders such as Alzheimer's (AD) or Parkinson's disease (PD) is needed to slow down or halt the disease at the earliest stage. Cerebrospinal fluid (CSF) biomarkers can be a good tool for early diagnosis. However, their use in clinical practice is challenging due to the high variability found between centers in the concentrations of both AD CSF biomarkers (Aβ42, total tau and phosphorylated tau) and PD CSF biomarker (α-synuclein). Such a variability has been partially attributed to different preanalytical procedures between laboratories, thus highlighting the need to establish standardized operating procedures. Here, we merge two previous consensus guidelines for preanalytical confounding factors in order to achieve one exhaustive guideline updated with new evidence for Aβ42, total tau and phosphorylated tau, and α-synuclein. The proposed standardized operating procedures are applicable not only to novel CSF biomarkers in AD and PD, but also to biomarkers for other neurodegenerative disorders.

  10. Survey material choices in haematology EQA: a confounding factor in automated counting performance assessment

    PubMed Central

    De la Salle, Barbara

    2017-01-01

    The complete blood count (CBC) is one of the most frequently requested tests in laboratory medicine, performed in a range of healthcare situations. The provision of an ideal assay material for external quality assessment is confounded by the fragility of the cellular components of blood, the lack of commutability of stabilised whole blood material and the lack of certified reference materials and methods to which CBC results can be traced. The choice of assay material between fresh blood, extended life assay material and fully stabilised, commercially prepared, whole blood material depends upon the scope and objectives of the EQA scheme. The introduction of new technologies in blood counting and the wider clinical application of parameters from the extended CBC will bring additional challenges for the EQA provider.

  11. Formulating tightest bounds on causal effects in studies with unmeasured confounders.

    PubMed

    Kuroki, Manabu; Cai, Zhihong

    2008-12-30

    This paper considers the problem of evaluating the causal effect of an exposure on an outcome in observational studies with both measured and unmeasured confounders between the exposure and the outcome. Under such a situation, MacLehose et al. (Epidemiology 2005; 16:548-555) applied linear programming optimization software to find the minimum and maximum possible values of the causal effect for specific numerical data. In this paper, we apply the symbolic Balke-Pearl linear programming method (Probabilistic counterfactuals: semantics, computation, and applications. Ph.D. Thesis, UCLA Cognitive Systems Laboratory, 1995; J. Amer. Statist. Assoc. 1997; 92:1172-1176) to derive the simple closed-form expressions for the lower and upper bounds on causal effects under various assumptions of monotonicity. These universal bounds enable epidemiologists and medical researchers to assess causal effects from observed data with minimum computational effort, and they further shed light on the accuracy of the assessment.

  12. Homophily and Contagion Are Generically Confounded in Observational Social Network Studies

    PubMed Central

    Shalizi, Cosma Rohilla; Thomas, Andrew C.

    2012-01-01

    The authors consider processes on social networks that can potentially involve three factors: homophily, or the formation of social ties due to matching individual traits; social contagion, also known as social influence; and the causal effect of an individual’s covariates on his or her behavior or other measurable responses. The authors show that generically, all of these are confounded with each other. Distinguishing them from one another requires strong assumptions on the parametrization of the social process or on the adequacy of the covariates used (or both). In particular the authors demonstrate, with simple examples, that asymmetries in regression coefficients cannot identify causal effects and that very simple models of imitation (a form of social contagion) can produce substantial correlations between an individual’s enduring traits and his or her choices, even when there is no intrinsic affinity between them. The authors also suggest some possible constructive responses to these results. PMID:22523436

  13. Assessing quality of nursing care as a confounding variable in an outcome study on neurodevelopmental treatment.

    PubMed

    Hafsteinsdóttir, Thóra B; Kruitwagen, Cas; Strijker, Karin; van der Weide, Lies; Grypdonck, Maria H F

    2007-01-01

    When planning a study measuring the effects of a neurodevelopmental treatment (NDT), we were confronted with the methodological problem that while measuring the effects of NDT, a rival hypothesis is that the decision to implement the NDT might be related to the quality of nursing care. Therefore, we measured the quality of nursing care as a possible confounding variable in relation to this outcome study. The quality of nursing care was measured on 12 wards participating in the experimental and control groups of the outcome study. Data were collected from 125 patients and 71 nurses and patients' records. The findings showed no significant differences in the quality of nursing care between the 2 groups of wards (P = .49). This method may be useful to other researchers conducting outcome research and who are confronted with a similar methodological problem.

  14. Spectral cytopathology: new aspects of data collection, manipulation and confounding effects.

    PubMed

    Miljković, Miloš; Bird, Benjamin; Lenau, Kathleen; Mazur, Antonella I; Diem, Max

    2013-07-21

    This paper presents a short review on the improvements in data processing for spectral cytopathology, the diagnostic method developed for large scale diagnostic analysis of spectral data of individual dried and fixed cells. This review is followed by the analysis of the confounding effects introduced by utilizing reflecting "low-emissivity" (low-e) slides as sample substrates in infrared micro-spectroscopy of biological samples such as individual dried cells or tissue sections. The artifact introduced by these substrates, referred to as the "standing electromagnetic wave" artifact, indeed, distorts the spectra noticeably, as postulated recently by several research groups. An analysis of the standing wave effect reveals that careful data pre-processing can reduce the spurious effects to a level where they are not creating a major problem for spectral cytopathology and spectral histopathology.

  15. Missing variables: how exclusion of human resources policy information confounds research connecting health and business outcomes.

    PubMed

    Lynch, Wendy D; Sherman, Bruce W

    2014-01-01

    When corporate health researchers examine the effects of health on business outcomes or the effect of health interventions on health and business outcomes, results will necessarily be confounded by the corporate environment(s) in which they are studied. In this research setting, most studies control for factors traditionally identified in public health, such as demographics and health status. Nevertheless, often overlooked is the extent to which company policies can also independently impact health care cost, work attendance, and productivity outcomes. With changes in employment and benefits practices resulting from health care reform, including incentives and plan design options, consideration of these largely neglected variables in research design has become increasingly important. This commentary summarizes existing knowledge regarding the implications of policy variations in research outcomes and provides a framework for incorporating them into future employer-based research.

  16. Task-independent effects are potential confounders in longitudinal imaging studies of learning in schizophrenia.

    PubMed

    Korostil, Michele; Fatima, Zainab; Kovacevic, Natasha; Menon, Mahesh; McIntosh, Anthony Randal

    2016-01-01

    Learning impairment is a core deficit in schizophrenia that impacts on real-world functioning and yet, elucidating its underlying neural basis remains a challenge. A key issue when interpreting learning-task experiments is that task-independent changes may confound interpretation of task-related signal changes in neuroimaging studies. The nature of these task-independent changes in schizophrenia is unknown. Therefore, we examined task-independent "time effects" in a group of participants with schizophrenia contrasted with healthy participants in a longitudinal fMRI learning-experiment designed to allow for examination of non-specific effects of time. Flanking the learning portions of the experiment with a task-of-no-interest allowed us to extract task-independent BOLD changes. Task-independent effects occurred in both groups, but were more robust in the schizophrenia group. There was a significant interaction effect between group and time in a distributed activity pattern that included inferior and superior temporal regions, frontal areas (left anterior insula and superior medial gyri), and parietal areas (posterior cingulate cortices and precuneus). This pattern showed task-independent linear decrease in BOLD amplitude over the two scanning sessions for the schizophrenia group, but showed either opposite effect or no activity changes for the control group. There was a trend towards a correlation between task-independent effects and the presence of more negative symptoms in the schizophrenia group. The strong interaction between group and time suggests that both the scanning experience as a whole and the transition between task-types evokes a different response in persons with schizophrenia and may confound interpretation of learning-related longitudinal imaging experiments if not explicitly considered.

  17. Sediment organic matter content as a confounding factor in toxicity tests with Chironomus tentans

    SciTech Connect

    Lacey, R.; Watzin, M.C.; McIntosh, A.W.

    1999-02-01

    Physicochemical characteristics of sediment unrelated to contaminant levels and bioavailability may influence the outcome of toxicity tests. In particular, sediment organic matter content has the potential to be a confounding factor in toxicity tests using the midge larva Chironomus tentans because the larvae are infaunal and feed on organic matter in the sediments. To examine the possibility, the authors conducted a series of tests using formulated sediments with varying organic matter contents following the standard US Environmental Protection Agency (US EPA) 10-day C. tentans growth and survival protocol. Formulated sediments made with peat moss, {alpha}-cellulose, and maple leaves were tested. An organic-rich natural sediment diluted with formulated sediment to achieve a range of organic matter contents was also examined. In a final experiment, sediments containing each of the four organic matter sources at the same concentration were tested against one another. Survival was not greatly affected by concentration of organic matter, except at the lowest concentrations in natural sediment, where survival dipped below 70%. In experiments using peat moss, {alpha}-cellulose, and maple leaves, significant differences in C. tentans growth were found at different organic matter concentrations. In contrast, concentration of organic matter in the natural sediment dilution series had little effect on growth, perhaps because much of this material was highly refractory. In the comparison experiment, growth differed significantly among the four sediments, with best growth achieved with {alpha}-cellulose and leaves. These results suggest that both organic matter quantity and quality can be confounding factors in toxicity tests using C. tentans.

  18. Correlation between heart rate variability and pulmonary function adjusted by confounding factors in healthy adults.

    PubMed

    Bianchim, M S; Sperandio, E F; Martinhão, G S; Matheus, A C; Lauria, V T; da Silva, R P; Spadari, R C; Gagliardi, A R T; Arantes, R L; Romiti, M; Dourado, V Z

    2016-03-01

    The autonomic nervous system maintains homeostasis, which is the state of balance in the body. That balance can be determined simply and noninvasively by evaluating heart rate variability (HRV). However, independently of autonomic control of the heart, HRV can be influenced by other factors, such as respiratory parameters. Little is known about the relationship between HRV and spirometric indices. In this study, our objective was to determine whether HRV correlates with spirometric indices in adults without cardiopulmonary disease, considering the main confounders (e.g., smoking and physical inactivity). In a sample of 119 asymptomatic adults (age 20-80 years), we evaluated forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1). We evaluated resting HRV indices within a 5-min window in the middle of a 10-min recording period, thereafter analyzing time and frequency domains. To evaluate daily physical activity, we instructed participants to use a triaxial accelerometer for 7 days. Physical inactivity was defined as <150 min/week of moderate to intense physical activity. We found that FVC and FEV1, respectively, correlated significantly with the following aspects of the RR interval: standard deviation of the RR intervals (r =0.31 and 0.35), low-frequency component (r =0.38 and 0.40), and Poincaré plot SD2 (r =0.34 and 0.36). Multivariate regression analysis, adjusted for age, sex, smoking, physical inactivity, and cardiovascular risk, identified the SD2 and dyslipidemia as independent predictors of FVC and FEV1 (R2=0.125 and 0.180, respectively, for both). We conclude that pulmonary function is influenced by autonomic control of cardiovascular function, independently of the main confounders.

  19. Dietary Soy May Not Confound Acute Experimental Stroke Infarct Volume Outcomes In Ovariectomized Female Rats

    PubMed Central

    Prongay, Kamm D.; Lewis, Anne D.; Hurn, Patricia D.; Murphy, Stephanie J.

    2009-01-01

    Estrogen administration can alter experimental stroke outcomes. Soy as a source of phytoestrogens may therefore modulate responses in “estrogen-sensitive” stroke models, thus potentially confounding results. We evaluated the effects of dietary soy on acute infarct volumes in a pilot study using a rat focal stroke model. We hypothesized that ovariectomized (OVX) rats fed a soy-rich diet would have smaller acute infarct volumes than rats fed a soy-free diet. OVX rats were randomly assigned to a soy-free (n=6) or a soy-rich (n=6) diet for 4 weeks and weighed weekly. Following the dietary trial, rats underwent 2 hours of middle cerebral artery occlusion (MCAO). Mean arterial blood pressure, rectal and temporalis muscle temperatures, arterial blood gases, and blood glucose were recorded peri-ischemia. Rats were euthanized 22 hours following 2 hours of MCAO. Brains were stained with 2,3,5-triphenyl tetrazolium chloride for acute infarct volume analysis. Uterine weight and histology were also evaluated as additional internal estrogen-sensitive controls. Rats on the soy-free diet had greater gains in body weight (259±6% baseline body weight) than rats on the soy-rich diet (238±4% baseline body weight). No differences were seen in uterine weight and histology, peri-ischemic physiological parameters, and infarct volumes between the treatment groups. Results of this pilot study suggest that the dietary soy level tested may not alter acute infarct volumes in ischemic female rat brain. More studies addressing the potential confounding effects of dietary soy in “estrogen-sensitive” stroke models are needed if investigators are to make informed choices regarding diets used in experimental stroke research. PMID:20147341

  20. Measurement confounding affects the extent to which verbal IQ explains social gradients in mortality

    PubMed Central

    Chapman, Benjamin; Fiscella, Kevin; Duberstein, Paul; Kawachi, Ichiro; Muennig, Peter

    2016-01-01

    Background IQ is thought to explain social gradients in mortality. IQ scores are based roughly equally on Verbal IQ (VIQ) and Performance IQ tests. VIQ tests, however, are suspected to confound true verbal ability with socioeconomic status (SES), raising the possibility that associations between SES and IQ scores might be overestimated. We examined, first, whether two of the most common types of VIQ tests exhibited differential item functioning (DIF) favouring persons of higher SES and/or majority race/ethnicity. Second, we assessed what impact, if any, this had on estimates of the extent to which VIQ explains social gradients in mortality. Methods Data from the General Social Survey-National Death Index cohort, a US population representative dataset, was used. Item response theory models queried social-factor DIF on the Thorndike Verbal Intelligence Scale and Wechsler Adult Intelligence Scales, Revised Similarities test. Cox models examined mortality associations among SES and VIQ scores corrected and uncorrected for DIF. Results When uncorrected for DIF, VIQ was correlated with income, education, occupational prestige and race, with correlation coefficients ranging between |0.12| and |0.43|. After correcting for DIF, correlations ranged from |0.06| to |0.16|. Uncorrected VIQ scores explained 11–40% of the Relative Index of Inequalities in mortality for social factors, while DIF-corrected scores explained 2–29%. Conclusions Two of the common forms of VIQ tests appear confound verbal intelligence with SES. Since these tests appear in most IQ batteries, circumspection may be warranted in estimating the amount of social inequalities in mortality attributable to IQ. PMID:24729404

  1. Antipsychotics and Mortality: Adjusting for Mortality Risk Scores to Address Confounding by Terminal Illness

    PubMed Central

    Park, Yoonyoung; Franklin, Jessica M.; Schneeweiss, Sebastian; Levin, Raisa; Crystal, Stephen; Gerhard, Tobias; Huybrechts, Krista F.

    2014-01-01

    OBJECTIVES Earlier studies have documented a greater mortality risk associated with conventional compared with atypical antipsychotics. Concern remains that the association is not causal, but due to residual confounding by differences in underlying health. To address this concern, we evaluated whether adjustment for prognostic indices specifically developed fornursing home (NH) populations affected the magnitude of the previously observed associations. DESIGN Cohort study SETTING A merged dataset of Medicaid, Medicare, the Minimum Data Set (MDS), the Online Survey Certification and Reporting system (OSCAR), and the National Death Index in the US for 2001-2005 PARTICIPANTS Dual eligible subjects ≥ 65 years who initiated antipsychotic treatment in a NH (n=75,445). MEASUREMENTS Three mortality risk scores (MRIS, MMRI-R, and ADEPT) were derived for each patient using baseline MDS data, and their performance was assessed using c-statistics and goodness-of-fit tests. The impact of adjusting for these indices in addition to propensity scores (PS) on the antipsychotic-mortality association was evaluated using Cox models with and without adjustment for risk scores. RESULTS Each risk score showed moderate discrimination for 6-month mortality with c-statistics ranging from 0.61 to 0.63. There was no evidence of lack of fit. Imbalances in risk scores between conventional and atypical antipsychotic users in the full cohort, suggesting potential confounding, were greatly reduced within PS deciles. Accounting for each score in the Cox model did not change the relative risk estimates: 2.24 with PS only adjustment vs. 2.20, 2.20, 2.22 after further adjustment for the three risk scores. CONCLUSION Although causality cannot be proven based on non-randomized studies, this study adds to the body of evidence rejecting alternative explanations for the increased mortality risk associated with conventional antipsychotics. PMID:25752911

  2. PERMANOVA-S: association test for microbial community composition that accommodates confounders and multiple distances

    PubMed Central

    Tang, Zheng-Zheng; Chen, Guanhua; Alekseyenko, Alexander V.

    2016-01-01

    Motivation: Recent advances in sequencing technology have made it possible to obtain high-throughput data on the composition of microbial communities and to study the effects of dysbiosis on the human host. Analysis of pairwise intersample distances quantifies the association between the microbiome diversity and covariates of interest (e.g. environmental factors, clinical outcomes, treatment groups). In the design of these analyses, multiple choices for distance metrics are available. Most distance-based methods, however, use a single distance and are underpowered if the distance is poorly chosen. In addition, distance-based tests cannot flexibly handle confounding variables, which can result in excessive false-positive findings. Results: We derive presence-weighted UniFrac to complement the existing UniFrac distances for more powerful detection of the variation in species richness. We develop PERMANOVA-S, a new distance-based method that tests the association of microbiome composition with any covariates of interest. PERMANOVA-S improves the commonly-used Permutation Multivariate Analysis of Variance (PERMANOVA) test by allowing flexible confounder adjustments and ensembling multiple distances. We conducted extensive simulation studies to evaluate the performance of different distances under various patterns of association. Our simulation studies demonstrate that the power of the test relies on how well the selected distance captures the nature of the association. The PERMANOVA-S unified test combines multiple distances and achieves good power regardless of the patterns of the underlying association. We demonstrate the usefulness of our approach by reanalyzing several real microbiome datasets. Availability and Implementation: miProfile software is freely available at https://medschool.vanderbilt.edu/tang-lab/software/miProfile. Contact: z.tang@vanderbilt.edu or g.chen@vanderbilt.edu Supplementary information: Supplementary data are available at Bioinformatics

  3. An assessment of the possible extent of confounding in epidemiological studies of lung cancer risk among roofers

    SciTech Connect

    Mundt, D.J.; van Wijngaarden, E.; Mundt, K.A.

    2007-07-01

    We evaluated the likelihood and extent to which the observed increased risk of lung cancer may be due to confounding (a mixing of effects of multiple exposures) by co-exposure to other potential carcinogens present in roofing or to lifestyle variables. We conducted a review of the epidemiological and industrial hygiene literature of asphalt-exposed workers. Peer-reviewed epidemiological studies of asphalt fumes, related occupational exposures, and confounding factors were identified from MEDLINE (1966 early 2004). Industrial hygiene studies of asphalt workers were identified through MEDLINE, publicly available government documents, and asphalt industry documents. Using well established statistical methods, we quantified the extent to which lung cancer relative risk estimates among roofers reflect confounding from other exposures, using different prevalence and risk scenarios. The relative risk of lung cancer varied from 1.2 to 5.0 in 13 epidemiological studies of roofers; most studies reported a relative risk between 1.2 and 1.4. Smoking, asbestos and coal tar were the most likely confounders, but the prevalence of these factors varied over time. The results of the study indicate that much of the observed risk reported in epidemiological studies of cancer among roofers is well within the range of what may have resulted from confounding by reasonable and expected levels of smoking, asbestos or coal tar. This may be particularly true for those studies that did not adjust for these confounders and where the exposure was defined as employment in the roofing industry. In addition to poorly defined asphalt exposure, uncontrolled confounding cannot reliably be ruled out in studies of lung cancer among asphalt-exposed roofers. Therefore, it is not possible to conclude whether roofers are at increased risk of lung cancer due to asphalt exposure.

  4. Accounting for uncertainty in confounder and effect modifier selection when estimating average causal effects in generalized linear models.

    PubMed

    Wang, Chi; Dominici, Francesca; Parmigiani, Giovanni; Zigler, Corwin Matthew

    2015-09-01

    Confounder selection and adjustment are essential elements of assessing the causal effect of an exposure or treatment in observational studies. Building upon work by Wang et al. (2012, Biometrics 68, 661-671) and Lefebvre et al. (2014, Statistics in Medicine 33, 2797-2813), we propose and evaluate a Bayesian method to estimate average causal effects in studies with a large number of potential confounders, relatively few observations, likely interactions between confounders and the exposure of interest, and uncertainty on which confounders and interaction terms should be included. Our method is applicable across all exposures and outcomes that can be handled through generalized linear models. In this general setting, estimation of the average causal effect is different from estimation of the exposure coefficient in the outcome model due to noncollapsibility. We implement a Bayesian bootstrap procedure to integrate over the distribution of potential confounders and to estimate the causal effect. Our method permits estimation of both the overall population causal effect and effects in specified subpopulations, providing clear characterization of heterogeneous exposure effects that may vary considerably across different covariate profiles. Simulation studies demonstrate that the proposed method performs well in small sample size situations with 100-150 observations and 50 covariates. The method is applied to data on 15,060 US Medicare beneficiaries diagnosed with a malignant brain tumor between 2000 and 2009 to evaluate whether surgery reduces hospital readmissions within 30 days of diagnosis.

  5. An Empirical Method of Detecting Time-Dependent Confounding: An Observational Study of Next Day Delirium in a Medical ICU.

    PubMed

    Murphy, T E; Van Ness, P H; Araujo, K L B; Pisani, M A

    Longitudinal research on older persons in the medical intensive care unit (MICU) is often complicated by the time-dependent confounding of concurrently administered interventions such as medications and intubation. Such temporal confounding can bias the respective longitudinal associations between concurrently administered treatments and a longitudinal outcome such as delirium. Although marginal structural models address time-dependent confounding, their application is non-trivial and preferably justified by empirical evidence. Using data from a longitudinal study of older persons in the MICU, we constructed a plausibility score from 0 - 10 where higher values indicate higher plausibility of time-dependent confounding of the association between a time-varying explanatory variable and an outcome. Based on longitudinal plots, measures of correlation, and longitudinal regression, the plausibility scores were compared to the differences in estimates obtained with non-weighted and marginal structural models of next day delirium. The plausibility scores of the three possible pairings of daily doses of fentanyl, haloperidol, and intubation indicated the following: low plausibility for haloperidol and intubation, moderate plausibility for fentanyl and haloperidol, and high plausibility for fentanyl and intubation. Comparing multivariable models of next day delirium with and without adjustment for time-dependent confounding, only intubation's association changed substantively. In our observational study of older persons in the MICU, the plausibility scores were generally reflective of the observed differences between coefficients estimated from non-weighted and marginal structural models.

  6. Biochemical and histological methodologies for assessing vitamin A status in human populations

    SciTech Connect

    Underwood, B.A.

    1990-01-01

    In recent years, new biochemical and histological methodologies have been developed for assessing vitamin A nutritional status in humans at subclinical levels of nutriture. Insensitive static blood levels no longer are the only practical assessment parameter. Some of the newer functional methodologies require additional testing of their sensitivity and specificity under a variety of conditions existing in human populations and that frequently are associated with an inadequate vitamin A status. Some of these conditions could confound the interpretation when only a single assessment method is applied.

  7. Hematologic and Biochemical Biologic Variation in Laboratory Cats

    PubMed Central

    Trumel, Catherine; Monzali, Céline; Geffré, Anne; Concordet, Didier V; Hourqueig, Louise; Braun, Jean-Pierre D; Bourgès-Abella, Nathalie H

    2016-01-01

    The biologic variation associated with a clinical pathology result is important to consider before reference intervals (RI) are used. Most available RI are population-based RI, in which the analytical variability, interindividual variability, and intraindividual variability are confounded. In addition, when the intraindividual variability is considerably less than the interindividual variability, a population-based RI is insufficiently sensitive to detect changes in a subject over time. Here we determined the biologic variation and reference change value (RCV) of hematologic and biochemical variables in laboratory cats. Blood specimens from 14 (7 females and 7 males) overnight-fasted laboratory cats sampled 7 times (days 1, 2, 7, 14, 31, 42, and 100) were analyzed regarding hematology and biochemistry variables. For each variable, analytical, intraindividual, and interindividual coefficients of variation were estimated prior to calculation of the index of individuality and the RCV. RBC variables (count, Hgb, Hct, MCV, MCH, MCHC, and RBC distribution width) and 5 biochemical analytes (cholesterol, creatinine, triglycerides, ALP, and calcium) exhibited marked individuality, therefore indicating that subject-based reference intervals or RCV would be preferable when monitoring these variables in laboratory cats. Population-based RI were shown to be adequate for glucose and sodium, and both types of population and individual RI were similarly efficient for albumin, total protein, urea, ALT, AST, creatine kinase, chloride, carbon dioxide, iron, magnesium, inorganic phosphate, and potassium and reticulocyte, WBC, neutrophil, lymphocyte, monocyte, eosinophil, and platelet counts. The RCV determined in the present study provide a valuable tool for monitoring hematologic and biochemical variables in healthy laboratory cats. PMID:27657703

  8. Biochemical Control of Marine Fouling

    DTIC Science & Technology

    1988-01-14

    amino acid and catecholamine analyses by ion-exchange chromatography, and determination with ninhydrin , performed in collaboration with Dr. Herbert...attempted to design and test new, potentially specific (nonhazardous, environmentally safe) biochemical inhibitors of the recruitment and fouling...reaction- sequences. In this effort, we have concentrated first on the design and testing of agents which specifically block the larval receptors and

  9. Do digestive contents confound body mass as a measure of relative condition in nestling songbirds?

    USGS Publications Warehouse

    Streby, Henry M.; Peterson, Sean M.; Lehman, Justin A.; Kramer, Gunnar R.; Vernasco, Ben J.; Andersen, David E.

    2014-01-01

    Relative nestling condition, typically measured as nestling mass or as an index including nestling mass, is commonly purported to correlate with fledgling songbird survival. However, most studies directly investigating fledgling survival have found no such relationship. We weighed feces and stomach contents of nestling golden-winged warblers (Vermivora chrysoptera) to investigate the potential contribution of variation in digestive contents to differences in nestling mass. We estimated that the mass of a seventh-day (near fledging) nestling golden-winged warbler varies by 0.65 g (approx. 9% of mean nestling mass) depending on the contents of the nestling's digestive system at the time of weighing, and that digestive contents are dissimilar among nestlings at any moment the brood is removed from the nest for weighing. Our conservative estimate of within-individual variation in digestive contents equals 72% and 24% of the mean within-brood and population-wide range in nestling mass, respectively. Based on our results, a substantive but typically unknown amount of the variation in body mass among nestlings is confounded by differences in digestive contents. We conclude that short-term variation in digestive contents likely precludes the use of body mass, and therefore any mass-dependent index, as a measure of relative nestling condition or as a predictor of survival in golden-winged warblers and likely in many other songbirds of similar size.

  10. Measuring oxidative stress: the confounding effect of lipid concentration in measures of lipid peroxidation.

    PubMed

    Pérez-Rodríguez, Lorenzo; Romero-Haro, Ana A; Sternalski, Audrey; Muriel, Jaime; Mougeot, Francois; Gil, Diego; Alonso-Alvarez, Carlos

    2015-01-01

    Lipid peroxidation products are widely used as markers of oxidative damage in the organism. To properly interpret the information provided by these markers, it is necessary to know potential sources of bias and control confounding factors. Here, we investigated the relationship between two indicators of lipid mobilization (circulating levels of triglycerides and cholesterol) and two common markers of oxidative damage (plasma levels of malondialdehyde and hydroperoxides; the latter estimated from the d-ROMs assay kit). The following five avian species were studied: red-legged partridge (Alectoris rufa), zebra finch (Taeniopygia guttata), spotless starling (Sturnus unicolor), marsh harrier (Circus aeroginosus), and Montagu's harrier (Circus pygargus). In all cases, plasma triglyceride levels positively and significantly correlated with lipid peroxidation markers, explaining between 8% and 34% of their variability. Plasma cholesterol, in contrast, showed a significant positive relationship only among spotless starling nestlings and a marginally significant association in zebra finches. These results indicate that lipid peroxidation marker levels covary with circulating lipid levels. We discuss the potential causes and implications of this covariation and recommend that future studies that measure oxidative damage using lipid peroxidation markers report both raw and relative levels (i.e., corrected for circulating triglycerides). Whether the observed pattern also holds for other tissues and in other taxa would deserve further research.

  11. Platelets confound the measurement of extracellular miRNA in archived plasma

    PubMed Central

    Mitchell, Adam J.; Gray, Warren D.; Hayek, Salim S.; Ko, Yi-An; Thomas, Sheena; Rooney, Kim; Awad, Mosaab; Roback, John D.; Quyyumi, Arshed; Searles, Charles D.

    2016-01-01

    Extracellular miRNAs are detectable in biofluids and represent a novel class of disease biomarker. Although many studies have utilized archived plasma for miRNA biomarker discovery, the effects of processing and storage have not been rigorously studied. Previous reports have suggested plasma samples are commonly contaminated by platelets, significantly confounding the measurement of extracellular miRNA, which was thought to be easily addressed by additional post-thaw plasma processing. In a case-control study of archived plasma, we noted a significant correlation between miRNA levels and platelet counts despite post-thaw processing. We thus examined the effects of a single freeze/thaw cycle on microparticles (MPs) and miRNA levels, and show that a single freeze/thaw cycle of plasma dramatically increases the number of platelet-derived MPs, contaminates the extracellular miRNA pool, and profoundly affects the levels of miRNAs detected. The measurement of extracellular miRNAs in archived samples is critically dependent on the removal of residual platelets prior to freezing plasma samples. Many previous clinical studies of extracellular miRNA in archived plasma should be interpreted with caution and future studies should avoid the effects of platelet contamination. PMID:27623086

  12. A chronic bioassay with the estuarine amphipod Corophium volutator: test method description and confounding factors.

    PubMed

    van den Heuvel-Greve, Martine; Postma, Jaap; Jol, Johan; Kooman, Hanneke; Dubbeldam, Marco; Schipper, Cor; Kater, Belinda

    2007-01-01

    Methods of conducting a chronic sediment toxicity test with the estuarine amphipod Corophium volutator are described. They consist of a 49-day exposure, after which mortality, growth and reproduction are determined. Pilot experiments were used to optimize test design parameters such as temperature, duration, feeding and refreshing regimes, and effects of indigenous organisms. By way of further validation, the present study focused on the effects of four different parameters: oxygen saturation, salinity, ammonium and nitrite. These confounding factors might play an important role especially if the test is used for risk assessment of field-contaminated sediments. It is concluded that the present experimental design is well suited for chronic sediment exposures with C. volutator. The test can be performed at a broad range of salinity values, provided that controls are performed at the same salinity. Results further demonstrate that with the endpoints growth and reproduction this chronic test procedure is a factor 7-18 more sensitive to ammonium and nitrate than the standardized acute bioassay (endpoint mortality).

  13. A comparison of confounding adjustment methods for assessment of asthma controller medication effectiveness.

    PubMed

    Li, Lingling; Vollmer, William M; Butler, Melissa G; Wu, Pingsheng; Kharbanda, Elyse O; Wu, Ann Chen

    2014-03-01

    We compared the impact of 3 confounding adjustment procedures-covariate-adjusted regression, propensity score regression, and high-dimensional propensity score regression-to assess the effects of selected asthma controller medication use (leukotriene antagonists and inhaled corticosteroids) on the following 4 asthma-related adverse outcomes: emergency department visits, hospitalizations, oral corticosteroid use, and the composite outcome of these. We examined a cohort of 24,680 new users who were 4-17 years of age at the incident dispensing from the Population-Based Effectiveness in Asthma and Lung Diseases (PEAL) Network of 5 commercial health plans and TennCare, the Tennessee Medicaid program, during the period January 1, 2004, to December 31, 2010. The 3 methods yielded similar results, indicating that pediatric patients treated with leukotriene antagonists were no more likely than those treated with inhaled corticosteroids to experience adverse outcomes. Children in the TennCare population who had a diagnosis of allergic rhinitis and who then initiated the use of leukotriene antagonists were less likely to experience an asthma-related emergency department visit. A plausible explanation is that our data set is large enough that the 2 advanced propensity score-based analyses do not have advantages over the traditional covariate-adjusted regression approach. We provide important observations on how to correctly apply the methods in observational data analysis and suggest statistical research areas that need more work to guide implementation.

  14. Platelets confound the measurement of extracellular miRNA in archived plasma.

    PubMed

    Mitchell, Adam J; Gray, Warren D; Hayek, Salim S; Ko, Yi-An; Thomas, Sheena; Rooney, Kim; Awad, Mosaab; Roback, John D; Quyyumi, Arshed; Searles, Charles D

    2016-09-13

    Extracellular miRNAs are detectable in biofluids and represent a novel class of disease biomarker. Although many studies have utilized archived plasma for miRNA biomarker discovery, the effects of processing and storage have not been rigorously studied. Previous reports have suggested plasma samples are commonly contaminated by platelets, significantly confounding the measurement of extracellular miRNA, which was thought to be easily addressed by additional post-thaw plasma processing. In a case-control study of archived plasma, we noted a significant correlation between miRNA levels and platelet counts despite post-thaw processing. We thus examined the effects of a single freeze/thaw cycle on microparticles (MPs) and miRNA levels, and show that a single freeze/thaw cycle of plasma dramatically increases the number of platelet-derived MPs, contaminates the extracellular miRNA pool, and profoundly affects the levels of miRNAs detected. The measurement of extracellular miRNAs in archived samples is critically dependent on the removal of residual platelets prior to freezing plasma samples. Many previous clinical studies of extracellular miRNA in archived plasma should be interpreted with caution and future studies should avoid the effects of platelet contamination.

  15. Alcohol confounds relationship between cannabis misuse and psychosis conversion in a high-risk sample

    PubMed Central

    Auther, A. M.; Cadenhead, K. S.; Carrión, R. E.; Addington, J.; Bearden, C. E.; Cannon, T. D.; McGlashan, T. H.; Perkins, D. O.; Seidman, L.; Tsuang, M.; Walker, E. F.; Woods, S. W.; Cornblatt, B. A.

    2015-01-01

    Objective Cannabis use has been examined as a predictor of psychosis in clinical high-risk (CHR) samples, but little is known about the impact of other substances on this relationship. Method Substance use was assessed in a large sample of CHR participants (N = 370, mean age = 18.3) enrolled in the multisite North American Prodrome Longitudinal Study Phase 1 project. Three hundred and forty-one participants with cannabis use data were divided into groups: No Use (NU, N = 211); Cannabis Use without impairment (CU, N = 63); Cannabis Abuse/Dependence (CA/CD, N = 67). Participants (N = 283) were followed for ≥2 years to determine psychosis conversion. Results Alcohol (45.3%) and cannabis (38.1%) were the most common substances. Cannabis use groups did not differ on baseline attenuated positive symptoms. Seventy-nine of 283 participants with cannabis and follow-up data converted to psychosis. Survival analysis revealed significant differences between conversion rates in the CA/CD group compared with the No Use (P = 0.031) and CU group (P = 0.027). CA/CD also significantly predicted psychosis in a regression analysis, but adjusting for alcohol use weakened this relationship. Conclusion The cannabis misuse and psychosis association was confounded by alcohol use. Non-impairing cannabis use was not related to psychosis. Results highlight the need to control for other substance use, so as to not overstate the cannabis/psychosis connection. PMID:25572323

  16. Metabolic equivalents of task are confounded by adiposity, which disturbs objective measurement of physical activity.

    PubMed

    Tompuri, Tuomo T

    2015-01-01

    Physical activity refers any bodily movements produced by skeletal muscles that expends energy. Hence the amount and the intensity of physical activity can be assessed by energy expenditure. Metabolic equivalents of task (MET) are multiplies of the resting metabolism reflecting metabolic rate during exercise. The standard MET is defined as 3.5 ml/min/kg. However, the expression of energy expenditure by body weight to normalize the size differences between subjects causes analytical hazards: scaling by body weight does not have a physiological, mathematical, or physical rationale. This review demonstrates by examples that false methodology may cause paradoxical observations if physical activity would be assessed by body weight scaled values such as standard METs. While standard METs are confounded by adiposity, lean mass proportional measures of energy expenditure would enable a more truthful choice to assess physical activity. While physical activity as a behavior and cardiorespiratory fitness or adiposity as a state represents major determinants of public health, specific measurements of health determinants must be understood to enable a truthful evaluation of the interactions and their independent role as a health predictor.

  17. Influence of potentially confounding factors on sea urchin porewater toxicity tests

    USGS Publications Warehouse

    Carr, R.S.; Biedenbach, J.M.; Nipper, M.

    2006-01-01

    The influence of potentially confounding factors has been identified as a concern for interpreting sea urchin porewater toxicity test data. The results from >40 sediment-quality assessment surveys using early-life stages of the sea urchin Arbacia punctulata were compiled and examined to determine acceptable ranges of natural variables such as pH, ammonia, and dissolved organic carbon on the fertilization and embryological development endpoints. In addition, laboratory experiments were also conducted with A. punctulata and compared with information from the literature. Pore water with pH as low as 6.9 is an unlikely contributor to toxicity for the fertilization and embryological development tests with A. punctulata. Other species of sea urchin have narrower pH tolerance ranges. Ammonia is rarely a contributing factor in pore water toxicity tests using the fertilization endpoint, but the embryological development endpoint may be influenced by ammonia concentrations commonly found in porewater samples. Therefore, ammonia needs to be considered when interpreting results for the embryological development test. Humic acid does not affect sea urchin fertilization at saturation concentrations, but it could have an effect on the embryological development endpoint at near-saturation concentrations. There was no correlation between sediment total organic carbon concentrations and porewater dissolved organic carbon concentrations. Because of the potential for many varying substances to activate parthenogenesis in sea urchin eggs, it is recommended that a no-sperm control be included with every fertilization test treatment. ?? 2006 Springer Science+Business Media, Inc.

  18. The Scalp Confounds Near-Infrared Signal from Rat Brain Following Innocuous and Noxious Stimulation

    PubMed Central

    He, Ji-Wei; Liu, Hanli; Peng, Yuan Bo

    2015-01-01

    Functional near-infrared imaging (fNIRI) is a non-invasive, low-cost and highly portable technique for assessing brain activity and functions. Both clinical and experimental evidence suggest that fNIRI is able to assess brain activity at associated regions during pain processing, indicating a strong possibility of using fNIRI-derived brain activity pattern as a biomarker for pain. However, it remains unclear how, especially in small animals, the scalp influences fNIRI signal in pain processing. Previously, we have shown that the use of a multi-channel system improves the spatial resolution of fNIRI in rats (without the scalp) during pain processing. Our current work is to investigate a scalp effect by comparing with new data from rats with the scalp during innocuous or noxious stimulation (n = 6). Results showed remarkable stimulus-dependent differences between the no-scalp and intact-scalp groups. In conclusion, the scalp confounded the fNIRI signal in pain processing likely via an autonomic mechanism; the scalp effect should be a critical factor in image reconstruction and data interpretation. PMID:26426058

  19. Octopus visual system: a functional MRI model for detecting neuronal electric currents without a BOLD confound

    PubMed Central

    Jiang, Xia; Lu, Hanbing; Shigeno, Shuichi; Tan, Li-Hai; Yang, Yihong; Ragsdale, Clifton W.; Gao, Jia-Hong

    2014-01-01

    Purpose Despite the efforts that have been devoted to detecting the transient magnetic fields generated by neuronal firing, the conclusion that a functionally relevant signal can be measured with magnetic resonance imaging (MRI) is still controversial. For human studies of neuronal current MRI (nc-MRI), the blood-oxygen-level-dependent (BOLD) effect remains an irresolvable confound. For tissue studies where hemoglobin is removed, natural sensory stimulation is not possible. This study investigates the feasibility of detecting a physiologically induced nc-MRI signal in vivo in a BOLD-free environment. Methods The cephalopod mollusc Octopus bimaculoides has vertebrate-like eyes, large optic lobes (OLs) and blood that does not contain hemoglobin. Visually evoked potentials were measured in the octopus retina and OL by electroretinogram and local field potential. nc-MRI scans were conducted at 9.4 Tesla to capture these activities. Results Electrophysiological recording detected strong responses in the retina and OL in vivo; however, nc-MRI failed to demonstrate any statistically significant signal change with a detection threshold of 0.2° for phase and 0.2% for magnitude. Experiments in a dissected eye-OL preparation yielded similar results. Conclusion These findings in a large hemoglobin-free nervous system suggest that sensory evoked neuronal magnetic fields are too weak for direct detection with current MRI technology. PMID:24301336

  20. Stream solute tracer timescales changing with discharge and reach length confound process interpretation

    NASA Astrophysics Data System (ADS)

    Schmadel, Noah M.; Ward, Adam S.; Kurz, Marie J.; Fleckenstein, Jan H.; Zarnetske, Jay P.; Hannah, David M.; Blume, Theresa; Vieweg, Michael; Blaen, Phillip J.; Schmidt, Christian; Knapp, Julia L. A.; Klaar, Megan J.; Romeijn, Paul; Datry, Thibault; Keller, Toralf; Folegot, Silvia; Arricibita, Amaia I. Marruedo; Krause, Stefan

    2016-04-01

    Improved understanding of stream solute transport requires meaningful comparison of processes across a wide range of discharge conditions and spatial scales. At reach scales where solute tracer tests are commonly used to assess transport behavior, such comparison is still confounded due to the challenge of separating dispersive and transient storage processes from the influence of the advective timescale that varies with discharge and reach length. To better resolve interpretation of these processes from field-based tracer observations, we conducted recurrent conservative solute tracer tests along a 1 km study reach during a storm discharge period and further discretized the study reach into six segments of similar length but different channel morphologies. The resulting suite of data, spanning an order of magnitude in advective timescales, enabled us to (1) characterize relationships between tracer response and discharge in individual segments and (2) determine how combining the segments into longer reaches influences interpretation of dispersion and transient storage from tracer tests. We found that the advective timescale was the primary control on the shape of the observed tracer response. Most segments responded similarly to discharge, implying that the influence of morphologic heterogeneity was muted relative to advection. Comparison of tracer data across combined segments demonstrated that increased advective timescales could be misinterpreted as a change in dispersion or transient storage. Taken together, our results stress the importance of characterizing the influence of changing advective timescales on solute tracer responses before such reach-scale observations can be used to infer solute transport at larger network scales.

  1. A causal examination of the effects of confounding factors on multimetric indices

    USGS Publications Warehouse

    Schoolmaster, Donald R.; Grace, James B.; Schweiger, E. William; Mitchell, Brian R.; Guntenspergen, Glenn R.

    2013-01-01

    The development of multimetric indices (MMIs) as a means of providing integrative measures of ecosystem condition is becoming widespread. An increasingly recognized problem for the interpretability of MMIs is controlling for the potentially confounding influences of environmental covariates. Most common approaches to handling covariates are based on simple notions of statistical control, leaving the causal implications of covariates and their adjustment unstated. In this paper, we use graphical models to examine some of the potential impacts of environmental covariates on the observed signals between human disturbance and potential response metrics. Using simulations based on various causal networks, we show how environmental covariates can both obscure and exaggerate the effects of human disturbance on individual metrics. We then examine from a causal interpretation standpoint the common practice of adjusting ecological metrics for environmental influences using only the set of sites deemed to be in reference condition. We present and examine the performance of an alternative approach to metric adjustment that uses the whole set of sites and models both environmental and human disturbance effects simultaneously. The findings from our analyses indicate that failing to model and adjust metrics can result in a systematic bias towards those metrics in which environmental covariates function to artificially strengthen the metric–disturbance relationship resulting in MMIs that do not accurately measure impacts of human disturbance. We also find that a “whole-set modeling approach” requires fewer assumptions and is more efficient with the given information than the more commonly applied “reference-set” approach.

  2. Detection rates of geckos in visual surveys: Turning confounding variables into useful knowledge

    USGS Publications Warehouse

    Lardner, Bjorn; Rodda, Gordon H.; Yackel Adams, Amy A.; Savidge, Julie A.; Reed, Robert N.

    2016-01-01

    Transect surveys without some means of estimating detection probabilities generate population size indices prone to bias because survey conditions differ in time and space. Knowing what causes such bias can help guide the collection of relevant survey covariates, correct the survey data, anticipate situations where bias might be unacceptably large, and elucidate the ecology of target species. We used negative binomial regression to evaluate confounding variables for gecko (primarily Hemidactylus frenatus and Lepidodactylus lugubris) counts on 220-m-long transects surveyed at night, primarily for snakes, on 9,475 occasions. Searchers differed in gecko detection rates by up to a factor of six. The worst and best headlamps differed by a factor of at least two. Strong winds had a negative effect potentially as large as those of searchers or headlamps. More geckos were seen during wet weather conditions, but the effect size was small. Compared with a detection nadir during waxing gibbous (nearly full) moons above the horizon, we saw 28% more geckos during waning crescent moons below the horizon. A sine function suggested that we saw 24% more geckos at the end of the wet season than at the end of the dry season. Fluctuations on a longer timescale also were verified. Disturbingly, corrected data exhibited strong short-term fluctuations that covariates apparently failed to capture. Although some biases can be addressed with measured covariates, others will be difficult to eliminate as a significant source of error in longterm monitoring programs.

  3. Disease Risk Score (DRS) as a Confounder Summary Method: Systematic Review and Recommendations

    PubMed Central

    Tadrous, Mina; Gagne, Joshua J.; Stürmer, Til; Cadarette, Suzanne M.

    2013-01-01

    Purpose To systematically examine trends and applications of the disease risk score (DRS) as a confounder summary method. Methods We completed a systematic search of MEDLINE and Web of Science® to identify all English language articles that applied DRS methods. We tabulated the number of publications by year and type (empirical application, methodological contribution, or review paper) and summarized methods used in empirical applications overall and by publication year (<2000, ≥2000). Results Of 714 unique articles identified, 97 examined DRS methods and 86 were empirical applications. We observed a bimodal distribution in the number of publications over time, with a peak 1979-1980, and resurgence since 2000. The majority of applications with methodological detail derived DRS using logistic regression (47%), used DRS as a categorical variable in regression (93%), and applied DRS in a non-experimental cohort (47%) or case-control (42%) study. Few studies examined effect modification by outcome risk (23%). Conclusion Use of DRS methods has increased yet remains low. Comparative effectiveness research may benefit from more DRS applications, particularly to examine effect modification by outcome risk. Standardized terminology may facilitate identification, application, and comprehension of DRS methods. More research is needed to support the application of DRS methods, particularly in case-control studies. PMID:23172692

  4. Metabolic equivalents of task are confounded by adiposity, which disturbs objective measurement of physical activity

    PubMed Central

    Tompuri, Tuomo T.

    2015-01-01

    Physical activity refers any bodily movements produced by skeletal muscles that expends energy. Hence the amount and the intensity of physical activity can be assessed by energy expenditure. Metabolic equivalents of task (MET) are multiplies of the resting metabolism reflecting metabolic rate during exercise. The standard MET is defined as 3.5 ml/min/kg. However, the expression of energy expenditure by body weight to normalize the size differences between subjects causes analytical hazards: scaling by body weight does not have a physiological, mathematical, or physical rationale. This review demonstrates by examples that false methodology may cause paradoxical observations if physical activity would be assessed by body weight scaled values such as standard METs. While standard METs are confounded by adiposity, lean mass proportional measures of energy expenditure would enable a more truthful choice to assess physical activity. While physical activity as a behavior and cardiorespiratory fitness or adiposity as a state represents major determinants of public health, specific measurements of health determinants must be understood to enable a truthful evaluation of the interactions and their independent role as a health predictor. PMID:26321958

  5. The confounding problem of polydrug use in recreational ecstasy/MDMA users: a brief overview.

    PubMed

    Gouzoulis-Mayfrank, Euphrosyne; Daumann, Jörg

    2006-03-01

    The popular dance drug ecstasy (3,4-methylenedioxymethamphetamine -- MDMA) is neurotoxic upon central serotonergic neurons in laboratory animals and possibly also in humans. In recent years, several studies reported alterations of serotonergic transmission and neuropsychiatric abnormalities in ecstasy users which might be related to MDMA-induced neurotoxic brain damage. To date, the most consistent findings associate subtle cognitive, particularly memory, deficits with heavy ecstasy use. However, most studies have important inherent methodological problems. One of the most serious confounds is the widespread pattern of polydrug use which makes it dif.cult to relate the findings in user populations to one specific drug. The present paper represents a brief overview on this issue. The most commonly co-used substances are alcohol, cannabis and stimulants (amphetamines and cocaine). Stimulants are also neurotoxic upon both serotonergic and dopaminergic neurons. Hence, they may act synergistically with MDMA and enhance its long-term adverse effects. The interactions between MDMA and cannabis use may be more complex: cannabis use is a well-recognized risk factor for neuropsychiatric disorders and it was shown to contribute to psychological problems and cognitive failures in ecstasy users. However, at the cellular level, cannabinoids have neuroprotective actions and they were shown to (partially) block MDMA-induced neurotoxicity in laboratory animals. In future, longitudinal and prospective research designs should hopefully lead to a better understanding of the relation between drug use and subclinical psychological symptoms or neurocognitive failures and, also, of questions around interactions between the various substances of abuse.

  6. Peripheral neuropathy of the upper extremity: medical comorbidity that confounds common orthopedic pathology.

    PubMed

    Bales, Joshua G; Meals, Roy

    2009-10-01

    In the orthopedic patient, the diagnosis of a compression neuropathy may be straightforward. However, various medical comorbidities can obscure this diagnosis. It is paramount for the practicing orthopedic surgeon to have an appreciation for the medical pathology of common axonal neuropathies to properly diagnose, treat, and refer a patient with altered sensation in the upper extremity. The prevalence of diabetes in the United States is 10%, and roughly 20% of diabetic patients have peripheral neuropathy. In addition to diabetes, 32% of heavy alcohol users present with polyneuropathy. With advancements in the treatment of human immunodeficiency virus/acquired immunodeficiency syndrome clinicians may see the long-term effects of the virus manifested as axonal neuropathies and extreme allodynia. In some regions of the world, Hansen's disease usurps diabetes as the most common cause of polyneuropathy. Based on patient demographics and social habits, Lyme disease, multiple sclerosis, and syphilis can all manifest as polyneuropathies. Understanding the common medical causes of neuropathy will aid the orthopedic surgeon in differentiating simple compression neuropathies from diseases mimicking or confounding them.

  7. Choroidal abnormalities and masquerade syndromes confounding the diagnosis of laser-induced eye injuries

    NASA Astrophysics Data System (ADS)

    Hacker, Henry D.; Zwick, Harry; Brown, Jeremiah, Jr.; Dicks, Ronald; Cheramie, Rachel; Stuck, Bruce E.

    2005-04-01

    The diagnosis of a laser-induced eye injury occurring in occupational or military environments is often complicated by confounding symptoms, the possibility of pre-existing pathology, and/or a lack of visual deficits that can be clearly associated with a specific incident. Two recent cases are described that illustrate the importance of a thorough differential diagnosis when coexisting retinal pathologies are present with potentially different (e.g. laser or disease) etiologies. Indocyanine green angiography (ICG) and ocular coherence tomography (OCT) used in combination with standard ophthalmic imaging can provide helpful insights as to the etiology of these lesions. Vascular choroidal abnormalities such as hemangiomas or occult histoplasmosis infection can produce findings that can mimic the leakage that may be evident from neovascular membranes associated with laser injury. Further evaluation with OCT and conventional fluorescein angiography (FA) is helpful to look for the classic signature of retinal disruption and retinal pigment layer changes that are often present in association with laser injury. Furthermore, a careful situational assessment of a potential laser exposure is important to confirm the diagnosis of laser-induced eye injury.

  8. Is it patience or motivation? On motivational confounds in intertemporal choice tasks.

    PubMed

    Paglieri, Fabio; Addessi, Elsa; Sbaffi, Agnese; Tasselli, Maria Isabella; Delfino, Alexia

    2015-01-01

    Intertemporal choices create a tension between amount maximization, which would favor the larger and later option (LL), and delay minimization, which would promote the smaller and sooner reward (SS). Two common interpretations of intertemporal choice behavior are discussed: looking at LL responses as indicative of self-control, and using intertemporal choices to assess delay aversion. We argue that both interpretations need to take into account motivational confounds, in order to be warranted by data. In intertemporal choices with prepotent, salient stimuli (e.g., food amounts, typically used with nonhuman primates), LL responses could also be indicative of failed inhibition of a "go for more" impulsive response-the opposite of self-control. Similarly, intertemporal choices can be used to measure delay aversion only with respect to the subject's baseline motivation to maximize the reinforcer in question, and this baseline is not always assessed in current experimental protocols. This concern is especially crucial in comparing intertemporal choices across different groups or manipulation. We focus in particular on the effects of reward types on intertemporal choices, presenting two experimental studies where the difference in behavior with monetary versus food rewards is the product of different baseline motivation, rather than variations in delay aversion. We conclude discussing the implications of these and other similar recent findings, which are far-reaching.

  9. Using high-dimensional propensity scores to automate confounding control in a distributed medical product safety surveillance system.

    PubMed

    Rassen, Jeremy A; Schneeweiss, Sebastian

    2012-01-01

    Distributed medical product safety monitoring systems such as the Sentinel System, to be developed as a part of Food and Drug Administration's Sentinel Initiative, will require automation of large parts of the safety evaluation process to achieve the necessary speed and scale at reasonable cost without sacrificing validity. Although certain functions will require investigator intervention, confounding control is one area that can largely be automated. The high-dimensional propensity score (hd-PS) algorithm is one option for automated confounding control in longitudinal healthcare databases. In this article, we discuss the use of hd-PS for automating confounding control in sequential database cohort studies, as applied to safety monitoring systems. In particular, we discuss the robustness of the covariate selection process, the potential for over- or under-selection of variables including the possibilities of M-bias and Z-bias, the computation requirements, the practical considerations in a federated database network, and the cases where automated confounding adjustment may not function optimally. We also outline recent improvements to the algorithm and show how the algorithm has performed in several published studies. We conclude that despite certain limitations, hd-PS offers substantial advantages over non-automated alternatives in active product safety monitoring systems.

  10. Doubly robust estimators of causal exposure effects with missing data in the outcome, exposure or a confounder.

    PubMed

    Williamson, E J; Forbes, A; Wolfe, R

    2012-12-30

    We consider the estimation of the causal effect of a binary exposure on a continuous outcome. Confounding and missing data are both likely to occur in practice when observational data are used to estimate this causal effect. In dealing with each of these problems, model misspecification is likely to introduce bias. We present augmented inverse probability weighted (AIPW) estimators that account for both confounding and missing data, with the latter occurring in a single variable only. These estimators have an element of robustness to misspecification of the models used. Our estimators require two models to be specified to deal with confounding and two to deal with missing data. Only one of each of these models needs to be correctly specified. When either the outcome or the exposure of interest is missing, we derive explicit expressions for the AIPW estimator. When a confounder is missing, explicit derivation is complex, so we use a simple algorithm, which can be applied using standard statistical software, to obtain an approximation to the AIPW estimator.

  11. Treatment Confounded Missingness: A Comparison of Methods for Addressing Censored or Truncated Data in School Reform Evaluations. CRESST Report 832

    ERIC Educational Resources Information Center

    Rickles, Jordan H.; Hansen, Mark; Wang, Jia

    2013-01-01

    In this paper we examine ways to conceptualize and address potential bias that can arise when the mechanism for missing outcome data is at least partially associated with treatment assignment, an issue we refer to as treatment confounded missingness (TCM). In discussing TCM, we bring together concepts from the methodological literature on missing…

  12. Who really gets strep sore throat? Confounding and effect modification of a time-varying exposure on recurrent events.

    PubMed

    Follmann, Dean; Huang, Chiung-Yu; Gabriel, Erin

    2016-10-30

    Unmeasured confounding is the fundamental obstacle to drawing causal conclusions about the impact of an intervention from observational data. Typically, covariates are measured to eliminate or ameliorate confounding, but they may be insufficient or unavailable. In the special setting where a transient intervention or exposure varies over time within each individual and confounding is time constant, a different tack is possible. The key idea is to condition on either the overall outcome or the proportion of time in the intervention. These measures can eliminate the unmeasured confounding either by conditioning or by use of a proxy covariate. We evaluate existing methods and develop new models from which causal conclusions can be drawn from such observational data even if no baseline covariates are measured. Our motivation for this work was to determine the causal effect of Streptococcus bacteria in the throat on pharyngitis (sore throat) in Indian schoolchildren. Using our models, we show that existing methods can be badly biased and that sick children who are rarely colonized have a high probability that the Streptococcus bacteria are causing their disease. Published 2016. This article is a U.S. Government work and is in the public domain in the USA.

  13. Clustering and Residual Confounding in the Application of Marginal Structural Models: Dialysis Modality, Vascular Access, and Mortality.

    PubMed

    Kasza, Jessica; Polkinghorne, Kevan R; Marshall, Mark R; McDonald, Stephen P; Wolfe, Rory

    2015-09-15

    In the application of marginal structural models to compare time-varying treatments, it is rare that the hierarchical structure of a data set is accounted for or that the impact of unmeasured confounding on estimates is assessed. These issues often arise when analyzing data sets drawn from clinical registries, where patients may be clustered within health-care providers, and the amount of data collected from each patient may be limited by design (e.g., to reduce costs or encourage provider participation). We compared the survival of patients undergoing treatment with various dialysis types, where some patients switched dialysis modality during the course of their treatment, by estimating a marginal structural model using data from the Australia and New Zealand Dialysis and Transplant Registry, 2003-2011. The number of variables recorded by the registry is limited, and patients are clustered within the dialysis centers responsible for their treatment, so we assessed the impact of accounting for unmeasured confounding or clustering on estimated treatment effects. Accounting for clustering had limited impact, and only unreasonable levels of unmeasured confounding would have changed conclusions about treatment comparisons. Our analysis serves as a case study in assessing the impact of unmeasured confounding and clustering in the application of marginal structural models.

  14. Are We Missing Something Pertinent? A Bias Analysis of Unmeasured Confounding in the Firearm-Suicide Literature.

    PubMed

    Miller, M; Swanson, S A; Azrael, D

    2016-01-01

    Despite the magnitude and consistency of risk estimates in the peer-reviewed literature linking firearm availability and suicide, inferring causality has been questioned on the theoretical basis that existing studies may have failed to account for the possibility that members of households with firearms differ from members of households without firearms in important ways related to suicide risk. The current bias analysis directly addresses this concern by describing the salient characteristics that such an unmeasured confounder would need to possess in order to yield the associations between firearm availability and suicide observed in the literature when, in fact, the causal effect is null. Four US studies, published between 1992 and 2003, met our eligibility criteria. We find that any such unmeasured confounder would need to possess an untenable combination of characteristics, such as being not only 1) as potent a suicide risk factor as the psychiatric disorders most tightly linked to suicide (e.g., major depressive and substance use disorders) but also 2) an order of magnitude more imbalanced across households with versus without firearms than is any known risk factor. No such confounder has been found or even suggested. The current study strongly suggests that unmeasured confounding alone is unlikely to explain the association between firearms and suicide.

  15. Interpretational Confounding Is Due to Misspecification, Not to Type of Indicator: Comment on Howell, Breivik, and Wilcox (2007)

    ERIC Educational Resources Information Center

    Bollen, Kenneth A.

    2007-01-01

    R. D. Howell, E. Breivik, and J. B. Wilcox (2007) have argued that causal (formative) indicators are inherently subject to interpretational confounding. That is, they have argued that using causal (formative) indicators leads the empirical meaning of a latent variable to be other than that assigned to it by a researcher. Their critique of causal…

  16. Differential dietary nutrient intake according to hormone replacement therapy use: an underestimated confounding factor in epidemiologic studies?

    PubMed

    Vercambre, Marie-Noël; Fournier, Agnès; Boutron-Ruault, Marie-Christine; Clavel-Chapelon, Françoise; Ringa, Virginie; Berr, Claudine

    2007-12-15

    Observational studies and randomized controlled trials have produced divergent results concerning the effect of hormone replacement therapy (HRT) on cardiovascular disease and, to a lesser extent, dementia. Residual confounding (confounding that remains even after adjustment for various socioeconomic and lifestyle factors) is one explanation that has been offered for these divergent results. The authors used data collected between 1990 and 1995 from 6,697 French women aged 61-72 years participating in a prospective cohort study to explore the hypothesis that nutritional intake varies according to HRT use and thus may be a source of residual confounding. After the authors adjusted for health and lifestyle factors, HRT users, compared with never users, had significantly higher intakes of alcohol; omega3 fatty acids; vitamins B6, B12, and D; and phosphorus and a lower intake of starch. These differential nutrient intakes were related to differences in eating habits. In particular, HRT users in the studied sample, compared with nonusers, ate significantly more fish. Most of the dietary differences were seen in both early users and delayers of HRT. To limit residual confounding in observational studies, dietary factors may be important parameters to be taken into account in analyses of HRT use and health outcomes.

  17. Applications of the propensity score weighting method in psychogeriatric research: correcting selection bias and adjusting for confounders.

    PubMed

    Chang, Chung-Chou H

    2017-05-01

    The propensity score (PS) weighting method is an analytic technique that has been applied in multiple fields for a number of purposes. Here, we discuss two common applications, which are (1) to correct for selection bias and (2) to adjust for confounding variables when estimating the effect of an exposure variable on the outcome of interest.

  18. Interferometric biochemical and chemical sensors

    NASA Astrophysics Data System (ADS)

    Gauglitz, Guenter; Brecht, Andreas; Kraus, Gerolf

    1995-09-01

    Interferometric principles have gained wide acceptance in the field of chemical and biochemical sensing. Reflectometric interference spectrometry sensors using white light multiple reflections at thin layers, structures of polymers, or monolayers of biochemicals are discussed in a survey. These are compared to other techniques, especially methods using surface plasmon resonance and grating couplers. Applications in the area of environmental monitoring in public safety are given, demonstrating the results for halogenated hydrocarbons in air and water as well as pesticides in ground water. Calibration curves, limits of decision, of detection, and of determination are specified and discussed with respect to EU limits. The application of multivariate data analysis is considered including artificial neuronal networks for multisensor systems and referencing in the case of gas sensors.

  19. Marked overlap of four genetic syndromes with dyskeratosis congenita confounds clinical diagnosis

    PubMed Central

    Walne, Amanda J.; Collopy, Laura; Cardoso, Shirleny; Ellison, Alicia; Plagnol, Vincent; Albayrak, Canan; Albayrak, Davut; Kilic, Sara Sebnem; Patıroglu, Turkan; Akar, Haluk; Godfrey, Keith; Carter, Tina; Marafie, Makia; Vora, Ajay; Sundin, Mikael; Vulliamy, Thomas; Tummala, Hemanth; Dokal, Inderjeet

    2016-01-01

    Dyskeratosis congenita is a highly pleotropic genetic disorder. This heterogeneity can lead to difficulties in making an accurate diagnosis and delays in appropriate management. The aim of this study was to determine the underlying genetic basis in patients presenting with features of dyskeratosis congenita and who were negative for mutations in the classical dyskeratosis congenita genes. By whole exome and targeted sequencing, we identified biallelic variants in genes that are not associated with dyskeratosis congenita in 17 individuals from 12 families. Specifically, these were homozygous variants in USB1 (8 families), homozygous missense variants in GRHL2 (2 families) and identical compound heterozygous variants in LIG4 (2 families). All patients had multiple somatic features of dyskeratosis congenita but not the characteristic short telomeres. Our case series shows that biallelic variants in USB1, LIG4 and GRHL2, the genes mutated in poikiloderma with neutropenia, LIG4/Dubowitz syndrome and the recently recognized ectodermal dysplasia/short stature syndrome, respectively, cause features that overlap with dyskeratosis congenita. Strikingly, these genes also overlap in their biological function with the known dyskeratosis congenita genes that are implicated in telomere maintenance and DNA repair pathways. Collectively, these observations demonstrate the marked overlap of dyskeratosis congenita with four other genetic syndromes, confounding accurate diagnosis and subsequent management. This has important implications for establishing a genetic diagnosis when a new patient presents in the clinic. Patients with clinical features of dyskeratosis congenita need to have genetic analysis of USB1, LIG4 and GRHL2 in addition to the classical dyskeratosis congenita genes and telomere length measurements. PMID:27612988

  20. Marked EEG worsening following Levetiracetam overdose: How a pharmacological issue can confound coma prognosis.

    PubMed

    Bouchier, Baptiste; Demarquay, Geneviève; Guérin, Claude; André-Obadia, Nathalie; Gobert, Florent

    2017-01-01

    Levetiracetam is an anti-epileptic drug commonly used in intensive care when seizure is suspected as a possible cause of coma. We propose to question the cofounding effect of Levetiracetam during the prognostication process in a case of anoxic coma. We report the story of a young woman presenting a comatose state following a hypoxic cardiac arrest. After a first EEG presenting an intermediate EEG pattern, a seizure suspicion led to prescribe Levetiracetam. The EEG showed then the appearance of burst suppression, which was compatible with a very severe pattern of post-anoxic coma. This aggravation was in fact related to an overdose of Levetiracetam (the only medication introduced recently) and was reversible after Levetiracetam cessation. The increased plasmatic dosages of Levetiracetam confirming this overdose could have been favoured by a moderate reduction of renal clearance, previously underestimated because of a low body-weight. This EEG dynamic was unexpected under Levetiracetam and could sign a functional instability after anoxia. Burst suppression is classically observed with high doses of anaesthetics, but is not expected after a minor anti-epileptic drug. This report proposes that Levetiracetam tolerance might not be straightforward after brain lesions and engages us to avoid confounding factors during the awakening prognostication, which is mainly based on the severity of the EEG. Hence, prognosis should not be decided on an isolated parameter, especially if the dynamic is atypical after a new prescription, even for well-known drugs. For any suspicion, the drug's dosage and replacement should be managed before any premature care's withdrawal.

  1. The confounded effects of age and exposure history in response to influenza vaccination.

    PubMed

    Mosterín Höpping, Ana; McElhaney, Janet; Fonville, Judith M; Powers, Douglas C; Beyer, Walter E P; Smith, Derek J

    2016-01-20

    Numerous studies have explored whether the antibody response to influenza vaccination in elderly adults is as strong as it is in young adults. Results vary, but tend to indicate lower post-vaccination titers (antibody levels) in the elderly, supporting the concept of immunosenescence-the weakening of the immunological response related to age. Because the elderly in such studies typically have been vaccinated against influenza before enrollment, a confounding of effects occurs between age, and previous exposures, as a potential extrinsic reason for immunosenescence. We conducted a four-year study of serial annual immunizations with inactivated trivalent influenza vaccines in 136 young adults (16 to 39 years) and 122 elderly adults (62 to 92 years). Compared to data sets of previously published studies, which were designed to investigate the effect of age, this detailed longitudinal study with multiple vaccinations allowed us to also study the effect of prior vaccination history on the response to a vaccine. In response to the first vaccination, young adults produced higher post-vaccination titers, accounting for pre-vaccination titers, than elderly adults. However, upon subsequent vaccinations the difference in response to vaccination between the young and elderly age groups declined rapidly. Although age is an important factor when modeling the outcome of the first vaccination, this term lost its relevance with successive vaccinations. In fact, when we examined the data with the assumption that the elderly group had received (on average) as few as two vaccinations prior to our study, the difference due to age disappeared. Our analyses therefore show that the initial difference between the two age groups in their response to vaccination may not be uniquely explained by immunosenescence due to ageing of the immune system, but could equally be the result of the different pre-study vaccination and infection histories in the elderly.

  2. Preformed biomarkers including dialkylphosphates (DAPs) in produce may confound biomonitoring in pesticide exposure and risk assessment.

    PubMed

    Chen, Li; Zhao, Taifeng; Pan, Canping; Ross, John H; Krieger, Robert I

    2012-09-12

    Low levels of pesticides and their metabolites/degradates occur in produce when pesticides are used in conventional or organic crop protection. Human dietary and nonoccupational urine biomonitoring studies may be confounded by preformed pesticide biomarkers in the diet. The extent of formation of putative urine biomarkers, including malathion specific (MMA, MDA; malathion mono- and diacids), organophosphorus generic (DMP, DMTP, DMDTP; dimethyl-, dimethylthio-, and dimethydithiophosphate), pyrethroid generic (3-PBA; 3-phenoxybenzoic acid), and captan-specific metabolites (THPI; tetrahydrophthalimide), was measured in produce samples containing the parent pesticide. Every produce sample of 19 types of fruits and vegetables contained biomarkers of potential human exposure. A total of 134 of 157 (85%) samples contained more molar equivalent biomarkers than parent pesticide. Malathion and fenpropathrin were sprayed (1 lb/A), and the time-dependent formation of pesticide biomarkers in strawberries was investigated under field conditions typical of commercial production in California. Malathion and fenpropathrin residues were always below established residue tolerances. Malathion, MMA, and MDA dissipated, while DMP, DMTP, and DMDTP increased, during a 20 day study period following the preharvest interval. The mole ratios of biomarkers/(malathion + malaoxon) were always greater than 1 and increased from day 4 to day 23 postapplication. Fenpropathrin and 3-PBA also dissipated in strawberries during each monitoring period. The mole ratios of 3-PBA/fenpropathrin were always less than 1 and decreased from day 4 to day 14. The absorption of pesticide biomarkers in produce and excretion in urine would falsely indicate consumer pesticide exposure if used to reconstruct dose for risk characterization.

  3. Nonradiographic axial spondyloarthritis background and confounding factors of this new terminology: an appraisal.

    PubMed

    Erbil, Jen; Espinoza, Luis R

    2015-03-01

    The advent of biologic therapy in the treatment of rheumatic diseases has intensified the need to further define and characterize spondyloarthritis (SpA). There has been a long debate over nomenclature of the SpA subtypes. There are those who are considered "lumpers," favoring the notion that different entities of the SpA groups are manifestations of the same disease, and "splitters," those who believe the different SpA groups represent separate diseases with shared clinical features. The influential work by Moll et al. has led to separation of entities and recognition of etiological processes of SpA subtypes. Among these subtypes has emerged nonradiographic axial spondyloarthritis (nr-axSpA), which is believed to be either an early form of ankylosing spondylitis (AS) or perhaps a different disease entity altogether. Recently attention has shifted to the characterization of early SpA, with special emphasis on nonradiographic axial SpA. The Assessment of Spondyloarthritis International Society (ASAS) has developed new criteria for the classification of this disease entity. Along with the advent of these criteria have come several unanswered questions. Although data suggests that nr-axSpA will evolve into AS over time, the natural evolution of disease is still undetermined since a proportion of cases do not progress. A number of questions also remain regarding features of patients with AS compared to those with nonradiographic disease. This appraisal highlights the differences in disease characteristics between men and women in regards to measures of disease activity, inflammatory markers, and radiologic findings. Recent studies also suggest fibromyalgia as a potential confounding factor in assessing disease activity and establishing a diagnosis of axSpA in the female population. Nonradiographic axial SpA is a relevant disease subgroup of axial SpA, and several questions have been left unanswered with more research needed regarding diagnosis (particularly in women

  4. Bordetella pseudohinzii as a Confounding Organism in Murine Models of Pulmonary Disease

    PubMed Central

    Clark, Sarah E; Purcell, Jeanette E; Sammani, Saad; Steffen, Earl K; Crim, Marcus J; Livingston, Robert S; Besch-Williford, Cynthia; Fortman, Jeffrey D

    2016-01-01

    A group studying acute lung injury observed an increased percentage of neutrophils in the bronchoalveolar lavage (BAL) fluid of mice. BAL was performed, and lung samples were collected sterilely from 5 C57BL/6 mice that had been bred inhouse. Pure colonies of bacteria, initially identified as Bordetella hinzii were cultured from 2 of the 5 mice which had the highest percentages of neutrophils (21% and 26%) in the BAL fluid. Subsequent sequencing of a portion of the ompA gene from this isolate demonstrated 100% homology with the published B. pseudohinzii sequence. We then selected 10 mice from the investigator's colony to determine the best test to screen for B. pseudohinzii in the facility. BAL was performed, the left lung lobe was collected for culture and PCR analysis, the right lung lobe and nasal passages were collected for histopathology, an oral swab was collected for culture, and an oral swab and fecal pellets were collected for PCR analysis. B. pseudohinzii was cultured from the oral cavity, lung, or both in 8 of the 10 mice analyzed. All 8 of these mice were fecal PCR positive for B. pseudohinzii; 7 had increased neutrophils (5% to 20%) in the BAL fluid, whereas the 8th mouse had a normal neutrophil percentage (2%). Active bronchopneumonia was not observed, but some infected mice had mild to moderate rhinitis. B. pseudohinzii appears to be a microbial agent of importance in mouse colonies that can confound pulmonary research. Commercial vendors and institutions should consider colony screening, routine reporting, and exclusion of B. pseudohinzii. PMID:27780002

  5. Increased Lactate Levels and Reduced pH in Postmortem Brains of Schizophrenics: Medication Confounds

    PubMed Central

    Halim, Nader D.; Lipska, Barbara K.; Hyde, Thomas M.; Deep-Soboslay, Amy; Saylor, E. Michael; Herman, Mary; Thakar, Jay; Verma, Ajay; Kleinman, Joel E.

    2008-01-01

    A number of postmortem studies have found decreased pH in brains of patients with schizophrenia. Insofar as lower pH has been associated with decreased mRNA expression in postmortem human brain, decreased pH in schizophrenia may represent an important potential confound in comparisons between patients and controls. We hypothesized that decreased pH may be related to increased concentration of lactic acid. However, in contrast to the previous notion that an increase in lactic acid represents evidence for primary metabolic abnormalities in schizophrenia, we hypothesized that this increase is secondary to prior antipsychotic treatment. We have tested this by first demonstrating that lactate levels in the cerebellum of patients with schizophrenia (n=35) are increased relative to control subjects (n=42) by 28%, p=0.001. Second, we have shown that there is an excellent correlation between lactate levels in the cerebellum and pH, and that this correlation is particularly strong in patients (r=− 0.78, p=3e-6). Third, we have shown in rats that chronic haloperidol (0.8 mg/kg/day) and clozapine (5 mg/kg/day) increase lactic acid concentration in the frontal cortex relative to vehicle (by 31% and 22% respectively, p<0.01). These data suggest that lactate increases in postmortem human brain of patients with schizophrenia are associated with decreased pH and that these changes are possibly related to antipsychotic treatment rather than a primary metabolic abnormality in the prefrontal cortex of patients with schizophrenia. PMID:18177946

  6. Prostate-Specific Antigen Velocity Before and After Elimination of Factors That Can Confound the Prostate-Specific Antigen Level

    SciTech Connect

    Park, Jessica J.; Chen, Ming-Hui; Loffredo, Marian; D'Amico, Anthony V.

    2012-03-01

    Purpose: Prostate-specific antigen (PSA) velocity, like PSA level, can be confounded. In this study, we estimated the impact that confounding factors could have on correctly identifying a patient with a PSA velocity >2 ng/ml/y. Methods and Materials: Between 2006 and 2010, a total of 50 men with newly diagnosed PC comprised the study cohort. We calculated and compared the false-positive and false-negative PSA velocity >2 ng/ml/y rates for all men and those with low-risk disease using two approaches to calculate PSA velocity. First, we used PSA values obtained within 18 months of diagnosis; second, we used values within 18 months of diagnosis, substituting the prebiopsy PSA for a repeat, nonconfounded PSA that was obtained using the same assay and without confounders. Results: Using PSA levels pre-biopsy, 46% of all men had a PSA velocity >2 ng/ml/y; whereas this value declined to 32% when substituting the last prebiopsy PSA for a repeat, nonconfounded PSA using the same assay and without confounders. The false-positive rate for PSA velocity >2 ng/ml/y was 43% as compared with a false-negative rate of PSA velocity >2 ng/ml/y of 11% (p = 0.0008) in the overall cohort. These respective values in the low-risk subgroup were 60% and 16.7% (p = 0.09). Conclusion: This study provides evidence to explain the discordance in cancer-specific outcomes among groups investigating the prognostic significance of PSA velocity >2 ng/ml/y, and highlights the importance of patient education on potential confounders of the PSA test before obtaining PSA levels.

  7. Timing of human preimplantation embryonic development is confounded by embryo origin

    PubMed Central

    Kirkegaard, K.; Sundvall, L.; Erlandsen, M.; Hindkjær, J.J.; Knudsen, U.B.; Ingerslev, H.J.

    2016-01-01

    STUDY QUESTION To what extent do patient- and treatment-related factors explain the variation in morphokinetic parameters proposed as embryo viability markers? SUMMARY ANSWER Up to 31% of the observed variation in timing of embryo development can be explained by embryo origin, but no single factor elicits a systematic influence. WHAT IS KNOWN ALREADY Several studies report that culture conditions, patient characteristics and treatment influence timing of embryo development, which have promoted the perception that each clinic must develop individual models. Most of the studies have, however, treated embryos from one patient as independent observations, and only very few studies that evaluate the influence from patient- and treatment-related factors on timing of development or time-lapse parameters as predictors of viability have controlled for confounding, which implies a high risk of overestimating the statistical significance of potential correlations. STUDY DESIGN, SIZE, DURATION Infertile patients were prospectively recruited to a cohort study at a hospital fertility clinic from February 2011 to May 2013. Patients aged <38 years without endometriosis were eligible if ≥8 oocytes were retrieved. Patients were included only once. All embryos were monitored for 6 days in a time-lapse incubator. PARTICIPANTS/MATERIALS, SETTING, METHODS A total of 1507 embryos from 243 patients were included. The influence of fertilization method, BMI, maternal age, FSH dose and number of previous cycles on timing of t2-t5, duration of the 2- and 3-cell stage, and development of a blastocoel (tEB) and full blastocoel (tFB) was tested in multivariate, multilevel linear regression analysis. Predictive parameters for live birth were tested in a logistic regression analysis for 223 single transferred blastocysts, where time-lapse parameters were investigated along with patient and embryo characteristics. MAIN RESULTS AND THE ROLE OF CHANCE Moderate intra-class correlation coefficients

  8. Biochemical adaptation to ocean acidification.

    PubMed

    Stillman, Jonathon H; Paganini, Adam W

    2015-06-01

    The change in oceanic carbonate chemistry due to increased atmospheric PCO2  has caused pH to decline in marine surface waters, a phenomenon known as ocean acidification (OA). The effects of OA on organisms have been shown to be widespread among diverse taxa from a wide range of habitats. The majority of studies of organismal response to OA are in short-term exposures to future levels of PCO2 . From such studies, much information has been gathered on plastic responses organisms may make in the future that are beneficial or harmful to fitness. Relatively few studies have examined whether organisms can adapt to negative-fitness consequences of plastic responses to OA. We outline major approaches that have been used to study the adaptive potential for organisms to OA, which include comparative studies and experimental evolution. Organisms that inhabit a range of pH environments (e.g. pH gradients at volcanic CO2 seeps or in upwelling zones) have great potential for studies that identify adaptive shifts that have occurred through evolution. Comparative studies have advanced our understanding of adaptation to OA by linking whole-organism responses with cellular mechanisms. Such optimization of function provides a link between genetic variation and adaptive evolution in tuning optimal function of rate-limiting cellular processes in different pH conditions. For example, in experimental evolution studies of organisms with short generation times (e.g. phytoplankton), hundreds of generations of growth under future conditions has resulted in fixed differences in gene expression related to acid-base regulation. However, biochemical mechanisms for adaptive responses to OA have yet to be fully characterized, and are likely to be more complex than simply changes in gene expression or protein modification. Finally, we present a hypothesis regarding an unexplored area for biochemical adaptation to ocean acidification. In this hypothesis, proteins and membranes exposed to the

  9. Connecting Biochemical Photosynthesis Models with Crop Models to Support Crop Improvement.

    PubMed

    Wu, Alex; Song, Youhong; van Oosterom, Erik J; Hammer, Graeme L

    2016-01-01

    The next advance in field crop productivity will likely need to come from improving crop use efficiency of resources (e.g., light, water, and nitrogen), aspects of which are closely linked with overall crop photosynthetic efficiency. Progress in genetic manipulation of photosynthesis is confounded by uncertainties of consequences at crop level because of difficulties connecting across scales. Crop growth and development simulation models that integrate across biological levels of organization and use a gene-to-phenotype modeling approach may present a way forward. There has been a long history of development of crop models capable of simulating dynamics of crop physiological attributes. Many crop models incorporate canopy photosynthesis (source) as a key driver for crop growth, while others derive crop growth from the balance between source- and sink-limitations. Modeling leaf photosynthesis has progressed from empirical modeling via light response curves to a more mechanistic basis, having clearer links to the underlying biochemical processes of photosynthesis. Cross-scale modeling that connects models at the biochemical and crop levels and utilizes developments in upscaling leaf-level models to canopy models has the potential to bridge the gap between photosynthetic manipulation at the biochemical level and its consequences on crop productivity. Here we review approaches to this emerging cross-scale modeling framework and reinforce the need for connections across levels of modeling. Further, we propose strategies for connecting biochemical models of photosynthesis into the cross-scale modeling framework to support crop improvement through photosynthetic manipulation.

  10. Connecting Biochemical Photosynthesis Models with Crop Models to Support Crop Improvement

    PubMed Central

    Wu, Alex; Song, Youhong; van Oosterom, Erik J.; Hammer, Graeme L.

    2016-01-01

    The next advance in field crop productivity will likely need to come from improving crop use efficiency of resources (e.g., light, water, and nitrogen), aspects of which are closely linked with overall crop photosynthetic efficiency. Progress in genetic manipulation of photosynthesis is confounded by uncertainties of consequences at crop level because of difficulties connecting across scales. Crop growth and development simulation models that integrate across biological levels of organization and use a gene-to-phenotype modeling approach may present a way forward. There has been a long history of development of crop models capable of simulating dynamics of crop physiological attributes. Many crop models incorporate canopy photosynthesis (source) as a key driver for crop growth, while others derive crop growth from the balance between source- and sink-limitations. Modeling leaf photosynthesis has progressed from empirical modeling via light response curves to a more mechanistic basis, having clearer links to the underlying biochemical processes of photosynthesis. Cross-scale modeling that connects models at the biochemical and crop levels and utilizes developments in upscaling leaf-level models to canopy models has the potential to bridge the gap between photosynthetic manipulation at the biochemical level and its consequences on crop productivity. Here we review approaches to this emerging cross-scale modeling framework and reinforce the need for connections across levels of modeling. Further, we propose strategies for connecting biochemical models of photosynthesis into the cross-scale modeling framework to support crop improvement through photosynthetic manipulation. PMID:27790232

  11. Cytokine and satellite cell responses to muscle damage: interpretation and possible confounding factors in human studies.

    PubMed

    van de Vyver, M; Myburgh, K H

    2012-08-01

    It is plausible that multiple muscle biopsies following a muscle damaging intervention can exacerbate the inflammatory and subsequent satellite cell responses. To elucidate confounding effects of muscle biopsy procedure on satellite cell number, indirect markers of damage and the inflammatory response following acute downhill running (DHR) were investigated. 10 healthy male participant were divided into a non-exercising control (n = 4) and DHR (12 × 5min bouts, 10 % decline at 85 % VO(2)max) (n = 6) group. Blood samples were taken pre, post and every 24 h for 9 days. Serum was analysed for creatine kinase (CK), myoglobin (Mb), lactate dehydrogenase (LDH), TNF-α, IL-6 and IL-10. Muscle biopsies taken on days 1 and 2 post intervention from opposing legs were analysed for Pax7(+) satellite cells. In the DHR group, Mb (536 ± 277 ng mL(-1)), IL-6 (12.6 ± 4.7 pg mL(-1)) and IL-10 (27.3 ± 11.5 pg mL(-1)) peaked immediately post DHR, while CK (2651 ± 1911 U L(-1)), LDH (202 ± 47 U L(-1)) and TNF-α (25.1 ± 8.7 pg mL(-1)) peaked on day 1. A 30 % increase in Pax7(+) satellite cells on day 1 in the DHR group was no longer apparent on day 2. H&E staining show evidence of phagocytosis in the DHR group. No significant changes over time were observed in the control group for any of the variables measured. Events observed in the DHR group were as a result of the intervention protocol and subsequent muscle damage. The relationship between SC proliferation and pro-inflammatory cytokine release appears to be complex since the IL-6/IL-10 response time differs significantly from the TNF-α response.

  12. Biochemical structure of Calendula officinalis.

    PubMed

    Korakhashvili, A; Kacharava, T; Kiknavelidze, N

    2007-01-01

    Calendula officinalis is a well known medicinal herb. It is common knowledge that its medicinal properties are conditioned on biologically active complex substances of Carotin (Provitamin A), Stearin, Triterpiniod, Plavonoid, Kumarin, macro and micro compound elements. Because of constant need in raw material of Calendula officinalis, features of its ontogenetic development agro-biological qualities in various eco regions of Georgia were investigated. The data of biologically active compounds, biochemical structure and the maintenance both in flowers and in others parts of plant is presented; the pharmacological activity and importance in medicine was reviewed.

  13. Hyponatraemia: biochemical and clinical perspectives.

    PubMed

    Gill, G; Leese, G

    1998-09-01

    Hyponatraemia is a common bio-chemical abnormality, occurring in about 15% of hospital inpatients. It is often associated with severe illness and relatively poor outcome. Pathophysiologically, hyponatraemia may be spurious, dilutional, depletional or redistributional. Particularly difficult causes and concepts of hyponatraemia are the syndrome of inappropriate antidiuresis and the sick cell syndrome, which are discussed here in detail. Therapy should always be targeted at the underlying disease process. 'Hyponatraemic symptoms' are of doubtful importance, and may be more related to water overload and/or the causative disease, than to hyponatraemia per se. Artificial elevation of plasma sodium by saline infusion carries the risk of induction of osmotic demyelination (central pontine myelinolysis).

  14. Relations between verbal and nonverbal memory performance: evidence of confounding effects particularly in patients with right temporal lobe epilepsy.

    PubMed

    Helmstaedter, C; Pohl, C; Elger, C E

    1995-06-01

    Confounding left hemisphere verbalization strategies can be suggested as being a major problem in the evaluation of the assumed involvement of right temporo-limbic structures in "nonverbal" visual/figural memory processing. We addressed this issue by evaluating the easily-verbalized Benton-visual-retention-test in 60 patients with either left (LTLE) or right temporal lobe epilepsy (RTLE) and 30 healthy controls. We formally estimated the informational (verbal) content of each item which hypothetically would be needed to solely retain the item from verbal memory. The results indicated confounding of verbal learning and figural memory only in the presence of right temporal lobe dysfunctions. Selective visual/figural learning deficits in RTLE patients became obvious when the verbal load of the figural material exceeded their verbal learning capacity. Instead of excluding verbalization by the use of abstract figural items, its inclusion provides a possibility to control compensatory strategies which overshadow the presence of visual/figural memory deficits.

  15. Residential proximity to electromagnetic field sources and birth weight: Minimizing residual confounding using multiple imputation and propensity score matching.

    PubMed

    de Vocht, Frank; Lee, Brian

    2014-08-01

    Studies have suggested that residential exposure to extremely low frequency (50 Hz) electromagnetic fields (ELF-EMF) from high voltage cables, overhead power lines, electricity substations or towers are associated with reduced birth weight and may be associated with adverse birth outcomes or even miscarriages. We previously conducted a study of 140,356 singleton live births between 2004 and 2008 in Northwest England, which suggested that close residential proximity (≤ 50 m) to ELF-EMF sources was associated with reduced average birth weight of 212 g (95%CI: -395 to -29 g) but not with statistically significant increased risks for other adverse perinatal outcomes. However, the cohort was limited by missing data for most potentially confounding variables including maternal smoking during pregnancy, which was only available for a small subgroup, while also residual confounding could not be excluded. This study, using the same cohort, was conducted to minimize the effects of these problems using multiple imputation to address missing data and propensity score matching to minimize residual confounding. Missing data were imputed using multiple imputation using chained equations to generate five datasets. For each dataset 115 exposed women (residing ≤ 50 m from a residential ELF-EMF source) were propensity score matched to 1150 unexposed women. After doubly robust confounder adjustment, close proximity to a residential ELF-EMF source remained associated with a reduction in birth weight of -116 g (95% confidence interval: -224:-7 g). No effect was found for proximity ≤ 100 m compared to women living further away. These results indicate that although the effect size was about half of the effect previously reported, close maternal residential proximity to sources of ELF-EMF remained associated with suboptimal fetal growth.

  16. Confounding by indication in non-experimental evaluation of vaccine effectiveness: the example of prevention of influenza complications

    PubMed Central

    Hak, E; Verheij, T.; Grobbee, D; Nichol, K; Hoes, A

    2002-01-01

    Randomised allocation of vaccine or placebo is the preferred method to assess the effects of the vaccine on clinical outcomes relevant to the individual patient. In the absence of phase 3 trials using clinical end points, notably post-influenza complications, alternative non-experimental designs to evaluate vaccine effects or safety are often used. The application of these designs may, however, lead to invalid estimates of vaccine effectiveness or safety. As patients with poor prognosis are more likely to be immunised, selection for vaccination is confounded by patient factors that are also related to clinical end points. This paper describes several design and analytical methods aimed at limiting or preventing this confounding by indication in non-experimental studies. In short, comparison of study groups with similar prognosis, restriction of the study population, and statistical adjustment for dissimilarities in prognosis are important tools and should be considered. Only if the investigator is able to show that confounding by indication is sufficiently controlled for, results of a non-experimental study may be of use to direct an evidence based vaccine policy. PMID:12461118

  17. Do pollution time-series studies contain uncontrolled or residual confounding by risk factors for acute health events?

    PubMed

    Bukowski, John

    2008-07-01

    Acute health effects from air pollution are based largely on weak associations identified in time-series studies comparing daily air pollution levels to daily mortality. Much of this mortality is due to cardiovascular disease. Time-series studies have many potential limitations, but are not thought to be confounded by traditional cardiovascular risk factors (e.g., smoking status or hypertension) because these chronic risk factors are not obviously associated with daily pollution levels. However, acute psychobehavioral variants of these risk factors (e.g., smoking patterns and episodes of stress on any given day) are plausible confounders for the associations observed in time-series studies, given that time-series studies attempt to predict acute rather than chronic health outcomes. There is a fairly compelling literature on the strong link between cardiovascular events and daily "triggers" such as stress. Stress-related triggers are plausibly associated with daily pollution levels through surrogate stressors such as ambient temperature, daily workload, local traffic congestion, or other correlates of air pollution. For example, variables such as traffic congestion and industrial activity increase both stress-related health events and air pollution, suggesting the potential for classical confounding. Support for this argument is illustrated through examples of the well-demonstrated relationship between emotional stress and heart attack/stroke.

  18. Biochemical aspects of Huntington's chorea.

    PubMed Central

    Caraceni, T; Calderini, G; Consolazione, A; Riva, E; Algeri, S; Girotti, F; Spreafico, R; Branciforti, A; Dall'olio, A; Morselli, P L

    1977-01-01

    Fifteen patients affected by Huntington's chorea were divided into two groups, 'slow' and 'fast', according to IQ scores on the Wechsler-Bellevue scale, and scores on some motor performance tests. A possible correlation was looked for between some biochemical data (cerebrospinal fluid (CSF), homovanillic acid (HVA), and 5-hydroxyindolacetic acid (5HIAA) levels, plasma dopamine-beta-hydroxylase (DBH), dopamine (DA) uptake by platelets), and clinical data (duration of illness, severity of symptoms, age of patients, IQ scores, 'slow' and 'fast' groups). The CSF, HVA, and 5HIAA levels were found to be significantly lowered in comparison with normal controls. DBH activity and DA uptake by platelets did not differ significantly from normal subjects. Treatment with haloperidol in all patients and with dipropylacetic acid in three patients did not appear to modify the CSF, HVA, and 5HIAA concentrations, the plasma DBH activity, or the DA uptake. There were no significant differences in the CSF, HVA, and 5HIAA contents between the two groups of patients, and there was no correlation between biochemical data and clinical features. PMID:143508

  19. Biochemical abnormalities in Pearson syndrome.

    PubMed

    Crippa, Beatrice Letizia; Leon, Eyby; Calhoun, Amy; Lowichik, Amy; Pasquali, Marzia; Longo, Nicola

    2015-03-01

    Pearson marrow-pancreas syndrome is a multisystem mitochondrial disorder characterized by bone marrow failure and pancreatic insufficiency. Children who survive the severe bone marrow dysfunction in childhood develop Kearns-Sayre syndrome later in life. Here we report on four new cases with this condition and define their biochemical abnormalities. Three out of four patients presented with failure to thrive, with most of them having normal development and head size. All patients had evidence of bone marrow involvement that spontaneously improved in three out of four patients. Unique findings in our patients were acute pancreatitis (one out of four), renal Fanconi syndrome (present in all patients, but symptomatic only in one), and an unusual organic aciduria with 3-hydroxyisobutyric aciduria in one patient. Biochemical analysis indicated low levels of plasma citrulline and arginine, despite low-normal ammonia levels. Regression analysis indicated a significant correlation between each intermediate of the urea cycle and the next, except between ornithine and citrulline. This suggested that the reaction catalyzed by ornithine transcarbamylase (that converts ornithine to citrulline) might not be very efficient in patients with Pearson syndrome. In view of low-normal ammonia levels, we hypothesize that ammonia and carbamylphosphate could be diverted from the urea cycle to the synthesis of nucleotides in patients with Pearson syndrome and possibly other mitochondrial disorders.

  20. Thermodynamic constraints for biochemical networks.

    PubMed

    Beard, Daniel A; Babson, Eric; Curtis, Edward; Qian, Hong

    2004-06-07

    The constraint-based approach to analysis of biochemical systems has emerged as a useful tool for rational metabolic engineering. Flux balance analysis (FBA) is based on the constraint of mass conservation; energy balance analysis (EBA) is based on non-equilibrium thermodynamics. The power of these approaches lies in the fact that the constraints are based on physical laws, and do not make use of unknown parameters. Here, we show that the network structure (i.e. the stoichiometric matrix) alone provides a system of constraints on the fluxes in a biochemical network which are feasible according to both mass balance and the laws of thermodynamics. A realistic example shows that these constraints can be sufficient for deriving unambiguous, biologically meaningful results. The thermodynamic constraints are obtained by comparing of the sign pattern of the flux vector to the sign patterns of the cycles of the internal cycle space via connection between stoichiometric network theory (SNT) and the mathematical theory of oriented matroids.

  1. Evaluating Public Health Interventions: 3. The Two-Stage Design for Confounding Bias Reduction-Having Your Cake and Eating It Two.

    PubMed

    Spiegelman, Donna; Rivera-Rodriguez, Claudia L; Haneuse, Sebastien

    2016-07-01

    In public health evaluations, confounding bias in the estimate of the intervention effect will typically threaten the validity of the findings. It is a common misperception that the only way to avoid this bias is to measure detailed, high-quality data on potential confounders for every intervention participant, but this strategy for adjusting for confounding bias is often infeasible. Rather than ignoring confounding altogether, the two-phase design and analysis-in which detailed high-quality confounding data are obtained among a small subsample-can be considered. We describe the two-stage design and analysis approach, and illustrate its use in the evaluation of an intervention conducted in Dar es Salaam, Tanzania, of an enhanced community health worker program to improve antenatal care uptake.

  2. Evaluating Public Health Interventions: 3. The Two-Stage Design for Confounding Bias Reduction—Having Your Cake and Eating It Two

    PubMed Central

    Spiegelman, Donna; Rivera-Rodriguez, Claudia L.; Haneuse, Sebastien

    2016-01-01

    In public health evaluations, confounding bias in the estimate of the intervention effect will typically threaten the validity of the findings. It is a common misperception that the only way to avoid this bias is to measure detailed, high-quality data on potential confounders for every intervention participant, but this strategy for adjusting for confounding bias is often infeasible. Rather than ignoring confounding altogether, the two-phase design and analysis—in which detailed high-quality confounding data are obtained among a small subsample—can be considered. We describe the two-stage design and analysis approach, and illustrate its use in the evaluation of an intervention conducted in Dar es Salaam, Tanzania, of an enhanced community health worker program to improve antenatal care uptake. PMID:27285260

  3. Diagnosis of hyperandrogenism: biochemical criteria.

    PubMed

    Stanczyk, Frank Z

    2006-06-01

    Biochemical derangements in ovarian, adrenal, and peripheral androgen production and metabolism play an important role in underlying causes of hyperandrogenism. Specific diagnostic serum markers such as testosterone (total) and dehydroepiandrosterone sulfate (DHEAS), respectively, may be helpful in the diagnosis of ovarian and adrenal hyperandrogenism, respectively. Validated immunoassays or mass spectrometry assays should be used to quantify testosterone, DHEAS and other principal androgens. Free testosterone measurements, determined by equilibrium dialysis or the calculated method, are advocated for routine evaluation of more subtle forms of hyperandrogenism. The skin, with its pilosebaceous units (PSUs), is an important site of active androgen production. A key regulator in PSUs is 5alpha-reductase, which transforms testosterone or androstenedione to dihydrotestosterone (DHT). DHT in blood is not effective in indicating the presence of hyperandrogenism. However, distal metabolites of DHT have been shown to be good markers of clinical manifestations of hirsutism, acne and alopecia. Assays for these peripheral markers need improvement for routine clinical testing.

  4. Biochemical nature of Russell Bodies

    PubMed Central

    Francesca Mossuto, Maria; Ami, Diletta; Anelli, Tiziana; Fagioli, Claudio; Maria Doglia, Silvia; Sitia, Roberto

    2015-01-01

    Professional secretory cells produce and release abundant proteins. Particularly in case of mutations and/or insufficient chaperoning, these can aggregate and become toxic within or amongst cells. Immunoglobulins (Ig) are no exception. In the extracellular space, certain Ig-L chains form fibrils causing systemic amyloidosis. On the other hand, Ig variants lacking the first constant domain condense in dilated cisternae of the early secretory compartment, called Russell Bodies (RB), frequently observed in plasma cell dyscrasias, autoimmune diseases and chronic infections. RB biogenesis can be recapitulated in lymphoid and non-lymphoid cells by expressing mutant Ig-μ, providing powerful models to investigate the pathophysiology of endoplasmic reticulum storage disorders. Here we analyze the aggregation propensity and the biochemical features of the intra- and extra-cellular Ig deposits in human cells, revealing β-aggregated features for RB. PMID:26223695

  5. Biochemical nature of Russell Bodies.

    PubMed

    Mossuto, Maria Francesca; Ami, Diletta; Anelli, Tiziana; Fagioli, Claudio; Doglia, Silvia Maria; Sitia, Roberto

    2015-07-30

    Professional secretory cells produce and release abundant proteins. Particularly in case of mutations and/or insufficient chaperoning, these can aggregate and become toxic within or amongst cells. Immunoglobulins (Ig) are no exception. In the extracellular space, certain Ig-L chains form fibrils causing systemic amyloidosis. On the other hand, Ig variants lacking the first constant domain condense in dilated cisternae of the early secretory compartment, called Russell Bodies (RB), frequently observed in plasma cell dyscrasias, autoimmune diseases and chronic infections. RB biogenesis can be recapitulated in lymphoid and non-lymphoid cells by expressing mutant Ig-μ, providing powerful models to investigate the pathophysiology of endoplasmic reticulum storage disorders. Here we analyze the aggregation propensity and the biochemical features of the intra- and extra-cellular Ig deposits in human cells, revealing β-aggregated features for RB.

  6. In Situ Biospectroscopic Investigation of Rapid Ischemic and Postmortem Induced Biochemical Alterations in the Rat Brain

    PubMed Central

    2015-01-01

    Rapid advances in imaging technologies have pushed novel spectroscopic modalities such as Fourier transform infrared spectroscopy (FTIR) and X-ray absorption spectroscopy (XAS) at the sulfur K-edge to the forefront of direct in situ investigation of brain biochemistry. However, few studies have examined the extent to which sample preparation artifacts confound results. Previous investigations using traditional analyses, such as tissue dissection, homogenization, and biochemical assay, conducted extensive research to identify biochemical alterations that occur ex vivo during sample preparation. In particular, altered metabolism and oxidative stress may be caused by animal death. These processes were a concern for studies using biochemical assays, and protocols were developed to minimize their occurrence. In this investigation, a similar approach was taken to identify the biochemical alterations that are detectable by two in situ spectroscopic methods (FTIR, XAS) that occur as a consequence of ischemic conditions created during humane animal killing. FTIR and XAS are well suited to study markers of altered metabolism such as lactate and creatine (FTIR) and markers of oxidative stress such as aggregated proteins (FTIR) and altered thiol redox (XAS). The results are in accordance with previous investigations using biochemical assays and demonstrate that the time between animal death and tissue dissection results in ischemic conditions that alter brain metabolism and initiate oxidative stress. Therefore, future in situ biospectroscopic investigations utilizing FTIR and XAS must take into consideration that brain tissue dissected from a healthy animal does not truly reflect the in vivo condition, but rather reflects a state of mild ischemia. If studies require the levels of metabolites (lactate, creatine) and markers of oxidative stress (thiol redox) to be preserved as close as possible to the in vivo condition, then rapid freezing of brain tissue via decapitation into

  7. Adjustment for missing confounders in studies based on observational databases: 2-stage calibration combining propensity scores from primary and validation data.

    PubMed

    Lin, Hui-Wen; Chen, Yi-Hau

    2014-08-01

    Bias caused by missing or incomplete information on confounding factors constitutes an important challenge in observational studies. The incorporation of external data on more detailed confounding information into the main study data may help remove confounding bias. This work was motivated by a study of the association between chronic obstructive pulmonary disease and herpes zoster. Analyses were based on administrative databases in which information on important confounders-cigarette smoking and alcohol consumption-was lacking. We consider adjusting for the confounding bias arising from missing confounders by incorporating a validation sample with data on smoking and alcohol consumption obtained from a small-scale National Health Interview Survey study. We propose a 2-stage calibration (TSC) method, which summarizes the confounding information through propensity scores and combines the analysis results from the main and the validation study samples, where the propensity score adjustment from the main sample is crude and that from the validation sample is more precise. Unlike the existing methods, the validity of the TSC approach does not rely on any specific measurement error model. When applying the TSC method to the motivating study above, the odds ratio of herpes zoster associated with chronic obstructive pulmonary disease is 1.91 (95% confidence interval: 1.62, 2.26) after adjustment for cumulative smoking and alcohol consumption.

  8. Biochemical values in free-ranging white rhinoceros (Ceratotherium simum) in Kruger National Park, South Africa.

    PubMed

    Mathebula, Nomkhosi; Miller, Michele; Buss, Peter; Joubert, Jennifer; Martin, Laura; Kruger, Marius; Hofmeyr, Markus; Olea-Popelka, Francisco

    2012-09-01

    Biochemical panels were analyzed on 181 individual free-ranging white rhinoceros (Ceratotherium simum) from Kruger National Park, South Africa. These animals were immobilized between July 2006 and May 2010 for management purposes. Serum and heparinized plasma samples were analyzed using an in-house chemistry analyser (ABAXIS VetScan2). The objectives of this study were to establish biochemical references ranges for Kruger National Park's population of white rhinoceros; to assess differences in values obtained using sera or plasma; and to assess differences in values between gender and different age categories. Significant differences between plasma and serum values were found in most measured parameters except minerals (calcium and magnesium). Because all animals appeared clinically healthy at the time of blood collection, it is hypothesized that choice of anticoagulant may affect certain parameters. Comparison between age categories and gender also resulted in significant differences in a few measured parameters. Identifying differences are important when establishing baseline reference ranges for wildlife populations to allow accurate monitoring of trends that may change over time. The paucity of data on normal biochemical ranges for free-ranging white rhinoceros demonstrates the value of this study and importance of evaluating potential confounding variables.

  9. Meta-analysis of lung cancer in asphalt roofing and paving workers with external adjustment for confounding by coal tar

    SciTech Connect

    Fayerweather, W.E.

    2007-07-01

    The study's objectives were to update Partanen's and Boffetta's 1994 meta-analysis of lung cancer among roofing and paving asphalt workers and explore the role of coal tar in explaining the statistical heterogeneity among these studies. Information retrieval strategies and eligibility criteria were defined for identifying the epidemiologic studies to be included in the analysis. The relative risk ratio (RR) for lung cancer was selected as the effect measure of interest. Coal tar bias factors were developed and used to externally adjust each eligible study's published RR for confounding by coal tar. The meta-Relative Risk (meta-RR) and its variance were estimated by general variance-based methods. Heterogeneity of the RRs was assessed by heterogeneity chi-square and I{sup 2} tests. The results from this update were similar to those in Partanen's and Boffetta's original meta-analysis. Although the meta-RRs for the roofers and the pavers were no longer statistically significantly different from one another, significant heterogeneity remained within each of the coal tar-adjusted sectors. Meta-analysis of non-experimental epidemiologic studies is subject to significant uncertainties as is externally correcting studies for confounding. Given these uncertainties, the specific quantitative estimates in this (or any similar) analysis must be viewed with caution. Nevertheless, this analysis provides support for the hypothesis proposed by several major reviewers that confounding by coal tar-related PAH exposures may explain most or all of the lung cancer risks found in the epidemiologic literature on asphalt roofing and paving workers.

  10. Examination of the Relationship between Oral Health and Arterial Sclerosis without Genetic Confounding through the Study of Older Japanese Twins

    PubMed Central

    Kurushima, Yuko; Ikebe, Kazunori; Matsuda, Ken-ichi; Enoki, Kaori; Ogata, Soshiro; Yamashita, Motozo; Murakami, Shinya; Maeda, Yoshinobu

    2015-01-01

    Objective Although researchers have recently demonstrated a relationship between oral health and arterial sclerosis, the genetic contribution to this relationship has been ignored even though genetic factors are expected to have some effect on various diseases. The aim of this study was to evaluate oral health as a significant risk factor related to arterial sclerosis after eliminating genetic confounding through study of older Japanese twins. Subjects and Methods Medical and dental surveys were conducted individually for 106 Japanese twin pairs over the age of 50 years. Maximal carotid intima-media thickness (IMT-Cmax) was measured as a surrogate marker of arterial sclerosis. IMT-Cmax > 1.0 mm was diagnosed as arterial sclerosis. All of the twins were examined for the number of remaining teeth, masticatory performance, and periodontal status. We evaluated each measurement related with IMT-Cmax and arterial sclerosis using generalized estimating equations analysis adjusted for potential risk factors. For non-smoking monozygotic twins, a regression analysis using a “between within” model was conducted to evaluate the relationship between IMT-Cmax and the number of teeth as the environmental factor controlling genetic and familial confounding. Results We examined 91 monozygotic and 15 dizygotic twin pairs (males: 42, females: 64) with a mean (± standard deviation) age of 67.4 ± 10.0 years. Out of all of the oral health-related measurements collected, only the number of teeth was significantly related to arterial sclerosis (odds ratio: 0.72, 95% confidence interval: 0.52-0.99 per five teeth). Regression analysis showed a significant association between the IMT-Cmax and the number of teeth as an environmental factor (p = 0.037). Conclusions Analysis of monozygotic twins older than 50 years of age showed that having fewer teeth could be a significant environmental factor related to arterial sclerosis, even after controlling for genetic and familial confounding

  11. Serum Biochemical Phenotypes in the Domestic Dog.

    PubMed

    Chang, Yu-Mei; Hadox, Erin; Szladovits, Balazs; Garden, Oliver A

    2016-01-01

    The serum or plasma biochemical profile is essential in the diagnosis and monitoring of systemic disease in veterinary medicine, but current reference intervals typically take no account of breed-specific differences. Breed-specific hematological phenotypes have been documented in the domestic dog, but little has been published on serum biochemical phenotypes in this species. Serum biochemical profiles of dogs in which all measurements fell within the existing reference intervals were retrieved from a large veterinary database. Serum biochemical profiles from 3045 dogs were retrieved, of which 1495 had an accompanying normal glucose concentration. Sixty pure breeds plus a mixed breed control group were represented by at least 10 individuals. All analytes, except for sodium, chloride and glucose, showed variation with age. Total protein, globulin, potassium, chloride, creatinine, cholesterol, total bilirubin, ALT, CK, amylase, and lipase varied between sexes. Neutering status significantly impacted all analytes except albumin, sodium, calcium, urea, and glucose. Principal component analysis of serum biochemical data revealed 36 pure breeds with distinctive phenotypes. Furthermore, comparative analysis identified 23 breeds with significant differences from the mixed breed group in all biochemical analytes except urea and glucose. Eighteen breeds were identified by both principal component and comparative analysis. Tentative reference intervals were generated for breeds with a distinctive phenotype identified by comparative analysis and represented by at least 120 individuals. This is the first large-scale analysis of breed-specific serum biochemical phenotypes in the domestic dog and highlights potential genetic components of biochemical traits in this species.

  12. Biochemical transformation of solid carbonaceous material

    DOEpatents

    Lin, Mow S.; Premuzic, Eugene T.

    2001-09-25

    A method of biochemically transforming macromolecular compounds found in solid carbonaceous materials, such as coal is provided. The preparation of new microorganisms, metabolically weaned through challenge growth processes to biochemically transform solid carbonaceous materials at extreme temperatures, pressures, pH, salt and toxic metal concentrations is also disclosed.

  13. Serum Biochemical Phenotypes in the Domestic Dog

    PubMed Central

    Chang, Yu-Mei; Hadox, Erin; Szladovits, Balazs; Garden, Oliver A.

    2016-01-01

    The serum or plasma biochemical profile is essential in the diagnosis and monitoring of systemic disease in veterinary medicine, but current reference intervals typically take no account of breed-specific differences. Breed-specific hematological phenotypes have been documented in the domestic dog, but little has been published on serum biochemical phenotypes in this species. Serum biochemical profiles of dogs in which all measurements fell within the existing reference intervals were retrieved from a large veterinary database. Serum biochemical profiles from 3045 dogs were retrieved, of which 1495 had an accompanying normal glucose concentration. Sixty pure breeds plus a mixed breed control group were represented by at least 10 individuals. All analytes, except for sodium, chloride and glucose, showed variation with age. Total protein, globulin, potassium, chloride, creatinine, cholesterol, total bilirubin, ALT, CK, amylase, and lipase varied between sexes. Neutering status significantly impacted all analytes except albumin, sodium, calcium, urea, and glucose. Principal component analysis of serum biochemical data revealed 36 pure breeds with distinctive phenotypes. Furthermore, comparative analysis identified 23 breeds with significant differences from the mixed breed group in all biochemical analytes except urea and glucose. Eighteen breeds were identified by both principal component and comparative analysis. Tentative reference intervals were generated for breeds with a distinctive phenotype identified by comparative analysis and represented by at least 120 individuals. This is the first large-scale analysis of breed-specific serum biochemical phenotypes in the domestic dog and highlights potential genetic components of biochemical traits in this species. PMID:26919479

  14. Associative learning in biochemical networks.

    PubMed

    Gandhi, Nikhil; Ashkenasy, Gonen; Tannenbaum, Emmanuel

    2007-11-07

    It has been recently suggested that there are likely generic features characterizing the emergence of systems constructed from the self-organization of self-replicating agents acting under one or more selection pressures. Therefore, structures and behaviors at one length scale may be used to infer analogous structures and behaviors at other length scales. Motivated by this suggestion, we seek to characterize various "animate" behaviors in biochemical networks, and the influence that these behaviors have on genomic evolution. Specifically, in this paper, we develop a simple, chemostat-based model illustrating how a process analogous to associative learning can occur in a biochemical network. Associative learning is a form of learning whereby a system "learns" to associate two stimuli with one another. Associative learning, also known as conditioning, is believed to be a powerful learning process at work in the brain (associative learning is essentially "learning by analogy"). In our model, two types of replicating molecules, denoted as A and B, are present in some initial concentration in the chemostat. Molecules A and B are stimulated to replicate by some growth factors, denoted as G(A) and G(B), respectively. It is also assumed that A and B can covalently link, and that the conjugated molecule can be stimulated by either the G(A) or G(B) growth factors (and can be degraded). We show that, if the chemostat is stimulated by both growth factors for a certain time, followed by a time gap during which the chemostat is not stimulated at all, and if the chemostat is then stimulated again by only one of the growth factors, then there will be a transient increase in the number of molecules activated by the other growth factor. Therefore, the chemostat bears the imprint of earlier, simultaneous stimulation with both growth factors, which is indicative of associative learning. It is interesting to note that the dynamics of our model is consistent with certain aspects of

  15. Biochemical genetic markers in sugarcane.

    PubMed

    Glaszmann, J C; Fautret, A; Noyer, J L; Feldmann, P; Lanaud, C

    1989-10-01

    Isozyme variation was used to identify biochemical markers of potential utility in sugarcane genetics and breeding. Electrophoretic polymorphism was surveyed for nine enzymes among 39 wild and noble sugarcane clones, belonging to the species most closely related to modern varieties. Up to 114 distinct bands showing presence versus absence type of variation were revealed and used for qualitative characterization of the materials. Multivariate analysis of the data isolated the Erianthus clone sampled and separated the Saccharum spontaneum clones from the S. robustum and S. officinarum clones; the latter two were not differentiated from one another. The analysis of self-progenies of a 2n=112 S. spontaneum and of a commercial variety showed examples of mono- and polyfactorial segregations. Within the progeny of the variety, co-segregation of two isozymes frequent in S. spontaneum led to them being assigned to a single chromosome initially contributed by a S. spontaneum donor. This illustrates how combined survey of ancestral species and segregation analysis in modern breeding materials should permit using the lack of interspecific cross-over to establish linkage groups in a sugarcane genome.

  16. Variation in faecal water content may confound estimates of gastro-intestinal parasite intensity in wild African herbivores.

    PubMed

    Turner, W C; Cizauskas, C A; Getz, W M

    2010-03-01

    Estimates of parasite intensity within host populations are essential for many studies of host-parasite relationships. Here we evaluated the seasonal, age- and sex-related variability in faecal water content for two wild ungulate species, springbok (Antidorcas marsupialis) and plains zebra (Equus quagga). We then assessed whether or not faecal water content biased conclusions regarding differences in strongyle infection rates by season, age or sex. There was evidence of significant variation in faecal water content by season and age for both species, and by sex in springbok. Analyses of faecal egg counts demonstrated that sex was a near-significant factor in explaining variation in strongyle parasite infection rates in zebra (P = 0.055) and springbok (P = 0.052) using wet-weight faecal samples. However, once these intensity estimates were re-scaled by the percent of dry matter in the faeces, sex was no longer a significant factor (zebra, P = 0.268; springbok, P = 0.234). These results demonstrate that variation in faecal water content may confound analyses and could produce spurious conclusions, as was the case with host sex as a factor in the analysis. We thus recommend that researchers assess whether water variation could be a confounding factor when designing and performing research using faecal indices of parasite intensity.

  17. Prior event rate ratio adjustment for hidden confounding in observational studies of treatment effectiveness: a pairwise Cox likelihood approach.

    PubMed

    Lin, Nan Xuan; Henley, William Edward

    2016-12-10

    Observational studies provide a rich source of information for assessing effectiveness of treatment interventions in many situations where it is not ethical or practical to perform randomized controlled trials. However, such studies are prone to bias from hidden (unmeasured) confounding. A promising approach to identifying and reducing the impact of unmeasured confounding is prior event rate ratio (PERR) adjustment, a quasi-experimental analytic method proposed in the context of electronic medical record database studies. In this paper, we present a statistical framework for using a pairwise approach to PERR adjustment that removes bias inherent in the original PERR method. A flexible pairwise Cox likelihood function is derived and used to demonstrate the consistency of the simple and convenient alternative PERR (PERR-ALT) estimator. We show how to estimate standard errors and confidence intervals for treatment effect estimates based on the observed information and provide R code to illustrate how to implement the method. Assumptions required for the pairwise approach (as well as PERR) are clarified, and the consequences of model misspecification are explored. Our results confirm the need for researchers to consider carefully the suitability of the method in the context of each problem. Extensions of the pairwise likelihood to more complex designs involving time-varying covariates or more than two periods are considered. We illustrate the application of the method using data from a longitudinal cohort study of enzyme replacement therapy for lysosomal storage disorders. © 2016 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd.

  18. A principal stratification approach for evaluating natural direct and indirect effects in the presence of treatment-induced intermediate confounding.

    PubMed

    Taguri, Masataka; Chiba, Yasutaka

    2015-01-15

    Recently, several authors have shown that natural direct and indirect effects (NDEs and NIEs) can be identified under the sequential ignorability assumptions, as long as there is no mediator-outcome confounder that is affected by the treatment. However, if such a confounder exists, NDEs and NIEs will generally not be identified without making additional identifying assumptions. In this article, we propose novel identification assumptions and estimators for evaluating NDEs and NIEs under the usual sequential ignorability assumptions, using the principal stratification framework. It is assumed that the treatment and the mediator are dichotomous. We must impose strong assumptions for identification. However, even if these assumptions were violated, the bias of our estimator would be small under typical conditions, which can be easily evaluated from the observed data. This conjecture is confirmed for binary outcomes by deriving the bounds of the bias terms. In addition, the advantage of our estimator is illustrated through a simulation study. We also propose a method of sensitivity analysis that examines what happens when our assumptions are violated. We apply the proposed method to data from the National Center for Health Statistics.

  19. A demonstration that task difficulty can confound the interpretation of lateral differences in brain activation between typical and dyslexic readers.

    PubMed

    Fisher, Janet McGraw; Liederman, Jacqueline; Johnsen, Jami; Lincoln, Alexis; Frye, Richard

    2012-01-01

    Dyslexic readers (DRs) manifest atypical patterns of brain activity, which may be attributed to aberrant neural connectivity and/or an attempt to activate compensatory pathways. This paper evaluates whether differences in brain activation patterns between DRs and typical readers (TRs) are confounded by task difficulty. Eight DRs and eight TRs matched for age, sex, and nonverbal IQ performed pseudoword rhyming tasks at two levels of difficulty during magnetoencephalography. Task difficulty varied with the number of successive target pseudowords presented before the test pseudoword. Regions of interest were: the temporoparietal area (TPA), the ventral occipital temporal area (VOT), and the inferior frontal gyrus (IFG). Activity was analysed for the 660-ms period after test pseudoword onset. During the discrepant performance condition left hemispheric TPA activation increased across time for TRs, but not DRs, and IFG bihemispheric activation was greater in TRs by the end of the trial. During the equivalent performance condition no group differences in TPA or IFG activation were found. We argue that these results indicate that direct comparison of DR versus TR brain activity is confounded when DRs are more challenged than TRs. This highlights the importance of equating reading group performance during neuroimaging of reading-related tasks.

  20. An apparent-motion confound causes the negative exogenous cuing effect at SOAs with larger numbers of target locations.

    PubMed

    Chen, Peii; Mordkoff, J Toby

    2012-01-01

    Salient but irrelevant stimuli seem to cause an automatic orienting of covert attention, facilitating the detection of targets at the cued location for a brief period of time. However, this finding is highly dependent on the number of possible target locations, at least when the simple detection of targets is all that the task requires. Whereas small numbers of possible target locations (e.g., 2 or 3) produce the well-known advantage in response time for valid cue trials (i.e., a positive cuing effect), larger numbers of possible target locations (e.g., 6 or 8) produce a negative cuing effect. If not explained in terms of a nonattentional mechanism, this latter finding raises serious questions about the standard interpretation of positive cuing effects. The present experiment tested a particular nonattentional mechanism: that a confound between target presence and apparent motion, which occurs only on invalid cue trials, is responsible for negative cuing effect. We reduced or eliminated this confound by the use of a new type of catch trial and eliminated the negative cuing effect with large numbers of target locations.

  1. Interpersonal discrimination and depressive symptomatology: examination of several personality-related characteristics as potential confounders in a racial/ethnic heterogeneous adult sample

    PubMed Central

    2013-01-01

    Background Research suggests that reports of interpersonal discrimination result in poor mental health. Because personality characteristics may either confound or mediate the link between these reports and mental health, there is a need to disentangle its role in order to better understand the nature of discrimination-mental health association. We examined whether hostility, anger repression and expression, pessimism, optimism, and self-esteem served as confounders in the association between perceived interpersonal discrimination and CESD-based depressive symptoms in a race/ethnic heterogeneous probability-based sample of community-dwelling adults. Methods We employed a series of ordinary least squares regression analyses to examine the potential confounding effect of hostility, anger repression and expression, pessimism, optimism, and self-esteem between interpersonal discrimination and depressive symptoms. Results Hostility, anger repression, pessimism and self-esteem were significant as possible confounders of the relationship between interpersonal discrimination and depressive symptoms, together accounting for approximately 38% of the total association (beta: 0.1892, p < 0.001). However, interpersonal discrimination remained a positive predictor of depressive symptoms (beta: 0.1176, p < 0.001). Conclusion As one of the first empirical attempts to examine the potential confounding role of personality characteristics in the association between reports of interpersonal discrimination and mental health, our results suggest that personality-related characteristics may serve as potential confounders. Nevertheless, our results also suggest that, net of these characteristics, reports of interpersonal discrimination are associated with poor mental health. PMID:24256578

  2. Disentangling the confounding effects of PAR and air temperature on net ecosystem exchange in time and scale

    NASA Astrophysics Data System (ADS)

    yang, Z.; Chen, J.; Becker, R.; Chu, H.; Xie, J.; Shao, C.

    2013-12-01

    Net ecosystem exchange of CO2 (NEE) in temperate forests is modulated by microclimatic factors. The effects of those factors differ at different time scales and during different time periods. Some of them are correlated across a number of time scales, so their effects on NEE are confounded by each other. PAR and air temperature (Ta) are among the two most important drivers of NEE in temperate forests, and among the two most correlated microclimatic factors. PAR and Ta have similar daily, seasonal, and annual cycles. Their influence on NEE is confounded by each other and entangled together especially at those scales. In this study, we tried to disentangle the confounding effects of them on NEE at different time scales and during different time periods. To accomplish this objective, we applied the innovative spectral analysis techniques including Continuous Wavelet Transformation (CWT), Cross Wavelet Transformation (XWT), Wavelet Coherent (WTC), and Partial Wavelet Coherence (PWC) on seven years time series (2004-2010) of PAR, Ta and NEE from the Ohio Oak Openings site (N 41.5545°, W 83.8438°), USA for spectral analysis. We found that PAR is the major driver at short time scales (e.g. semidiurnal and daily) and Ta is the major driver at long time scales (e.g. seasonal and annual). At daily scale during growing seasons, PAR is anti-phase with NEE with no time delay while Ta lagged PAR about 2-3 hours, which could be explained by the strong dependence of photosynthesis on PAR and a 2-3 hours lags of the daily course of Ta to PAR. At daily scale during non-growing season, NEE has little variation and thus neither Ta nor PAR has high common wavelet power and significant coherence with NEE. At annual scale, Ta is anti-phase with NEE and PAR leads NEE about 34 days, which could be explained by the strong dependence of LAI dynamics on Ta and the lag between the LAI/biomass development and the progress of sunlight. We also found that NEE distributes most of its variation

  3. Biochemical Lab Activity Supports Evolution Theory

    ERIC Educational Resources Information Center

    Dyman, Daniel J.

    1974-01-01

    Described is thin-layer chromatography (TLC), a technique that can be conveniently used in the laboratory to generate evidence supporting the principle that degrees of biochemical similarity reflect degrees of evolutionary relatedness among organisms. (Author/PEB)

  4. Raman spectroscopic biochemical mapping of tissues

    NASA Astrophysics Data System (ADS)

    Stone, Nicholas; Hart Prieto, Maria C.; Kendall, Catherine A.; Shetty, Geeta; Barr, Hugh

    2006-02-01

    Advances in technologies have brought us closer to routine spectroscopic diagnosis of early malignant disease. However, there is still a poor understanding of the carcinogenesis process. For example it is not known whether many cancers follow a logical sequence from dysplasia, to carcinoma in situ, to invasion. Biochemical tissue changes, triggered by genetic mutations, precede morphological and structural changes. These can be probed using Raman or FTIR microspectroscopy and the spectra analysed for biochemical constituents. Local microscopic distribution of various constituents can then be visualised. Raman mapping has been performed on a number of tissues including oesophagus, breast, bladder and prostate. The biochemical constituents have been calculated at each point using basis spectra and least squares analysis. The residual of the least squares fit indicates any unfit spectral components. The biochemical distribution will be compared with the defined histopathological boundaries. The distribution of nucleic acids, glycogen, actin, collagen I, III, IV, lipids and others appear to follow expected patterns.

  5. A Program on Biochemical and Biomedical Engineering.

    ERIC Educational Resources Information Center

    San, Ka-Yiu; McIntire, Larry V.

    1989-01-01

    Presents an introduction to the Biochemical and Biomedical Engineering program at Rice University. Describes the development of the academic and enhancement programs, including organizational structure and research project titles. (YP)

  6. Using instrumental variables to disentangle treatment and placebo effects in blinded and unblinded randomized clinical trials influenced by unmeasured confounders

    PubMed Central

    Chaibub Neto, Elias

    2016-01-01

    Clinical trials traditionally employ blinding as a design mechanism to reduce the influence of placebo effects. In practice, however, it can be difficult or impossible to blind study participants and unblinded trials are common in medical research. Here we show how instrumental variables can be used to quantify and disentangle treatment and placebo effects in randomized clinical trials comparing control and active treatments in the presence of confounders. The key idea is to use randomization to separately manipulate treatment assignment and psychological encouragement conversations/interactions that increase the participants’ desire for improved symptoms. The proposed approach is able to improve the estimation of treatment effects in blinded studies and, most importantly, opens the doors to account for placebo effects in unblinded trials. PMID:27869205

  7. Using instrumental variables to disentangle treatment and placebo effects in blinded and unblinded randomized clinical trials influenced by unmeasured confounders

    NASA Astrophysics Data System (ADS)

    Chaibub Neto, Elias

    2016-11-01

    Clinical trials traditionally employ blinding as a design mechanism to reduce the influence of placebo effects. In practice, however, it can be difficult or impossible to blind study participants and unblinded trials are common in medical research. Here we show how instrumental variables can be used to quantify and disentangle treatment and placebo effects in randomized clinical trials comparing control and active treatments in the presence of confounders. The key idea is to use randomization to separately manipulate treatment assignment and psychological encouragement conversations/interactions that increase the participants’ desire for improved symptoms. The proposed approach is able to improve the estimation of treatment effects in blinded studies and, most importantly, opens the doors to account for placebo effects in unblinded trials.

  8. Biochemical-Pathway Diversity in Archaebacteria

    DTIC Science & Technology

    1990-08-30

    characteristic of much or all of the Gram-positive lineage of eubacteria . We have extended the enzymological base of information to include organisms...to compare the biochemical diversitv within the archaebacteria to the biochemical diversity already known or now emerging within the eubacteria . RAI...INALL: In eubacteria aromatic-pathway character states are exceedingly diverse. A given feature will cluster at a hierarchical level ot phylogeny that

  9. [Biochemical diagnostics of fatal opium intoxication].

    PubMed

    Papyshev, I P; Astashkina, O G; Tuchik, E S; Nikolaev, B S; Cherniaev, A L

    2013-01-01

    Biochemical diagnostics of fatal opium intoxication remains a topical problem in forensic medical science and practice. We investigated materials obtained in the course of forensic medical expertise of the cases of fatal opium intoxication. The study revealed significant differences between myoglobin levels in blood, urine, myocardium, and skeletal muscles. The proposed approach to biochemical diagnostics of fatal opium intoxication enhances the accuracy and the level of evidence of expert conclusions.

  10. Soil acidification as a confounding factor on metal phytotoxicity in soils spiked with copper-rich mine wastes.

    PubMed

    Ginocchio, Rosanna; De la Fuente, Luz María; Sánchez, Pablo; Bustamante, Elena; Silva, Yasna; Urrestarazu, Paola; Rodríguez, Patricio H

    2009-10-01

    Pollution of soil with mine wastes results in both Cu enrichment and soil acidification. This confounding effect may be very important in terms of phytotoxicity, because pH is a key parameter influencing Cu solubility in soil solution. Laboratory toxicity tests were used to assess the effect of acidification by acidic mine wastes on Cu solubility and on root elongation of barley (Hordeum vulgare L.). Three contrasting substrates (two soils and a commercial sand) and two acidic, Cu-rich mine wastes (oxidized tailings [OxT] and smelter dust [SmD]) were selected as experimental materials. Substrates were spiked with a fixed amount of either SmD or OxT, and the pH of experimental mixtures was then modified in the range of 4.0 to 6.0 and 7.0 using PIPES (piperazine-1,4-bis(2-ethanesulfonic acid)), MES (2-(N-morpholino)ethanesulfonic acid), and MOPS (3-(N-Morpholino)-propanesulfonic acid) buffers. Chemical (pore-water Cu and pH) and toxicological (root length of barley plants) parameters were determined for experimental mixtures. Addition of SmD and OxT to substrates resulted in acidification (0.11-1.16 pH units) and high levels of soluble Cu and Zn. Neutralization of experimental mixtures with MES (pH 6.0) and MOPS (pH 7.0) buffers resulted in a marked decrease in soluble Cu and Zn, but the intensity of the effect was substrate-dependent. Adjustment of soil pH above the range normally considered to be toxic to plants (pH in water extract, > 5.5) significantly reduced metal toxicity in barley, but phytotoxicity was not completely eliminated. The present results stress the importance of considering confounding effects on derivation of toxicity thresholds to plants when using laboratory phytotoxicity tests.

  11. Genetic variation of loci potentially under selection confounds species-genetic diversity correlations in a fragmented habitat.

    PubMed

    Bertin, Angeline; Gouin, Nicolas; Baumel, Alex; Gianoli, Ernesto; Serratosa, Juan; Osorio, Rodomiro; Manel, Stephanie

    2017-01-01

    Positive species-genetic diversity correlations (SGDCs) are often thought to result from the parallel influence of neutral processes on genetic and species diversity. Yet, confounding effects of non-neutral mechanisms have not been explored. Here, we investigate the impact of non-neutral genetic diversity on SGDCs in high Andean wetlands. We compare correlations between plant species diversity and genetic diversity (GD) calculated with and without loci potentially under selection (outlier loci). The study system includes 2188 specimens from five species (three common aquatic macroinvertebrate and two dominant plant species) that were genotyped for 396 amplified fragment length polymorphism loci. We also appraise the importance of neutral processes on SGDCs by investigating the influence of habitat fragmentation features. Significant positive SGDCs were detected for all five species (mean SGDC = 0.52 ± 0.05). While only a few outlier loci were detected in each species, they resulted in significant decreases in GD and in SGDCs. This supports the hypothesis that neutral processes drive species-genetic diversity relationships in high Andean wetlands. Unexpectedly, the effects on genetic diversity GD of the habitat fragmentation characteristics in this study increased with the presence of outlier loci in two species. Overall, our results reveal pitfalls in using habitat features to infer processes driving SGDCs and show that a few loci potentially under selection are enough to cause a significant downward bias in SGDC. Investigating confounding effects of outlier loci thus represents a useful approach to evidence the contribution of neutral processes on species-genetic diversity relationships.

  12. Clinical and methodological confounders in assessing the cerebellar cognitive affective syndrome in adult patients with posterior fossa tumours.

    PubMed

    Omar, Dashne; Ryan, Tracy; Carson, Alan; Bak, Thomas H; Torrens, Lorna; Whittle, Ian

    2014-12-01

    The cerebellar cognitive affective syndrome (CCAS) was first described by Schmahmann and Sherman as a constellation of symptoms including dysexecutive syndrome, spatial cognitive deficit, linguistic deficits and behavioural abnormalities in patients with a lesion in the cerebellum with otherwise normal brain. Neurosurgical patients with cerebellar tumours constitute one of the cohorts in which the CCAS has been described. In this paper, we present a critical review of the literature of this syndrome in neurosurgical patients. Thereafter, we present a prospective clinical study of 10 patients who underwent posterior fossa tumour resection and had a detailed post-operative neuropsychological, neuropsychiatric and neuroradiological assessment. Because our findings revealed a large number of perioperative neuroradiological confounding variables, we reviewed the neuroimaging of a further 20 patients to determine their prevalence. Our literature review revealed that study design, methodological quality and sometimes both diagnostic criteria and findings were inconsistent. The neuroimaging study (pre-operative, n = 10; post-operative, n = 10) showed very frequent neuroradiological confounding complications (e.g. hydrocephalus; brainstem compression; supratentorial lesions and post-operative subdural hygroma); the impact of such features had largely been ignored in the literature. Findings from our clinical study showed various degree of deficits in neuropsychological testing (n = 1, memory; n = 3, verbal fluency; n = 3, attention; n = 2, spatial cognition deficits; and n = 1, behavioural changes), but no patient had full-blown features of CCAS. Our study, although limited, finds no robust evidence of the CCAS following surgery. This and our literature review highlight a need for guidelines regarding study design and methodology when attempting to evaluate neurosurgical cases with regard to the potential CCAS.

  13. Prevalence of non-confounded HIV-associated neurocognitive impairment in the context of plasma HIV RNA suppression.

    PubMed

    Cysique, Lucette A; Brew, Bruce J

    2011-04-01

    HIV-associated neurocognitive disorder is known to occur in the context of successful combination antiretroviral therapy (cART; plasma HIV RNA <50 copies/ml). Here, we newly provide an analysis of its prevalence and nature in the absence of medical or psychiatric confounds that may otherwise inflate the prevalence rate. We enrolled a cohort of 116 advanced HIV + individuals on cART (51% virally suppressed (VS)). They were screened for active Hepatitis C, current substance use disorder and were assessed with standard neuropsychological (NP) testing. Our results showed that out of the entire sample, NP impairment occurred in 18.1% (21/116) in VS individuals which was not statistically different from the 24.1% (28/116) that were found to be NP-impaired and not VS. In comparison with NP-normal-VS persons, NP impairment in VS individuals was associated with shorter duration of current cART and lower pre-morbid ability. Higher cART CNS penetration effectiveness tended to be associated with lesser cognitive severity in NP-impaired VS individuals. Current CD4 cell count, depression symptoms and past CNS HIV-related diseases did not specifically account for persistent NP impairment in VS individuals. In conclusion, despite suppression of systemic viral load, non-confounded HIV-related NP-impairment prevalence reached 18.1%. Of the potential explanations for this persistent deficit, a "burnt-out" form of the disease and immune reconstitution inflammatory syndrome were the less likely explanations, while a shorter current cART duration and lower pre-morbid intellectual capacity were significant. Nonetheless, predictive modelling with these last two factors misclassified 27% and had low sensitivity (43%) emphasising that other yet-to-be-defined factors were operative.

  14. Confounding of the association between radiation exposure from CT scans and risk of leukemia and brain tumors by cancer susceptibility syndromes.

    PubMed

    Meulepas, Johanna M; Ronckers, Cécile M; Merks, Johannes; Weijerman, Michel E; Lubin, Jay H; Hauptmann, Michael

    2016-12-01

    Recent studies linking radiation exposure from pediatric computed tomography (CT) to increased risks of leukemia and brain tumors lacked data to control for cancer susceptibility syndromes (CSS). These syndromes might be confounders because they are associated with an increased cancer risk and may increase the likelihood of pediatric CT scans. We identify CSS predisposing to leukemia and brain tumors through a systematic literature search and summarize prevalence and risk. Since empirical evidence is lacking in published literature on patterns of CT use for most types of CSS, we estimate confounding bias of relative risks (RR) for categories of radiation exposure based on expert opinion about patterns of CT scans among CSS patients. We estimate that radiation-related RRs for leukemia are not meaningfully confounded by Down syndrome, Noonan syndrome and other CSS. Moreover, tuberous sclerosis complex, von Hippel-Lindau disease, neurofibromatosis type 1 and other CSS do not meaningfully confound RRs for brain tumors. Empirical data on the use of CT scans among CSS patients is urgently needed. Our assessment indicates that associations with radiation exposure from pediatric CT scans and leukemia or brain tumors reported in previous studies are unlikely to be substantially confounded by unmeasured CSS.

  15. 40 CFR 158.2000 - Biochemical pesticides definition and applicability.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 23 2010-07-01 2010-07-01 false Biochemical pesticides definition and...) PESTICIDE PROGRAMS DATA REQUIREMENTS FOR PESTICIDES Biochemical Pesticides § 158.2000 Biochemical pesticides definition and applicability. This subpart applies to all biochemical pesticides as defined in paragraphs...

  16. 40 CFR 158.2000 - Biochemical pesticides definition and applicability.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 25 2012-07-01 2012-07-01 false Biochemical pesticides definition and...) PESTICIDE PROGRAMS DATA REQUIREMENTS FOR PESTICIDES Biochemical Pesticides § 158.2000 Biochemical pesticides definition and applicability. This subpart applies to all biochemical pesticides as defined in paragraphs...

  17. 40 CFR 158.2000 - Biochemical pesticides definition and applicability.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 24 2014-07-01 2014-07-01 false Biochemical pesticides definition and...) PESTICIDE PROGRAMS DATA REQUIREMENTS FOR PESTICIDES Biochemical Pesticides § 158.2000 Biochemical pesticides definition and applicability. This subpart applies to all biochemical pesticides as defined in paragraphs...

  18. 40 CFR 158.2000 - Biochemical pesticides definition and applicability.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 25 2013-07-01 2013-07-01 false Biochemical pesticides definition and...) PESTICIDE PROGRAMS DATA REQUIREMENTS FOR PESTICIDES Biochemical Pesticides § 158.2000 Biochemical pesticides definition and applicability. This subpart applies to all biochemical pesticides as defined in paragraphs...

  19. 40 CFR 158.2000 - Biochemical pesticides definition and applicability.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 24 2011-07-01 2011-07-01 false Biochemical pesticides definition and...) PESTICIDE PROGRAMS DATA REQUIREMENTS FOR PESTICIDES Biochemical Pesticides § 158.2000 Biochemical pesticides definition and applicability. This subpart applies to all biochemical pesticides as defined in paragraphs...

  20. Medical treatment for biochemical relapse after radiotherapy.

    PubMed

    Quero, L; Hennequin, C

    2014-10-01

    This article's purpose was to review the medical data justifying the use of a medical treatment for biochemical relapse after external beam radiotherapy. The MEDLINE database was searched to identify relevant information with the following medical subject headings: "prostate cancer", "radiotherapy" and "biochemical relapse". Prognostic factors affecting the overall survival of patients with a biochemical relapse after external beam radiotherapy have been identified: short prostate specific antigen (PSA)-doubling time (< 12 months), high PSA value (> 10 ng/mL) and short interval between treatment and biochemical relapse (< 18 months). If a second local treatment is not feasible, timing to initiate a salvage medical treatment is not defined. Particularly, randomized trials did not demonstrate a significant benefit of an early initiation of androgen deprivation treatment. Some retrospective studies suggest that an early androgen deprivation is justified if poor prognostic factors are found. However, if an androgen deprivation treatment is prescribed, intermittent schedule is non-inferior to a continuous administration and seems to offer a better quality of life. Many non-hormonal treatments have also been evaluated in this setting: only 5-alpha-reductase inhibitors could be proposed in some specific situations. In conclusion, the judicious use of a medical treatment for biochemical relapse is still debated. Given the natural history of this clinical situation, a simple surveillance is justified in many cases.

  1. Nonlinear biochemical signal processing via noise propagation

    NASA Astrophysics Data System (ADS)

    Kim, Kyung Hyuk; Qian, Hong; Sauro, Herbert M.

    2013-10-01

    Single-cell studies often show significant phenotypic variability due to the stochastic nature of intra-cellular biochemical reactions. When the numbers of molecules, e.g., transcription factors and regulatory enzymes, are in low abundance, fluctuations in biochemical activities become significant and such "noise" can propagate through regulatory cascades in terms of biochemical reaction networks. Here we develop an intuitive, yet fully quantitative method for analyzing how noise affects cellular phenotypes based on identifying a system's nonlinearities and noise propagations. We observe that such noise can simultaneously enhance sensitivities in one behavioral region while reducing sensitivities in another. Employing this novel phenomenon we designed three biochemical signal processing modules: (a) A gene regulatory network that acts as a concentration detector with both enhanced amplitude and sensitivity. (b) A non-cooperative positive feedback system, with a graded dose-response in the deterministic case, that serves as a bistable switch due to noise-induced ultra-sensitivity. (c) A noise-induced linear amplifier for gene regulation that requires no feedback. The methods developed in the present work allow one to understand and engineer nonlinear biochemical signal processors based on fluctuation-induced phenotypes.

  2. Biochemical Removal of HAP Precursors From Coal

    SciTech Connect

    Olson, G.; Tucker, L.; Richards, J.

    1997-07-01

    This project addresses DOE`s interest in advanced concepts for controlling emissions of air toxics from coal-fired utility boilers. We are determining the feasibility of developing a biochemical process for the precombustion removal of substantial percentages of 13 inorganic hazardous air pollutant (HAP) precursors from coal. These HAP precursors are Sb, As, Be, Cd, Cr, Cl, Co, F, Pb, Hg, Mn, Ni, and Se. Although rapid physical coal cleaning is done routinely in preparation plants, biochemical processes for removal of HAP precursors from coal potentially offer advantages of deeper cleaning, more specificity, and less coal loss. Compared to chemical processes for coal cleaning, biochemical processes potentially offer lower costs and milder process conditions. Pyrite oxidizing bacteria, most notably Thiobacillusferrooxidans, are being evaluated in this project for their ability to remove HAP precursors from U.S. coals.

  3. eQuilibrator--the biochemical thermodynamics calculator.

    PubMed

    Flamholz, Avi; Noor, Elad; Bar-Even, Arren; Milo, Ron

    2012-01-01

    The laws of thermodynamics constrain the action of biochemical systems. However, thermodynamic data on biochemical compounds can be difficult to find and is cumbersome to perform calculations with manually. Even simple thermodynamic questions like 'how much Gibbs energy is released by ATP hydrolysis at pH 5?' are complicated excessively by the search for accurate data. To address this problem, eQuilibrator couples a comprehensive and accurate database of thermodynamic properties of biochemical compounds and reactions with a simple and powerful online search and calculation interface. The web interface to eQuilibrator (http://equilibrator.weizmann.ac.il) enables easy calculation of Gibbs energies of compounds and reactions given arbitrary pH, ionic strength and metabolite concentrations. The eQuilibrator code is open-source and all thermodynamic source data are freely downloadable in standard formats. Here we describe the database characteristics and implementation and demonstrate its use.

  4. Advances in Biochemical Indices of Zooplankton Production.

    PubMed

    Yebra, L; Kobari, T; Sastri, A R; Gusmão, F; Hernández-León, S

    2017-01-01

    Several new approaches for measuring zooplankton growth and production rates have been developed since the publication of the ICES (International Council for the Exploration of the Sea) Zooplankton Methodology Manual (Harris et al., 2000). In this review, we summarize the advances in biochemical methods made in recent years. Our approach explores the rationale behind each method, the design of calibration experiments, the advantages and limitations of each method and their suitability as proxies for in situ rates of zooplankton community growth and production. We also provide detailed protocols for the existing methods and information relevant to scientists wanting to apply, calibrate or develop these biochemical indices for zooplankton production.

  5. Rainfall and temperatures changes have confounding impacts on Phytophthora cinnamomi occurrence risk in the southwestern USA under climate change scenarios.

    PubMed

    Thompson, Sally E; Levin, Simon; Rodriguez-Iturbe, Ignacio

    2014-04-01

    Global change will simultaneously impact many aspects of climate, with the potential to exacerbate the risks posed by plant pathogens to agriculture and the natural environment; yet, most studies that explore climate impacts on plant pathogen ranges consider individual climatic factors separately. In this study, we adopt a stochastic modeling approach to address multiple pathways by which climate can constrain the range of the generalist plant pathogen Phytophthora cinnamomi (Pc): through changing winter soil temperatures affecting pathogen survival; spring soil temperatures and thus pathogen metabolic rates; and changing spring soil moisture conditions and thus pathogen growth rates through host root systems. We apply this model to the southwestern USA for contemporary and plausible future climate scenarios and evaluate the changes in the potential range of Pc. The results indicate that the plausible range of this pathogen in the southwestern USA extends over approximately 200,000 km(2) under contemporary conditions. While warming temperatures as projected by the IPCC A2 and B1 emissions scenarios greatly expand the range over which the pathogen can survive winter, projected reductions in spring rainfall reduce its feasible habitat, leading to spatially complex patterns of changing risk. The study demonstrates that temperature and rainfall changes associated with possible climate futures in the southwestern USA have confounding impacts on the range of Pc, suggesting that projections of future pathogen dynamics and ranges should account for multiple pathways of climate-pathogen interaction.

  6. Application of Mycobacterium Leprae-specific cellular and serological tests for the differential diagnosis of leprosy from confounding dermatoses.

    PubMed

    Freitas, Aline Araújo; Hungria, Emerith Mayra; Costa, Maurício Barcelos; Sousa, Ana Lúcia Osório Maroccolo; Castilho, Mirian Lane Oliveira; Gonçalves, Heitor Sá; Pontes, Maria Araci Andrade; Duthie, Malcolm S; Stefani, Mariane Martins Araújo

    2016-10-01

    Mycobacterium leprae-specific serological and cell-mediated-immunity/CMI test were evaluated for the differential diagnosis of multibacillary/MB, and paucibacillary/PB leprosy from other dermatoses. Whole-blood assay/WBA/IFNγ stimulated with LID-1 antigen and ELISA tests for IgG to LID-1 and IgM to PGL-I were performed. WBA/LID-1/IFNγ production was observed in 72% PB, 11% MB leprosy, 38% dermatoses, 40% healthy endemic controls/EC. The receiver operating curve/ROC for WBA/LID-1 in PB versus other dermatoses showed 72.5% sensitivity, 61.5% specificity and an area-under-the-curve/AUC=0.75; 74% positive predictive value/PPV, 59% negative predictive value/NPV. Anti PGL-I serology was positive in 67% MB, 8% PB leprosy, 6% of other dermatoses; its sensitivity for MB=66%, specificity=93%, AUC=0.89; PPV=91%, NPV=72%. Anti-LID-1 serology was positive in 87% MB, 7% PB leprosy, all other participants were seronegative; 87.5% sensitivity for MB, 100% specificity, AUC=0.97; PPV=100%, NPV=88%. In highly endemic areas anti-LID-1/PGL-I serology and WBA/LID-1-represent useful tools for the differential diagnosis of leprosy from other confounding dermatoses.

  7. Confounding effects of microbiome on the susceptibility of TNFSF15 to Crohn's disease in the Ryukyu Islands.

    PubMed

    Nakagome, Shigeki; Chinen, Hiroshi; Iraha, Atsushi; Hokama, Akira; Takeyama, Yasuaki; Sakisaka, Shotaro; Matsui, Toshiyuki; Kidd, Judith R; Kidd, Kenneth K; Said, Heba S; Suda, Wataru; Morita, Hidetoshi; Hattori, Masahira; Hanihara, Tsunehiko; Kimura, Ryosuke; Ishida, Hajime; Fujita, Jiro; Kinjo, Fukunori; Mano, Shuhei; Oota, Hiroki

    2017-04-01

    Crohn's disease (CD) involves chronic inflammation in the gastrointestinal tract due to dysregulation of the host immune response to the gut microbiome. Even though the host-microbiome interactions are likely contributors to the development of CD, a few studies have detected genetic variants that change bacterial compositions and increase CD risk. We focus on one of the well-replicated susceptible genes, tumor necrosis factor superfamily member 15 (TNFSF15), and apply statistical analyses for personal profiles of genotypes and salivary microbiota collected from CD cases and controls in the Ryukyu Islands, southernmost islands of the Japanese archipelago. Our association test confirmed the susceptibility of TNFSF15 in the Ryukyu Islands. We found that the recessive model was supported to fit the observed genotype frequency of risk alleles slightly better than the additive model, defining the genetic effect on CD if a pair of the chromosomes in an individual consists of all risk alleles. The combined analysis of haplotypes and salivary microbiome from a small set of samples showed a significant association of the genetic effect with the increase of Prevotella, which led to a significant increase of CD risk. However, the genetic effect on CD disappeared if the abundance of Prevotella was low, suggesting the genetic contribution to CD is conditionally independent given a fixed amount of Prevotella. Although our statistical power is limited due to the small sample size, these results support an idea that the genetic susceptibility of TNFSF15 to CD may be confounded, in part, by the increase of Prevotella.

  8. Zooplankton community changes confound the biodilution theory of methylmercury accumulation in a recovering mercury-contaminated lake.

    PubMed

    Todorova, Svetoslava; Driscoll, Charles T; Matthews, David A; Effler, Steven W

    2015-04-07

    In this study, the biodilution hypothesis of methylmercury (MeHg) accumulation was examined in a Hg-contaminated ecosystem that has undergone concurrent changes in nutrient loading and zooplankton community composition. Using a long-term record of 17 years (between 1980 and 2009), we demonstrate that zooplankton MeHg concentrations in Onondaga Lake, NY, are strongly driven by changes in the zooplankton community and body size. MeHg concentrations in zooplankton increased with an increase in body size and biomass. The highest concentrations of MeHg were observed under eutrophic and hypereutrophic conditions when large-bodied Daphnia species, Daphnia pulicaria and Daphnia galeata mendotae, were present. Bioconcentration rather than biodilution was governing the accumulation of MeHg in zooplankton without apparent growth dilution or zooplankton biomass dilution. Algal-bloom dilution controlled the variability in the MeHg concentration only under hypereutrophic conditions when Ceriodaphnia predominated the cladoceran population. Our study demonstrates that changes in zooplankton community composition confound the biodilution theory in Onondaga Lake and that the presence of large-bodied zooplankton species drives elevated MeHg concentrations.

  9. Is exposure temperature a confounding factor for the assessment of reproductive parameters of New Zealand mudsnails Potamopyrgus antipodarum (Gray)?

    PubMed

    Gust, M; Buronfosse, T; André, C; Mons, R; Gagné, F; Garric, J

    2011-01-25

    Potamopyrgus antipodarum is a promising test organism often used in ecotoxicology testing, both in laboratory and in field exposure experiments. It has been recommended for use in the development of an OECD reproduction test. However, exposure temperature is important to take into account when assessing reproduction and related biomarkers, because it can act as a confounding factor inducing variability in physiological values. The effect of three environmentally realistic exposure temperatures (8, 16 and 24°C) was examined with respect to the number of neonates born, the number of embryos in the brood pouch and the duration of embryonic development. We also measured additional markers likely to be related to the modulation of reproductive performance, such as vertebrate-like sex steroid, energy status and vitellin-like proteins. Exposure temperature had a significant effect on reproduction in P. antipodarum, on both the duration of embryonic development and the quantity of embryos and neonates. The consequences of these observations must not be neglected when using this species in laboratory and field experiments. This study determined suitable temperatures for field experiments and a mean duration for embryonic development independent of temperature. In addition to steroid levels, energy status and Vn-like protein levels were only slightly modified by exposure temperature between 8 and 24°C. Thus, they can be easily implemented and their variations related to anthropogenic factors during field exposure of mudsnails.

  10. Grandparental help in Indonesia is directed preferentially towards needier descendants: a potential confounder when exploring grandparental influences on child health.

    PubMed

    Snopkowski, Kristin; Sear, Rebecca

    2015-03-01

    A considerable body of evidence has now demonstrated positive correlations between grandparental presence and child health outcomes. It is typically assumed that such correlations exist because grandparental investment in their grandchildren improves child health and wellbeing. However, less is known about how grandparents allocate help to adult children and grandchildren, particularly in lower income contexts. Here we use detailed quantitative data from the longitudinal Indonesia Family Life Survey (data collected in 1993, 1997, 2000, 2007; n = 16,250) to examine grandparental help in a society transitioning both demographically and economically. We test the hypothesis that grandparents direct help preferentially towards those adult children and grandchildren most in need of help. This hypothesis was supported for help provided by married grandparents and single grandmothers, who tended to: provide more help to their adult children when this generation had young children themselves, provide financial help if their adult children were poorer, and provide more household help if their adult daughters worked outside the home. One unexpected result was that help from maternal and paternal grandparents is positively correlated; if one set of grandparents is helping the other set is more likely to help, counter to our predictions. These results provide support for the hypothesis that grandparents preferentially invest in some descendants over others, where married grandparents and single grandmothers tend to invest in those adult children and grandchildren with the most need. Investigating the effect of grandparents on child health outcomes may therefore be confounded by grandparent's preferential investment in needier descendants.

  11. Does environmental confounding mask pleiotropic effects of a multiple sclerosis susceptibility variant on vitamin D in psychosis?

    PubMed Central

    Iyegbe, Conrad O; Acharya, Anita; Lally, John; Gardner-Sood, Poonam; Smith, Louise S; Smith, Shubulade; Murray, Robin; Howes, Oliver; Gaughran, Fiona

    2015-01-01

    Background: This work addresses the existing and emerging evidence of overlap within the environmental and genetic profiles of multiple sclerosis (MS) and schizophrenia. Aims: To investigate whether a genetic risk factor for MS (rs703842), whose variation is indicative of vitamin D status in the disorder, could also be a determinant of vitamin D status in chronic psychosis patients. Methods: A cohort of 224 chronic psychosis cases was phenotyped and biologically profiled. The relationship between rs703842 and physiological vitamin D status in the blood plasma was assessed by logistic regression. Deficiency was defined as a blood plasma concentration below 10 ng/µl. Potential environmental confounders of the vitamin D status were considered as part of the analysis. Results: We report suggestive evidence of an association with vitamin D status in established psychosis (ßstandardized=0.51, P=0.04). The logistic model fit significantly benefited from controlling for body mass index, depression and ethnicity (χ2=91.7; 2 degrees of freedom (df); P=1.2×1020). Conclusions: The results suggest that, in addition to lifestyle changes that accompany the onset of illness, vitamin D dysregulation in psychosis has a genetic component that links into MS. Further, comprehensive studies are needed to evaluate this prospect. PMID:27336042

  12. Potential sources of 2-aminoacetophenone to confound the Pseudomonas aeruginosa breath test, including analysis of a food challenge study.

    PubMed

    Scott-Thomas, Amy; Pearson, John; Chambers, Stephen

    2011-12-01

    2-Aminoacetophenone can be detected in the breath of Pseudomonas aeruginosa colonized cystic fibrosis patients; however, low levels were also detected in a small proportion of healthy subjects. It was hypothesized that food, beverages, cosmetics or medications could be a source of contamination of 2-aminoacetophenone in breath. To determine the potential confounding of these products on 2-aminoacetophenone breath analysis, screening for this volatile was performed in the laboratory by gas chromatography/mass spectrometry and a food challenge study carried out. 2-Aminoacetophenone was detected in four of the 78 samples tested in vitro: corn chips and canned tuna (high pmol mol(-1)) and egg white and one of the three beers (low pmol mol(-1)). No 2-aminoacetophenone was detected in the CF medication or cosmetics tested. Twenty-eight out of 30 environmental air samples were negative for 2-aminoacetophenone (below 50 pmol mol(-1)). A challenge study with ten healthy subjects was performed to determine if 2-aminoacetophenone from corn chips was detectable on the breath after consumption. Analysis of mixed breath samples reported that the levels of 2-aminoacetophenone were immediately elevated after corn chip consumption, but after 2 h the level of 2-aminoacetophenone had reduced back to the 'baseline' for each subject.

  13. Influence of explanatory and confounding variables on HRQoL after controlling for measurement bias and response shift in measurement.

    PubMed

    Gandhi, Pranav K; Ried, L Douglas; Kimberlin, Carole L; Kauf, Teresa L; Huang, I-Chan

    2013-12-01

    The purpose of this study was to examine the influence of explanatory and confounding variables on health-related quality of life after accounting for response shift, measurement bias and response shift in measurement using structural equation modeling. Hypertensive patients with coronary artery disease randomized to anti-hypertensive treatment, completed the ShortForm-36 questionnaire at both baseline and 1 year (n = 788). Three measurement biases were found and all three were considered as response shift in measurement. Older patients reported worse scores for both physical functioning (PF) and role-physical at baseline and 1 year later compared to younger patients; and males reported better PF than females after conditioning on the latent trait of general physical health. Before controlling for response shift, patients' PF scores were not statistically different over time; however, PF scores significantly improved (p < 0.01) after controlling for recalibration response shift. Assessment of how patients perceive their change in health-related quality of life over time is warranted.

  14. Environment- and eye-centered inhibitory cueing effects are both observed after a methodological confound is eliminated

    PubMed Central

    He, Tao; Ding, Yun; Wang, Zhiguo

    2015-01-01

    Inhibition of return (IOR), typically explored in cueing paradigms, is a performance cost associated with previously attended locations and has been suggested as a crucial attentional mechanism that biases orientation towards novelty. In their seminal IOR paper, Posner and Cohen (1984) showed that IOR is coded in spatiotopic or environment-centered coordinates. Recent studies, however, have consistently reported IOR effects in both spatiotopic and retinotopic (eye-centered) coordinates. One overlooked methodological confound of all previous studies is that the spatial gradient of IOR is not considered when selecting the baseline for estimating IOR effects. This methodological issue makes it difficult to tell if the IOR effects reported in previous studies were coded in retinotopic or spatiotopic coordinates, or in both. The present study addresses this issue with the incorporation of no-cue trials to a modified cueing paradigm in which the cue and target are always intervened by a gaze-shift. The results revealed that a) IOR is indeed coded in both spatiotopic and retinotopic coordinates, and b) the methodology of previous work may have underestimated spatiotopic and retinotopic IOR effects. PMID:26565380

  15. Cryptic confounding compounds: A brief consideration of the influences of anthropogenic contaminants on courtship and mating behavior

    PubMed Central

    Blocker, Tomica D.; Ophir, Alexander G.

    2012-01-01

    Contaminants, like pesticides, polychlorinated biphenyls (PCBs), dioxins and metals, are persistent and ubiquitous and are known to threaten the environment. Traditionally, scientists have considered the direct physiological risks that these contaminants pose. However, scientists have just begun to integrate ethology and toxicology to investigate the effects that contaminants have on behavior. This review considers the potential for contaminant effects on mating behavior. Here we assess the growing body of research concerning disruptions in sexual differentiation, courtship, sexual receptivity, arousal, and mating. We discuss the implications of these disruptions on conservation efforts and highlight the importance of recognizing the potential for environmental stressors to affect behavioral experimentation. More specifically, we consider the negative implications for anthropogenic contaminants to affect the immediate behavior of animals, and their potential to have cascading and/or long-term effects on the behavioral ecology and evolution of populations. Overall, we aim to raise awareness of the confounding influence that contaminants can have, and promote caution when interpreting results where the potential for cryptic affects are possible. PMID:24244068

  16. Biochemical changes in the injured brain.

    PubMed

    Sahu, Seelora; Nag, Deb Sanjay; Swain, Amlan; Samaddar, Devi Prasad

    2017-02-26

    Brain metabolism is an energy intensive phenomenon involving a wide spectrum of chemical intermediaries. Various injury states have a detrimental effect on the biochemical processes involved in the homeostatic and electrophysiological properties of the brain. The biochemical markers of brain injury are a recent addition in the armamentarium of neuro-clinicians and are being increasingly used in the routine management of neuro-pathological entities such as traumatic brain injury, stroke, subarachnoid haemorrhage and intracranial space occupying lesions. These markers are increasingly being used in assessing severity as well as in predicting the prognostic course of neuro-pathological lesions. S-100 protein, neuron specific enolase, creatinine phosphokinase isoenzyme BB and myelin basic protein are some of the biochemical markers which have been proven to have prognostic and clinical value in the brain injury. While S-100, glial fibrillary acidic protein and ubiquitin C terminal hydrolase are early biomarkers of neuronal injury and have the potential to aid in clinical decision-making in the initial management of patients presenting with an acute neuronal crisis, the other biomarkers are of value in predicting long-term complications and prognosis in such patients. In recent times cerebral microdialysis has established itself as a novel way of monitoring brain tissue biochemical metabolites such as glucose, lactate, pyruvate, glutamate and glycerol while small non-coding RNAs have presented themselves as potential markers of brain injury for future.

  17. A Course in Biochemical Engineering Fundamentals (Revisited).

    ERIC Educational Resources Information Center

    Bailey, J. E.; Ollis, D. F.

    1985-01-01

    Provides: (1) a glossary of terms used in biochemical engineering; (2) a list of key developments in the field; and (3) emphases placed in 15 topic areas in a course restructured on the basis of these developments. Topic areas include enzyme kinetics/applications, genetics and microbial control, transport phenomena, and others. (JN)

  18. The Biochemical Basis of Minimal Brain Dysfunction

    ERIC Educational Resources Information Center

    Shaywitz, Sally E.; And Others

    1978-01-01

    Available from: C. V. Mosby Company 11830 Westline Industrial Drive St. Louis, Missouri 63141 The research review examines evidence suggesting a biochemical basis for minimal brain dysfunction (MBD), which includes both a relationship between MBD and metabolic abnormalities and a significant genetic influence on the disorder in children. (IM)

  19. 2009 Biochemical Conversion Platform Review Report

    SciTech Connect

    Ferrell, John

    2009-12-01

    This document summarizes the recommendations and evaluations provided by an independent external panel of experts at the U.S. Department of Energy Biomass Program’s Biochemical Conversion platform review meeting, held on April 14-16, 2009, at the Sheraton Denver Downtown, Denver, Colorado.

  20. Biochemical Approaches to Improved Nitrogen Fixation

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Improving symbiotic nitrogen fixation by legumes has emerged again as an important topic on the world scene due to the energy crisis and lack of access to nitrogen fertilizer in developing countries. We have taken a biochemical genomics approach to improving symbiotic nitrogen fixation in legumes. L...

  1. Survey of Biochemical Education in Japanese Universities.

    ERIC Educational Resources Information Center

    Kagawa, Yasuo

    1995-01-01

    Reports findings of questionnaires sent to faculty in charge of biochemical education in medical schools and other programs from dentistry to agriculture. Total class hours have declined since 1984. New trends include bioethics and computer-assisted learning. Tables show trends in lecture hours, lecture content, laboratory hours, core subject…

  2. Biochemical changes in the injured brain

    PubMed Central

    Sahu, Seelora; Nag, Deb Sanjay; Swain, Amlan; Samaddar, Devi Prasad

    2017-01-01

    Brain metabolism is an energy intensive phenomenon involving a wide spectrum of chemical intermediaries. Various injury states have a detrimental effect on the biochemical processes involved in the homeostatic and electrophysiological properties of the brain. The biochemical markers of brain injury are a recent addition in the armamentarium of neuro-clinicians and are being increasingly used in the routine management of neuro-pathological entities such as traumatic brain injury, stroke, subarachnoid haemorrhage and intracranial space occupying lesions. These markers are increasingly being used in assessing severity as well as in predicting the prognostic course of neuro-pathological lesions. S-100 protein, neuron specific enolase, creatinine phosphokinase isoenzyme BB and myelin basic protein are some of the biochemical markers which have been proven to have prognostic and clinical value in the brain injury. While S-100, glial fibrillary acidic protein and ubiquitin C terminal hydrolase are early biomarkers of neuronal injury and have the potential to aid in clinical decision-making in the initial management of patients presenting with an acute neuronal crisis, the other biomarkers are of value in predicting long-term complications and prognosis in such patients. In recent times cerebral microdialysis has established itself as a novel way of monitoring brain tissue biochemical metabolites such as glucose, lactate, pyruvate, glutamate and glycerol while small non-coding RNAs have presented themselves as potential markers of brain injury for future. PMID:28289516

  3. Biochemical Applications in the Analytical Chemistry Lab

    ERIC Educational Resources Information Center

    Strong, Cynthia; Ruttencutter, Jeffrey

    2004-01-01

    An HPLC and a UV-visible spectrophotometer are identified as instruments that helps to incorporate more biologically-relevant experiments into the course, in order to increase the students understanding of selected biochemistry topics and enhances their ability to apply an analytical approach to biochemical problems. The experiment teaches…

  4. Biochemical Thermodynamics under near Physiological Conditions

    ERIC Educational Resources Information Center

    Mendez, Eduardo

    2008-01-01

    The recommendations for nomenclature and tables in Biochemical Thermodynamics approved by IUBMB and IUPAC in 1994 can be easily introduced after the chemical thermodynamic formalism. Substitution of the usual standard thermodynamic properties by the transformed ones in the thermodynamic equations, and the use of appropriate thermodynamic tables…

  5. Do time-invariant confounders explain away the association between job stress and workers' mental health? Evidence from Japanese occupational panel data.

    PubMed

    Oshio, Takashi; Tsutsumi, Akizumi; Inoue, Akiomi

    2015-02-01

    It is well known that job stress is negatively related to workers' mental health, but most recent studies have not controlled for unobserved time-invariant confounders. In the current study, we attempted to validate previous observations on the association between job stress and workers' mental health, by removing the effects of unobserved time-invariant confounders. We used data from three to four waves of an occupational Japanese cohort survey, focusing on 31,382 observations of 9741 individuals who participated in at least two consecutive waves. We estimated mean-centered fixed effects models to explain psychological distress in terms of the Kessler 6 (K6) scores (range: 0-24) by eight job stress indicators related to the job demands-control, effort-reward imbalance, and organizational injustice models. Mean-centered fixed effects models reduced the magnitude of the association between jobs stress and K6 scores to 44.8-54.2% of those observed from pooled ordinary least squares. However, the association remained highly significant even after controlling for unobserved time-invariant confounders for all job stress indicators. In addition, alternatively specified models showed the robustness of the results. In all, we concluded that the validity of major job stress models, which link job stress and workers' mental health, was robust, although unobserved time-invariant confounders led to an overestimation of the association.

  6. Lumbar disc degeneration was not related to spine and hip bone mineral densities in Chinese: facet joint osteoarthritis may confound the association.

    PubMed

    Pan, Jianjiang; Lu, Xuan; Yang, Ge; Han, Yongmei; Tong, Xiang; Wang, Yue

    2017-12-01

    A sample of 512 Chinese was studied and we observed that greater disc degeneration on MRI was associated with greater spine DXA BMD. Yet, this association may be confounded by facet joint osteoarthritis. BMD may not be a risk factor for lumbar disc degeneration in Chinese.

  7. Effects of categorization method, regression type, and variable distribution on the inflation of Type-I error rate when categorizing a confounding variable.

    PubMed

    Barnwell-Ménard, Jean-Louis; Li, Qing; Cohen, Alan A

    2015-03-15

    The loss of signal associated with categorizing a continuous variable is well known, and previous studies have demonstrated that this can lead to an inflation of Type-I error when the categorized variable is a confounder in a regression analysis estimating the effect of an exposure on an outcome. However, it is not known how the Type-I error may vary under different circumstances, including logistic versus linear regression, different distributions of the confounder, and different categorization methods. Here, we analytically quantified the effect of categorization and then performed a series of 9600 Monte Carlo simulations to estimate the Type-I error inflation associated with categorization of a confounder under different regression scenarios. We show that Type-I error is unacceptably high (>10% in most scenarios and often 100%). The only exception was when the variable categorized was a continuous mixture proxy for a genuinely dichotomous latent variable, where both the continuous proxy and the categorized variable are error-ridden proxies for the dichotomous latent variable. As expected, error inflation was also higher with larger sample size, fewer categories, and stronger associations between the confounder and the exposure or outcome. We provide online tools that can help researchers estimate the potential error inflation and understand how serious a problem this is.

  8. Issues Relating to Confounding and Meta-analysis When Including Non-Randomized Studies in Systematic Reviews on the Effects of Interventions

    ERIC Educational Resources Information Center

    Valentine, Jeffrey C.; Thompson, Simon G.

    2013-01-01

    Background: Confounding caused by selection bias is often a key difference between non-randomized studies (NRS) and randomized controlled trials (RCTs) of interventions. Key methodological issues: In this third paper of the series, we consider issues relating to the inclusion of NRS in systematic reviews on the effects of interventions. We discuss…

  9. Using Rich Data on Comorbidities in Case-Control Study Design with Electronic Health Record Data Improves Control of Confounding in the Detection of Adverse Drug Reactions

    PubMed Central

    Chase, Herbert

    2016-01-01

    Recent research has suggested that the case-control study design, unlike the self-controlled study design, performs poorly in controlling confounding in the detection of adverse drug reactions (ADRs) from administrative claims and electronic health record (EHR) data, resulting in biased estimates of the causal effects of drugs on health outcomes of interest (HOI) and inaccurate confidence intervals. Here we show that using rich data on comorbidities and automatic variable selection strategies for selecting confounders can better control confounding within a case-control study design and provide a more solid basis for inference regarding the causal effects of drugs on HOIs. Four HOIs are examined: acute kidney injury, acute liver injury, acute myocardial infarction and gastrointestinal ulcer hospitalization. For each of these HOIs we use a previously published reference set of positive and negative control drugs to evaluate the performance of our methods. Our methods have AUCs that are often substantially higher than the AUCs of a baseline method that only uses demographic characteristics for confounding control. Our methods also give confidence intervals for causal effect parameters that cover the expected no effect value substantially more often than this baseline method. The case-control study design, unlike the self-controlled study design, can be used in the fairly typical setting of EHR databases without longitudinal information on patients. With our variable selection method, these databases can be more effectively used for the detection of ADRs. PMID:27716785

  10. Are the effects of psychosocial exposures attributable to confounding? Evidence from a prospective observational study on psychological stress and mortality

    PubMed Central

    Macleod, J; Davey, S; Heslop, P; Metcalfe, C; Carroll, D; Hart, C

    2001-01-01

    .69 (95% CI 0.44, 1.09), p for trend 0.12, fully adjusted 0.76 (95% CI 0.48, 1.21), p for trend 0.25; increased compared with decreased stress, age adjusted 0.65 (95% CI 0.40, 1.06), p for trend 0.09, fully adjusted 0.65 (95% CI 0.40, 1.06), p for trend 0.08.
CONCLUSIONS—This implausible protective relation between higher levels of stress, which were associated with increased smoking, and mortality from smoking related cancers, was probably a product of confounding. Plausible reported associations between psychosocial exposures and disease, in populations where such exposures are associated with material disadvantage, may be similarly produced by confounding, and of no causal significance.


Keywords: socioeconomic differentials; psychosocial factors; mortality PMID:11707481

  11. A new automated method for rat sleep deprivation with minimal confounding effects on corticosterone and locomotor activity.

    PubMed

    Leenaars, Cathalijn H C; Dematteis, Maurice; Joosten, Ruud N J M A; Eggels, Leslie; Sandberg, Hans; Schirris, Mischa; Feenstra, Matthijs G P; Van Someren, Eus J W

    2011-03-15

    The function of sleep in physiology, behaviour and cognition has become a primary focus of neuroscience. Its study inevitably includes experimental sleep deprivation designs. However, concerns exist regarding confounds like stress, increased locomotor activity levels, and decreased motivation to perform operant tasks induced by the methods employed. We here propose a novel procedure for sleep deprivation in rats and evaluate how it affects sleep, corticosterone concentration profiles, locomotor activity levels, and motivation to perform an operant task. Before, during and after 12h of total sleep deprivation by means of gradually increasing the rotation variability and the speed of a novel automated, two-compartment sleep deprivation device, sleep-wake states were assessed by electroencephalography (n=21), brain extracellular corticosterone concentrations using microdialysis (n=11), locomotor activity by infrared measurements (n=8), and operant performance using a fixed-interval-fixed-ratio task (n=16). Sleep was effectively prevented during the procedure; rats on average slept less than 1% of the time (0.8±0.2%, mean±standard error). Brain corticosterone concentrations were mildly increased during the procedure, but did not exceed normal peak concentrations. Locomotor activity was not only increased during the procedure, but also did not exceed the peak levels found during undisturbed wakefulness. Food restriction to 12 g/rat/day prevented sleep deprivation from reducing the motivation to perform an operant task. This novel procedure can be applied to sleep deprive rats in a highly effective way, while keeping corticosterone and locomotor activity within the normal range.

  12. Parametric Mediational g-Formula Approach to Mediation Analysis with Time-varying Exposures, Mediators, and Confounders.

    PubMed

    Lin, Sheng-Hsuan; Young, Jessica; Logan, Roger; Tchetgen Tchetgen, Eric J; VanderWeele, Tyler J

    2017-03-01

    The assessment of direct and indirect effects with time-varying mediators and confounders is a common but challenging problem, and standard mediation analysis approaches are generally not applicable in this context. The mediational g-formula was recently proposed to address this problem, paired with a semiparametric estimation approach to evaluate longitudinal mediation effects empirically. In this article, we develop a parametric estimation approach to the mediational g-formula, including a feasible algorithm implemented in a freely available SAS macro. In the Framingham Heart Study data, we apply this method to estimate the interventional analogues of natural direct and indirect effects of smoking behaviors sustained over a 10-year period on blood pressure when considering weight change as a time-varying mediator. Compared with not smoking, smoking 20 cigarettes per day for 10 years was estimated to increase blood pressure by 1.2 mm Hg (95% CI: -0.7, 2.7). The direct effect was estimated to increase blood pressure by 1.5 mm Hg (95% CI: -0.3, 2.9), and the indirect effect was -0.3 mm Hg (95% CI: -0.5, -0.1), which is negative because smoking which is associated with lower weight is associated in turn with lower blood pressure. These results provide evidence that weight change in fact partially conceals the detrimental effects of cigarette smoking on blood pressure. Our study represents, to our knowledge, the first application of the parametric mediational g-formula in an epidemiologic cohort study (see video abstract at, http://links.lww.com/EDE/B159.).

  13. Type 2 diabetes as a risk factor for Alzheimer's disease: the confounders, interactions, and neuropathology associated with this relationship.

    PubMed

    Vagelatos, Nicholas T; Eslick, Guy D

    2013-01-01

    We performed a systematic review and meta-analysis to explore whether type 2 diabetes mellitus (T2DM) increases the risk of Alzheimer's disease (AD). We also reviewed interactions with smoking, hypertension, and apolipoprotein E ɛ4. Using a series of databases (MEDLINE, EMBASE, PubMed, Current Contents Connect, and Google Scholar), we identified a total of 15 epidemiologic studies. Fourteen studies reported positive associations, of which 9 were statistically significant. Risk estimates ranged from 0.83 to 2.45. The pooled adjusted risk ratio was 1.57 (95% confidence interval: 1.41, 1.75), with a population-attributable risk of 8%. Smoking and hypertension, when comorbid with T2DM, had odds of 14 and 3, respectively. Of the 5 studies that investigated the interaction between T2DM and apolipoprotein E ɛ4, 4 showed positive associations, of which 3 were significant, with odds ranging from 2.4 to 4.99. The pooled adjusted risk ratio was 2.91 (95% confidence interval: 1.51, 5.61). Risk estimates were presented in the context of a key confounder-cerebral infarcts-which are more common in those with T2DM and might contribute to the manifestation of clinical AD. We provide evidence from clinico-neuropathologic studies that demonstrates the following: First, cerebral infarcts are more common than AD-type pathology in those with T2DM and dementia. Second, those with dementia at postmortem are more likely to have both AD-type and cerebrovascular pathologies. Finally, cerebral infarcts reduce the number of AD lesions required for the manifestation of clinical dementia, but they do not appear to interact synergistically with AD-type pathology. Therefore, the increased risk of clinically diagnosed AD seems to be mediated through cerebrovascular pathology.

  14. Global climate change in large European rivers: long-term effects on macroinvertebrate communities and potential local confounding factors.

    PubMed

    Floury, Mathieu; Usseglio-Polatera, Philippe; Ferreol, Martial; Delattre, Cecile; Souchon, Yves

    2013-04-01

    Aquatic species living in running waters are widely acknowledged to be vulnerable to climate-induced, thermal and hydrological fluctuations. Climate changes can interact with other environmental changes to determine structural and functional attributes of communities. Although such complex interactions are most likely to occur in a multiple-stressor context as frequently encountered in large rivers, they have received little attention in such ecosystems. In this study, we aimed at specifically addressing the issue of relative long-term effects of global and local changes on benthic macroinvertebrate communities in multistressed large rivers. We assessed effects of hydroclimatic vs. water quality factors on invertebrate community structure and composition over 30 years (1979-2008) in the Middle Loire River, France. As observed in other large European rivers, water warming over the three decades (+0.9 °C between 1979-1988 and 1999-2008) and to a lesser extent discharge reduction (-80 m(3) s(-1) ) were significantly involved in the disappearance or decrease in taxa typical from fast running, cold waters (e.g. Chloroperlidae and Potamanthidae). They explained also a major part of the appearance and increase of taxa typical from slow flowing or standing waters and warmer temperatures, including invasive species (e.g. Corbicula sp. and Atyaephyra desmarestii). However, this shift towards a generalist and pollution tolerant assemblage was partially confounded by local improvement in water quality (i.e. phosphate input reduction by about two thirds and eutrophication limitation by almost one half), explaining a significant part of the settlement of new pollution-sensitive taxa (e.g. the caddisfly Brachycentridae and Philopotamidae families) during the last years of the study period. The regain in such taxa allowed maintaining a certain level of specialization in the invertebrate community despite climate change effects.

  15. Post-study therapy as a source of confounding in survival analysis of first-line studies in patients with advanced non-small-cell lung cancer.

    PubMed

    Zietemann, Vera D; Schuster, Tibor; Duell, Thomas Hg

    2011-06-01

    Clinical trials exploring the long-term effects of first-line therapy in patients with advanced non-small-cell lung cancer generally disregard subsequent treatment although most patients receive second and third-line therapies. The choice of further therapy depends on critical intermediate events such as disease progression and it is usually left at the physician's discretion. Time-dependent confounding may then arise with standard survival analyses producing biased effect estimates, even in randomized trials. Herein we describe the concept of time-dependent confounding in detail and discuss whether the response to first-line treatment may be a potential time-dependent confounding factor for survival in the context of subsequent therapy. A prospective observational study of 406 patients with advanced non-small-cell lung cancer served as an example base. There is evidence that time-dependent confounding may occur in multivariate survival analysis after first-line therapy when disregarding subsequent treatment. In the light of this important but underestimated aspect some of the large and meaningful recent clinical first-line lung cancer studies are discussed, focussing on subsequent treatment and its potential impact on the survival of the study patients. No recently performed lung cancer trial applied adequate statistical analyses despite the frequent use of subsequent therapies. In conclusion, effect estimates from standard survival analysis may be biased even in randomized controlled trials because of time-dependent confounding. To adequately assess treatment effects on long-term outcomes appropriate statistical analyses need to take subsequent treatment into account.

  16. Kombucha tea fermentation: Microbial and biochemical dynamics.

    PubMed

    Chakravorty, Somnath; Bhattacharya, Semantee; Chatzinotas, Antonis; Chakraborty, Writachit; Bhattacharya, Debanjana; Gachhui, Ratan

    2016-03-02

    Kombucha tea, a non-alcoholic beverage, is acquiring significant interest due to its claimed beneficial properties. The microbial community of Kombucha tea consists of bacteria and yeast which thrive in two mutually non-exclusive compartments: the soup or the beverage and the biofilm floating on it. The microbial community and the biochemical properties of the beverage have so far mostly been described in separate studies. This, however, may prevent understanding the causal links between the microbial communities and the beneficial properties of Kombucha tea. Moreover, an extensive study into the microbial and biochemical dynamics has also been missing. In this study, we thus explored the structure and dynamics of the microbial community along with the biochemical properties of Kombucha tea at different time points up to 21 days of fermentation. We hypothesized that several biochemical properties will change during the course of fermentation along with the shifts in the yeast and bacterial communities. The yeast community of the biofilm did not show much variation over time and was dominated by Candida sp. (73.5-83%). The soup however, showed a significant shift in dominance from Candida sp. to Lachancea sp. on the 7th day of fermentation. This is the first report showing Candida as the most dominating yeast genus during Kombucha fermentation. Komagateibacter was identified as the single largest bacterial genus present in both the biofilm and the soup (~50%). The bacterial diversity was higher in the soup than in the biofilm with a peak on the seventh day of fermentation. The biochemical properties changed with the progression of the fermentation, i.e., beneficial properties of the beverage such as the radical scavenging ability increased significantly with a maximum increase at day 7. We further observed a significantly higher D-saccharic acid-1,4-lactone content and caffeine degradation property compared to previously described Kombucha tea fermentations. Our

  17. Pitfalls in the interpretation of common biochemical tests

    PubMed Central

    Ayling, R.

    2000-01-01

    This review considers some of the more common problems in the interpretation of the results of biochemical tests and, where possible, highlights ways in which errors can be identified or avoided.


Keywords: biochemical tests PMID:10684320

  18. Construction and analysis of biochemical networks

    NASA Astrophysics Data System (ADS)

    Binns, Michael; Theodoropoulos, Constantinos

    2012-09-01

    Bioprocesses are being implemented for a range of different applications including the production of fuels, chemicals and drugs. Hence, it is becoming increasingly important to understand and model how they function and how they can be modified or designed to give the optimal performance. Here we discuss the construction and analysis of biochemical networks which are the first logical steps towards this goal. The construction of a reaction network is possible through reconstruction: extracting information from literature and from databases. This can be supplemented by reaction prediction methods which can identify steps which are missing from the current knowledge base. Analysis of biochemical systems generally requires some experimental input but can be used to identify important reactions and targets for enhancing the performance of the organism involved. Metabolic flux, pathway and metabolic control analysis can be used to determine the limits, capabilities and potential targets for enhancement respectively.

  19. Biochemical correlates of neurosensory changes in weightlessness

    NASA Technical Reports Server (NTRS)

    Leach, Carolyn S.; Reschke, Millard F.

    1989-01-01

    The possible existence of a relationship between space motion sickness and chemical and biochemical variables measured in body fluids is studied. Clinical chemistry and endocrine measurements from blood and urine samples taken before and after Space Shuttle flights were analyzed along with the occurrence of SMS during flight and provocative testing before flight. Significant positive correlations were observed with serum chloride and significant negative correlations with serum phosphate, serum uric acid, and plasma thyroid stimulating hormone.

  20. Differential Recall Bias, Intermediate Confounding, and Mediation Analysis in Life Course Epidemiology: An Analytic Framework with Empirical Example.

    PubMed

    Sheikh, Mashhood A; Abelsen, Birgit; Olsen, Jan Abel

    2016-01-01

    The mechanisms by which childhood socioeconomic status (CSES) affects adult mental health, general health, and well-being are not clear. Moreover, the analytical assumptions employed when assessing mediation in social and psychiatric epidemiology are rarely explained. The aim of this paper was to explain the intermediate confounding assumption, and to quantify differential recall bias in the association between CSES, childhood abuse, and mental health (SCL-10), general health (EQ-5D), and subjective well-being (SWLS). Furthermore, we assessed the mediating role of psychological and physical abuse in the association between CSES and mental health, general health, and well-being; and the influence of differential recall bias in the estimation of total effects, direct effects, and proportion of mediated effects. The assumptions employed when assessing mediation are explained with reference to a causal diagram. Poisson regression models (relative risk, RR and 99% CIs) were used to assess the association between CSES and psychological and physical abuse in childhood. Mediation analysis (difference method) was used to assess the indirect effect of CSES (through psychological and physical abuse in childhood) on mental health, general health, and well-being. Exposure (CSES) was measured at two time points. Mediation was assessed with both cross-sectional and longitudinal data. Psychological abuse and physical abuse mediated the association between CSES and adult mental health, general health, and well-being (6-16% among men and 7-14% among women, p < 0.001). The results suggest that up to 27% of the association between CSES and childhood abuse, 23% of the association between childhood abuse, and adult mental health, general health, and well-being, and 44% of the association between CSES and adult mental health, general health, and well-being is driven by differential recall bias. Assessing mediation with cross-sectional data (exposure, mediator, and outcome measured at the

  1. Land surface controls on afternoon precipitation diagnosed from observational data: Uncertainties, confounding factors and the possible role of interception storage

    NASA Astrophysics Data System (ADS)

    Guillod, B. P.; Orlowsky, B.; Seneviratne, S. I.

    2013-12-01

    ://www.nature.com/doifinder/10.1038/ngeo1174. Guillod, B. P., et al.: 'Land surface controls on afternoon precipitation diagnosed from observational data: Uncertainties, confounding factors and the possible role of interception storage', manuscript in preparation. Miralles, D. G., et al., 2011: Global land-surface evaporation estimated from satellite-based observations. Hydrol. Earth Syst. Sci., 15 (2), 453-469, doi:10.5194/hess-15-453-2011, URL http://www.hydrol-earth-syst-sci.net/15/453/2011/. Acknowledgement: We thank a number of people for their comments and contributions: Diego Miralles, Kirsten Findell, Adriaan Teuling, Nina Buchmann, Philippe Ciais, Bart Van den Hurk, Pierre Gentine, Benjamin Lintner, Markus Reichstein, Han Dolman and PIs from the used Fluxnet sites as well as the FLUXNET community.

  2. Differential Recall Bias, Intermediate Confounding, and Mediation Analysis in Life Course Epidemiology: An Analytic Framework with Empirical Example

    PubMed Central

    Sheikh, Mashhood A.; Abelsen, Birgit; Olsen, Jan Abel

    2016-01-01

    The mechanisms by which childhood socioeconomic status (CSES) affects adult mental health, general health, and well-being are not clear. Moreover, the analytical assumptions employed when assessing mediation in social and psychiatric epidemiology are rarely explained. The aim of this paper was to explain the intermediate confounding assumption, and to quantify differential recall bias in the association between CSES, childhood abuse, and mental health (SCL-10), general health (EQ-5D), and subjective well-being (SWLS). Furthermore, we assessed the mediating role of psychological and physical abuse in the association between CSES and mental health, general health, and well-being; and the influence of differential recall bias in the estimation of total effects, direct effects, and proportion of mediated effects. The assumptions employed when assessing mediation are explained with reference to a causal diagram. Poisson regression models (relative risk, RR and 99% CIs) were used to assess the association between CSES and psychological and physical abuse in childhood. Mediation analysis (difference method) was used to assess the indirect effect of CSES (through psychological and physical abuse in childhood) on mental health, general health, and well-being. Exposure (CSES) was measured at two time points. Mediation was assessed with both cross-sectional and longitudinal data. Psychological abuse and physical abuse mediated the association between CSES and adult mental health, general health, and well-being (6–16% among men and 7–14% among women, p < 0.001). The results suggest that up to 27% of the association between CSES and childhood abuse, 23% of the association between childhood abuse, and adult mental health, general health, and well-being, and 44% of the association between CSES and adult mental health, general health, and well-being is driven by differential recall bias. Assessing mediation with cross-sectional data (exposure, mediator, and outcome measured at

  3. Confounders in the assessment of the renal effects associated with low-level urinary cadmium: an analysis in industrial workers

    PubMed Central

    2011-01-01

    Background Associations of proteinuria with low-level urinary cadmium (Cd) are currently interpreted as the sign of renal dysfunction induced by Cd. Few studies have considered the possibility that these associations might be non causal and arise from confounding by factors influencing the renal excretion of Cd and proteins. Methods We examined 184 healthy male workers (mean age, 39.5 years) from a zinc smelter (n = 132) or a blanket factory (n = 52). We measured the concentrations of Cd in blood (B-Cd) and the urinary excretion of Cd (U-Cd), retinol-binding protein (RBP), protein HC and albumin. Associations between biomarkers of metal exposure and urinary proteins were assessed by simple and multiple regression analyses. Results The medians (interquartile range) of B-Cd (μg/l) and U-Cd (μg/g creatinine) were 0.80 (0.45-1.16) and 0.70 (0.40-1.3) in smelter workers and 0.66 (0.47-0.87) and 0.55 (0.40-0.90) in blanket factory workers, respectively. Occupation had no influence on these values, which varied mainly with smoking habits. In univariate analysis, concentrations of RBP and protein HC in urine were significantly correlated with both U-Cd and B-Cd but these associations were substantially weakened by the adjustment for current smoking and the residual influence of diuresis after correction for urinary creatinine. Albumin in urine did not correlate with B-Cd but was consistently associated with U-Cd through a relationship, which was unaffected by smoking or diuresis. Further analyses showed that RBP and albumin in urine mutually distort their associations with U-Cd and that the relationship between RBP and Cd in urine was almost the replicate of that linking RBP to albumin Conclusions Associations between proteinuria and low-level urinary Cd should be interpreted with caution as they appear to be largely driven by diuresis, current smoking and probably also the co-excretion of Cd with plasma proteins. PMID:21569589

  4. Biochemical assessment of acute myocardial ischaemia.

    PubMed Central

    Perez-Cárceles, M D; Osuna, E; Vieira, D N; Martínez, A; Luna, A

    1995-01-01

    AIMS--To evaluate the efficacy of biochemical parameters in different fluids in the diagnosis of myocardial infarction of different causes, analysed after death. METHODS--The myoglobin concentration and total creatine kinase (CK) and creatine kinase MB isoenzyme (CK-MB) activities were measured in serum, pericardial fluid, and vitreous humour from seven diagnostic groups of cadavers classified according to the severity of myocardial ischaemia and cause of death. Lactate dehydrogenase (LDH) and myosin were measured only in serum and pericardial fluid, and cathepsin D only in pericardial fluid. Routine haematoxylin and eosin and acridine orange staining were used for microscopy studies of heart tissue. RESULTS--In pericardial fluid there were substantial differences between the different groups with respect to CK, CK-MB, and LDH activities and myosin concentrations. The highest values were found in cases with morphological evidence of myocardial ischaemia. CONCLUSIONS--Biochemical parameters, which reach the pericardial fluid via passive diffusion and ultrafiltration due to a pressure gradient, were thus detectable in this fluid earlier than in serum in cases with myocardial ischaemia. These biochemical parameters may be of use for ruling out myocardial ischaemia in those controversial cases in which reliable morphological findings are lacking. PMID:7745110

  5. Electronic modulation of biochemical signal generation

    NASA Astrophysics Data System (ADS)

    Gordonov, Tanya; Kim, Eunkyoung; Cheng, Yi; Ben-Yoav, Hadar; Ghodssi, Reza; Rubloff, Gary; Yin, Jun-Jie; Payne, Gregory F.; Bentley, William E.

    2014-08-01

    Microelectronic devices that contain biological components are typically used to interrogate biology rather than control biological function. Patterned assemblies of proteins and cells have, however, been used for in vitro metabolic engineering, where coordinated biochemical pathways allow cell metabolism to be characterized and potentially controlled on a chip. Such devices form part of technologies that attempt to recreate animal and human physiological functions on a chip and could be used to revolutionize drug development. These ambitious goals will, however, require new biofabrication methodologies that help connect microelectronics and biological systems and yield new approaches to device assembly and communication. Here, we report the electrically mediated assembly, interrogation and control of a multi-domain fusion protein that produces a bacterial signalling molecule. The biological system can be electrically tuned using a natural redox molecule, and its biochemical response is shown to provide the signalling cues to drive bacterial population behaviour. We show that the biochemical output of the system correlates with the electrical input charge, which suggests that electrical inputs could be used to control complex on-chip biological processes.

  6. Hydrogel-based piezoresistive biochemical microsensors

    NASA Astrophysics Data System (ADS)

    Guenther, Margarita; Schulz, Volker; Gerlach, Gerald; Wallmersperger, Thomas; Solzbacher, Florian; Magda, Jules J.; Tathireddy, Prashant; Lin, Genyao; Orthner, Michael P.

    2010-04-01

    This work is motivated by a demand for inexpensive, robust and reliable biochemical sensors with high signal reproducibility and long-term-stable sensitivity, especially for medical applications. Micro-fabricated sensors can provide continuous monitoring and on-line control of analyte concentrations in ambient aqueous solutions. The piezoresistive biochemical sensor containing a special biocompatible polymer (hydrogel) with a sharp volume phase transition in the neutral physiological pH range near 7.4 can detect a specific analyte, for example glucose. Thereby the hydrogel-based biochemical sensors are useful for the diagnosis and monitoring of diabetes. The response of the glucosesensitive hydrogel was studied at different regimes of the glucose concentration change and of the solution supply. Sensor response time and accuracy with which a sensor can track gradual changes in glucose was estimated. Additionally, the influence of various recommended sterilization methods on the gel swelling properties and on the mechano-electrical transducer of the pH-sensors has been evaluated in order to choose the most optimal sterilization method for the implantable sensors. It has been shown that there is no negative effect of gamma irradiation with a dose of 25.7 kGy on the hydrogel sensitivity. In order to achieve an optimum between sensor signal amplitude and sensor response time, corresponding calibration and measurement procedures have been proposed and evaluated for the chemical sensors.

  7. Controllability of non-linear biochemical systems.

    PubMed

    Ervadi-Radhakrishnan, Anandhi; Voit, Eberhard O

    2005-07-01

    Mathematical methods of biochemical pathway analysis are rapidly maturing to a point where it is possible to provide objective rationale for the natural design of metabolic systems and where it is becoming feasible to manipulate these systems based on model predictions, for instance, with the goal of optimizing the yield of a desired microbial product. So far, theory-based metabolic optimization techniques have mostly been applied to steady-state conditions or the minimization of transition time, using either linear stoichiometric models or fully kinetic models within biochemical systems theory (BST). This article addresses the related problem of controllability, where the task is to steer a non-linear biochemical system, within a given time period, from an initial state to some target state, which may or may not be a steady state. For this purpose, BST models in S-system form are transformed into affine non-linear control systems, which are subjected to an exact feedback linearization that permits controllability through independent variables. The method is exemplified with a small glycolytic-glycogenolytic pathway that had been analyzed previously by several other authors in different contexts.

  8. Cytokines as biochemical markers for knee osteoarthritis

    PubMed Central

    Mabey, Thomas; Honsawek, Sittisak

    2015-01-01

    Osteoarthritis (OA) is a debilitating degenerative joint disease particularly affecting weightbearing joints within the body, principally the hips and knees. Current radiographic techniques are insufficient to show biochemical changes within joint tissue which can occur many years before symptoms become apparent. The need for better diagnostic and prognostic tools is heightened with the prevalence of OA set to increase in aging and obese populations. As inflammation is increasingly being considered an important part of OAs pathophysiology, cytokines are being assessed as possible candidates for biochemical markers. Cytokines, both pro- and anti-inflammatory, as well as angiogenic and chemotactic, have in recent years been studied for relevant characteristics. Biochemical markers show promise in determination of the severity of disease in addition to monitoring of the efficacy and safety of disease-modifying OA drugs, with the potential to act as diagnostic and prognostic tools. Currently, the diagnostic power of interleukin (IL)-6 and the relationship to disease burden of IL-1β, IL-15, tumor necrosis factor-α, and vascular endothelial growth factor make these the best candidates for assessment. Grouping appropriate cytokine markers together and assessing them collectively alongside other bone and cartilage degradation products will yield a more statistically powerful tool in research and clinical applications, and additionally aid in distinguishing between OA and a number of other diseases in which cytokines are known to have an involvement. Further large scale studies are needed to assess the validity and efficacy of current biomarkers, and to discover other potential biomarker candidates. PMID:25621214

  9. [Basic biochemical processes in glaucoma progression].

    PubMed

    von Thun und Hohenstein-Blaul, N; Kunst, S; Pfeiffer, N; Grus, F H

    2015-05-01

    The term glaucoma summarizes a group of eye diseases that are accompanied by impairments of the optic nerve and related visual field deficits. An early diagnosis of glaucoma is currently not possible due to a lack of diagnostic tests; therefore, in most cases the disease is diagnosed many years after onset, which prevents an early therapy. The known risk factors for the development and progression of glaucomatous optic neuropathy comprise elevated intraocular pressure and a broad range of pressure fluctuations as well as lipometabolic disorders, genetic factor and diabetes. The consequences include the induction of anti-inflammatory proteins, elevated levels of oxidative stress and the destruction of retinal ganglion cells. Changes in the autoantibody repertoire have also been observed in the course of the disease. Basic ophthalmological research therefore focuses on the investigation of basic biochemical processes in the course of the disease. A better understanding of physiological and biochemical events is sought in order to develop new and more sensitive diagnostic options and to allow more targeted therapeutic measures. The understanding of biochemical processes allows a better insight into glaucoma progression to be gained, which will lead to improvements in diagnosis and therapy.

  10. Explorations into Chemical Reactions and Biochemical Pathways.

    PubMed

    Gasteiger, Johann

    2016-12-01

    A brief overview of the work in the research group of the present author on extracting knowledge from chemical reaction data is presented. Methods have been developed to calculate physicochemical effects at the reaction site. It is shown that these physicochemical effects can quite favourably be used to derive equations for the calculation of data on gas phase reactions and on reactions in solution such as aqueous acidity of alcohols or carboxylic acids or the hydrolysis of amides. Furthermore, it is shown that these physicochemical effects are quite effective for assigning reactions into reaction classes that correspond to chemical knowledge. Biochemical reactions constitute a particularly interesting and challenging task for increasing our understanding of living species. The BioPath.Database is a rich source of information on biochemical reactions and has been used for a variety of applications of chemical, biological, or medicinal interests. Thus, it was shown that biochemical reactions can be assigned by the physicochemical effects into classes that correspond to the classification of enzymes by the EC numbers. Furthermore, 3D models of reaction intermediates can be used for searching for novel enzyme inhibitors. It was shown in a combined application of chemoinformatics and bioinformatics that essential pathways of diseases can be uncovered. Furthermore, a study showed that bacterial flavor-forming pathways can be discovered.

  11. Stoichiometric network theory for nonequilibrium biochemical systems.

    PubMed

    Qian, Hong; Beard, Daniel A; Liang, Shou-dan

    2003-02-01

    We introduce the basic concepts and develop a theory for nonequilibrium steady-state biochemical systems applicable to analyzing large-scale complex isothermal reaction networks. In terms of the stoichiometric matrix, we demonstrate both Kirchhoff's flux law sigma(l)J(l)=0 over a biochemical species, and potential law sigma(l) mu(l)=0 over a reaction loop. They reflect mass and energy conservation, respectively. For each reaction, its steady-state flux J can be decomposed into forward and backward one-way fluxes J = J+ - J-, with chemical potential difference deltamu = RT ln(J-/J+). The product -Jdeltamu gives the isothermal heat dissipation rate, which is necessarily non-negative according to the second law of thermodynamics. The stoichiometric network theory (SNT) embodies all of the relevant fundamental physics. Knowing J and deltamu of a biochemical reaction, a conductance can be computed which directly reflects the level of gene expression for the particular enzyme. For sufficiently small flux a linear relationship between J and deltamu can be established as the linear flux-force relation in irreversible thermodynamics, analogous to Ohm's law in electrical circuits.

  12. Genetic and Biochemical Biomarkers in Canine Glaucoma.

    PubMed

    Graham, K L; McCowan, C; White, A

    2017-03-01

    In many health-related fields, there is great interest in the identification of biomarkers that distinguish diseased from healthy individuals. In addition to identifying the diseased state, biomarkers have potential use in predicting disease risk, monitoring disease progression, evaluating treatment efficacy, and informing pathogenesis. This review details the genetic and biochemical markers associated with canine primary glaucoma. While there are numerous molecular markers (biochemical and genetic) associated with glaucoma in dogs, there is no ideal biomarker that allows early diagnosis and/or identification of disease progression. Genetic mutations associated with canine glaucoma include those affecting ADAMTS10, ADAMTS17, Myocilin, Nebulin, COL1A2, RAB22A, and SRBD1. With the exception of Myocilin, there is very limited crossover in genetic biomarkers identified between human and canine glaucomas. Mutations associated with canine glaucoma vary between and within canine breeds, and gene discoveries therefore have limited overall effects as a screening tool in the general canine population. Biochemical markers of glaucoma include indicators of inflammation, oxidative stress, serum autoantibodies, matrix metalloproteinases, tumor necrosis factor-α, and transforming growth factor-β. These markers include those that indicate an adaptive or protective response, as well as those that reflect the damage arising from oxidative stress.

  13. The Use of Item Analysis for Improvement of Biochemical Teaching

    ERIC Educational Resources Information Center

    Nagata, Ryoichi

    2004-01-01

    Item analysis was used to find out which biochemical explanations need to be improved in biochemical teaching, not which items are to be discarded, improved, or reusable in biochemical examinations. The analysis revealed the basic facts of which less able students had more misunderstanding than able students. Identifying these basic facts helps…

  14. Estimating the monetary value of willingness to pay for E-book reader's attributes using partially confounded factorial conjoint choice experiment

    NASA Astrophysics Data System (ADS)

    Yong, Chin-Khian

    2013-09-01

    A partially confounded factorial conjoint choice experiments design was used to examine the monetary value of the willingness to pay for E-book Reader's attributes. Conjoint analysis is an efficient, cost-effective, and most widely used quantitative method in marketing research to understand consumer preferences and value trade-off. Value can be interpreted by customer or consumer as the received of multiple benefits from a price that was paid. The monetary value of willingness to pay for battery life, internal memory, external memory, screen size, text to Speech, touch screen, and converting handwriting to digital text of E-book reader were estimated in this study. Due to the significant interaction effect of the attributes with the price, the monetary values for the seven attributes were found to be different at different values of odds of purchasing versus not purchasing. The significant interactions effects were one of the main contribution of the partially confounded factorial conjoint choice experiment.

  15. Is the relation between ozone and mortality confounded by chemical components of particulate matter? Analysis of 7 components in 57 US communities.

    PubMed

    Anderson, G Brooke; Krall, Jenna R; Peng, Roger D; Bell, Michelle L

    2012-10-15

    Epidemiologic studies have linked tropospheric ozone pollution and human mortality. Although research has shown that this relation is not confounded by particulate matter when measured by mass, little scientific evidence exists on whether confounding exists by chemical components of the particle mixture. Using mortality and particulate matter with aerodynamic diameter ≤2.5 µm (PM(2.5)) component data from 57 US communities (2000-2005), the authors investigate whether the ozone-mortality relation is confounded by 7 components of PM(2.5): sulfate, nitrate, silicon, elemental carbon, organic carbon matter, sodium ion, and ammonium. Together, these components constitute most PM(2.5) mass in the United States. Estimates of the effect of ozone on mortality were almost identical before and after controlling for the 7 components of PM(2.5) considered (mortality increase/10-ppb ozone increase, before and after controlling: ammonium, 0.34% vs. 0.35%; elemental carbon, 0.36% vs. 0.37%; nitrate, 0.27% vs. 0.26%; organic carbon matter, 0.34% vs. 0.31%; silicon, 0.36% vs. 0.37%; sodium ion, 0.21% vs. 0.18%; and sulfate, 0.35% vs. 0.38%). Additionally, correlations were weak between ozone and each particulate component across all communities. Previous research found that the ozone-mortality relation is not confounded by particulate matter measured by mass; this national study indicates that the relation is also robust to control for specific components of PM(2.5).

  16. Confounding factors to predict the awakening effect-site concentration of propofol in target-controlled infusion based on propofol and fentanyl anesthesia.

    PubMed

    Chan, Shun-Ming; Lee, Meei-Shyuan; Lu, Chueng-He; Cherng, Chen-Hwan; Huang, Yuan-Shiou; Yeh, Chun-Chang; Kuo, Chan-Yang; Wu, Zhi-Fu

    2015-01-01

    We conducted a large retrospective study to investigate the confounding factors that predict Ce ROC under propofol-based TIVA with TCI. We recorded sex, age, height, weight, Ce LOC, Ce ROC, total propofol and fentanyl consumption dose, and anesthetic time. Simple linear regression models were used to identify potential predictors of Ce ROC, and multiple linear regression models were used to identify the confounding predictors of Ce ROC. We found that Ce ROC correlated with age, sex, Ce LOC, and both total fentanyl and propofol consumption dose. The prediction formula was: Ce ROC = 0.87 - 0.06 × age + 0.18 × Ce LOC + 0.04 (if fentanyl consumption > 150 μg; if not, ignore this value) + 0.07 × (1 or 2, according to the total propofol consumption dose, 1 for a propofol amount 1000-2000 mg and 2 for a propofol amount > 2000 mg). We simplified the formula further as Ce ROC = 0.87 - 0.06 × age + 0.18 × Ce LOC. In conclusion, Ce ROC can be predicted under TCI with propofol- and fentanyl-based TIVA. The confounding factors that predicted propofol Ce ROC are age, sex, Ce LOC, and total consumption dose of propofol and fentanyl.

  17. [COMPUTER TECHNOLOGY FOR ACCOUNTING OF CONFOUNDERS IN THE RISK ASSESSMENT IN COMPARATIVE STUDIES ON THE BASE OF THE METHOD OF STANDARDIZATION].

    PubMed

    Shalaumova, Yu V; Varaksin, A N; Panov, V G

    2016-01-01

    There was performed an analysis of the accounting of the impact of concomitant variables (confounders), introducing a systematic error in the assessment of the impact of risk factors on the resulting variable. The analysis showed that standardization is an effective method for the reduction of the shift of risk assessment. In the work there is suggested an algorithm implementing the method of standardization based on stratification, providing for the minimization of the difference of distributions of confounders in groups on risk factors. To automate the standardization procedures there was developed a software available on the website of the Institute of Industrial Ecology, UB RAS. With the help of the developed software by numerically modeling there were determined conditions of the applicability of the method of standardization on the basis of stratification for the case of the normal distribution on the response and confounder and linear relationship between them. Comparison ofresults obtained with the help of the standardization with statistical methods (logistic regression and analysis of covariance) in solving the problem of human ecology, has shown that obtaining close results is possible if there will be met exactly conditions for the applicability of statistical methods. Standardization is less sensitive to violations of conditions of applicability.

  18. Propensity Score-Based Approaches to Confounding by Indication in Individual Patient Data Meta-Analysis: Non-Standardized Treatment for Multidrug Resistant Tuberculosis

    PubMed Central

    Fox, Gregory J.; Benedetti, Andrea; Mitnick, Carole D.; Pai, Madhukar; Menzies, Dick

    2016-01-01

    Background In the absence of randomized clinical trials, meta-analysis of individual patient data (IPD) from observational studies may provide the most accurate effect estimates for an intervention. However, confounding by indication remains an important concern that can be addressed by incorporating individual patient covariates in different ways. We compared different analytic approaches to account for confounding in IPD from patients treated for multi-drug resistant tuberculosis (MDR-TB). Methods Two antibiotic classes were evaluated, fluoroquinolones—considered the cornerstone of effective MDR-TB treatment—and macrolides, which are known to be safe, yet are ineffective in vitro. The primary outcome was treatment success against treatment failure, relapse or death. Effect estimates were obtained using multivariable and propensity-score based approaches. Results Fluoroquinolone antibiotics were used in 28 included studies, within which 6,612 patients received a fluoroquinolone and 723 patients did not. Macrolides were used in 15 included studies, within which 459 patients received this class of antibiotics and 3,670 did not. Both standard multivariable regression and propensity score-based methods resulted in similar effect estimates for early and late generation fluoroquinolones, while macrolide antibiotics use was associated with reduced treatment success. Conclusions In this individual patient data meta-analysis, standard multivariable and propensity-score based methods of adjusting for individual patient covariates for observational studies yielded produced similar effect estimates. Even when adjustment is made for potential confounding, interpretation of adjusted estimates must still consider the potential for residual bias. PMID:27022741

  19. Annual survival estimation of migratory songbirds confounded by incomplete breeding site-fidelity: Study designs that may help

    USGS Publications Warehouse

    Marshall, M.R.; Diefenbach, D.R.; Wood, L.A.; Cooper, R.J.

    2004-01-01

    Many species of bird exhibit varying degrees of site-fidelity to the previous year's territory or breeding area, a phenomenon we refer to as incomplete breeding site-fidelity. If the territory they occupy is located beyond the bounds of the study area or search area (i.e., they have emigrated from the study area), the bird will go undetected and is therefore indistinguishable from dead individuals in capture-mark-recapture studies. Differential emigration rates confound inferences regarding differences in survival between sexes and among species if apparent survival rates are used as estimates of true survival. Moreover, the bias introduced by using apparent survival rates for true survival rates can have profound effects on the predictions of population persistence through time, source/sink dynamics, and other aspects of life-history theory. We investigated four study design and analysis approaches that result in apparent survival estimates that are closer to true survival estimates. Our motivation for this research stemmed from a multi-year capture-recapture study of Prothonotary Warblers (Protonotaria citrea) on multiple study plots within a larger landscape of suitable breeding habitat where substantial inter-annual movements of marked individuals among neighboring study plots was documented. We wished to quantify the effects of this type of movement on annual survival estimation. The first two study designs we investigated involved marking birds in a core area and resighting them in the core as well as an area surrounding the core. For the first of these two designs, we demonstrated that as the resighting area surrounding the core gets progressively larger, and more "emigrants" are resighted, apparent survival estimates begin to approximate true survival rates (bias < 0.01). However, given observed inter-annual movements of birds, it is likely to be logistically impractical to resight birds on sufficiently large surrounding areas to minimize bias. Therefore

  20. Mechanisms of Ovarian Cancer Metastasis: Biochemical Pathways

    PubMed Central

    Nakayama, Kentaro; Nakayama, Naomi; Katagiri, Hiroshi; Miyazaki, Kohji

    2012-01-01

    Ovarian cancer is the most lethal gynecologic malignancy. Despite advances in chemotherapy, the five-year survival rate of advanced ovarian cancer patients with peritoneal metastasis remains around 30%. The most significant prognostic factor is stage, and most patients present at an advanced stage with peritoneal dissemination. There is often no clearly identifiable precursor lesion; therefore, the events leading to metastatic disease are poorly understood. This article reviews metastatic suppressor genes, the epithelial-mesenchymal transition (EMT), and the tumor microenvironment as they relate to ovarian cancer metastasis. Additionally, novel chemotherapeutic agents targeting the metastasis-related biochemical pathways are discussed. PMID:23109879

  1. Sampling rare switching events in biochemical networks.

    PubMed

    Allen, Rosalind J; Warren, Patrick B; Ten Wolde, Pieter Rein

    2005-01-14

    Bistable biochemical switches are widely found in gene regulatory networks and signal transduction pathways. Their switching dynamics are difficult to study, however, because switching events are rare, and the systems are out of equilibrium. We present a simulation method for predicting the rate and mechanism of the flipping of these switches. We apply it to a genetic switch and find that it is highly efficient. The path ensembles for the forward and reverse processes do not coincide. The method is widely applicable to rare events and nonequilibrium processes.

  2. [Chronic fatigue syndrome: biochemical examination of blood].

    PubMed

    Hakariya, Yukiko; Kuratsune, Hirohiko

    2007-06-01

    Though patients with chronic fatigue syndrome (CFS) have lots of complaints, abnormal findings cannot be detected by biochemical screening tests. However, some specialized blood tests have revealed neuroendocrine immune axis abnormalities, which is closely associated with each other. Recent studies indicate that CFS can be understood as a special condition based on abnormality of the psycho-neuro-endocrino-immunological system, with the distinguishing feature of CFS seeming to be the secondary brain dysfunction caused by several cytokines and/or autoantibodies. In this paper, we summarize these abnormalities found in CFS and show the neuro-molecular mechanism leading to chronic fatigue.

  3. Azoospermia: clinical, hormonal, and biochemical investigation.

    PubMed

    Papadimas, J; Papadopoulou, F; Ioannidis, S; Spanos, E; Tarlatzis, B; Bontis, J; Mantalenakis, S

    1996-01-01

    The aim of this study was to evaluate the clinical, hormonal and biochemical characteristics of infertile men with azoospermia. A total of 187 azoospermic out of 2610 infertile men (7.2%) were studied. Mean testicular volume and basal plasma levels of FSH were the most useful parameters concerning the evaluation of azoospermia. Basal plasma levels of LH and T were useful only in azoospermic men with hypogonadism, whereas plasma PRL levels, semen volume, and seminal plasma fructose levels were not found to be of common use except in selected cases.

  4. Biochemical Disincentives to Fertilizing Cellulosic Ethanol Crops

    NASA Astrophysics Data System (ADS)

    Gallagher, M. E.; Hockaday, W. C.; Snapp, S.; McSwiney, C.; Baldock, J.

    2010-12-01

    Corn grain biofuel crops produce the highest yields when the cropping ecosystem is not nitrogen (N)-limited, achieved by application of fertilizer. There are environmental consequences for excessive fertilizer application to crops, including greenhouse gas emissions, hypoxic “dead zones,” and health problems from N runoff into groundwater. The increase in corn acreage in response to demand for alternative fuels (i.e. ethanol) could exacerbate these problems, and divert food supplies to fuel production. A potential substitute for grain ethanol that could reduce some of these impacts is cellulosic ethanol. Cellulosic ethanol feedstocks include grasses (switchgrass), hardwoods, and crop residues (e.g. corn stover, wheat straw). It has been assumed that these feedstocks will require similar N fertilization rates to grain biofuel crops to maximize yields, but carbohydrate yield versus N application has not previously been monitored. We report the biochemical stocks (carbohydrate, protein, and lignin in Mg ha-1) of a corn ecosystem grown under varying N levels. We measured biochemical yield in Mg ha-1 within the grain, leaf and stem, and reproductive parts of corn plants grown at seven N fertilization rates (0-202 kg N ha-1), to evaluate the quantity and quality of these feedstocks across a N fertilization gradient. The N fertilization rate study was performed at the Kellogg Biological Station-Long Term Ecological Research Site (KBS-LTER) in Michigan. Biochemical stocks were measured using 13C nuclear magnetic resonance spectroscopy (NMR), combined with a molecular mixing model (Baldock et al. 2004). Carbohydrate and lignin are the main biochemicals of interest in ethanol production since carbohydrate is the ethanol feedstock, and lignin hinders the carbohydrate to ethanol conversion process. We show that corn residue carbohydrate yields respond only weakly to N fertilization compared to grain. Grain carbohydrate yields plateau in response to fertilization at

  5. Physiological and biochemical changes with Vamana procedure

    PubMed Central

    Gupta, Bharti; Mahapatra, Sushil C.; Makhija, Renu; Kumar, Adarsh; Jirankalgikar, Nikhil M.; Padhi, Madan M.; Devalla, Ramesh Babu

    2012-01-01

    Vamana Karma (therapeutic emesis) primarily a Samshodhana Karma (purification procedure) is one of the five Pradhana Karmas (chief procedures) of Panchakarma. It is mentioned in Ayurvedic texts that a person after Samyak Vamana (proper Vamana) experiences lightness of the body, Hrit (precordium), Kantha (throat/voice), and Shirah (head) and weakness. This procedure is effectively used in healthy and ailing persons for purification of body and extraction of Doshas (especially Kapha) in Ayurvedic system. It has been found worth to observe the physiological and biochemical changes during Vamana and after the procedure to understand the effect/safety margins of the procedure in healthy volunteers. PMID:23723640

  6. [Optical detection system for micro biochemical analyses].

    PubMed

    Li, Feng; Wu, Yi-hui; Zhao, Hua-bing; Ju, Hui

    2005-04-01

    For the need of biochemical chip, which consumes fewer specimens and is easy to integrate with micro-fluid chip, two kinds of spectrophotometric analysis methods are described in the present paper. Both the direct detection method and evanescent wave detection method are used in the experiments with visible light (460-800 nm). The experimental results proved that the direct detection is simple and evident; on the other hand the evanescent wave detection method consumes much less reagent and is easy to integrate with microchips.

  7. Biochemical responses of the Skylab crewman

    NASA Technical Reports Server (NTRS)

    Leach, C. S.; Rambaut, P. C.

    1974-01-01

    The biochemical investigations of the Skylab crewmen were designed to study the physiological changes that were observed on flight crews returning from previous space flight missions as well as to study those changes expected to result from prolonged weightless exposure. These studies can be divided into two broad categories. One category included routine blood studies similar to those used in clinical medical practice. The second included research-type endocrine analyses used to investigate more thoroughly the metabolic/endocrine responses to the space flight environment. The premission control values indicated that all Skylab crewmen were healthy and were free from biochemical abnormalities. The routine results during and after flight showed slight but significant changes in electrolytes, glucose, total protein, osmolality, uric acid, cholesterol, and creatinine. Plasma hormal changes included adrenocorticotrophic hormone, cortisol, angiotensin I, aldosterone, insulin, and thyroxine. The 24-hour urine analyses results revealed increased excretion of cortisol, catecholamines, antidiuretic hormone, and aldosterone as well as excretion of significant electrolyte and uric acid during the Skylab flights.

  8. [Biochemical principles of early saturnism recognition].

    PubMed

    Tsimakuridze, M P; Mansuradze, E A; Zurashvili, D G; Tsimakuridze, M P

    2009-03-01

    The aim of the work is to determine the major sensitive criteria of biochemical indicators that allow timely discovery of negative influence of lead on organism and assist in early diagnosis of primary stages of saturnism. The workers of Georgian typographies, performing technological processes of letterpress printing were observed. Professional groups having contact with lead aerosols (main group of 66 people) and the workers of the same typography not being in touch with the poison (control group of 24 people) were studied. It was distinguished that, protracted professional contact with lead causes moderate increase of lead, coproporphyrin and DALA in daily urine in most cases; it is more clearly evidenced in the professional groups of lead smelters and lino operators and less clearly among typesetter and printers. Upon the checkup of people, having a direct contact with lead, biochemical analysis of urine should be given a preference, especially the determination of quantitative content of lead and coproporphyrin in urine with the aim of revealing the lead carrier, which is one of the first signals for occupational lookout and medical monitoring of the similar contingent.

  9. Pheochromocytoma-paraganglioma: Biochemical and genetic diagnosis.

    PubMed

    Cano Megías, Marta; Rodriguez Puyol, Diego; Fernández Rodríguez, Loreto; Sención Martinez, Gloria Lisette; Martínez Miguel, Patricia

    Pheochromocytomas and paragangliomas are tumours derived from neural crest cells, which can be diagnosed by biochemical measurement of metanephrine and methoxytyramine. Advances in genetic research have identified many genes involved in the pathogenesis of these tumours, suggesting that up to 35-45% may have an underlying germline mutation. These genes have a singular transcriptional signature and can be grouped into 2 clusters (or groups): cluster 1 (VHL and SHDx), involved in angiogenesis and hypoxia pathways; and cluster 2 (MEN2 and NF1), linked to the kinase signalling pathway. In turn, these genes are associated with a characteristic biochemical phenotype (noradrenergic and adrenergic), and clinical features (location, biological behaviour, age of presentation, etc.) in a large number of cases. Early diagnosis of these tumours, accompanied by a correct genetic diagnosis, should eventually become a priority to enable better treatment, early detection of complications, proper screening of family members and related tumours, as well as an improvement in the overall prognosis of these patients.

  10. Biochemical effects of oral sodium phosphate.

    PubMed

    DiPalma, J A; Buckley, S E; Warner, B A; Culpepper, R M

    1996-04-01

    Our objective was to monitor serum and urine biochemical changes after oral sodium phosphate cleansing in a prospectively designed study. The study subjects were seven healthy, asymptomatic adults. Sodium phosphate 45 ml diluted in 45 ml water was given orally at baseline and 12 hr later. Calcium, ionized calcium, phosphorus, sodium, potassium, creatinine, and PTH were analyzed at 2, 4, 6, 9, 12, 14, 16, 18, 21 and 24 hr after the first challenge. Urinary calcium, phosphorus, sodium, potassium, and cyclic AMP were analyzed at baseline and every 2 hr after oral sodium phosphate. Blood pressure, pulse, and respiratory rate were recorded every 2 hr and symptom questionnaires using visual analog scales were completed. A marked rise in phosphorus (peak range 3.6-12.4 mg/dl, P < 0.001) and falls in calcium (P < 0.001) and ionized calcium (P < 0.001) were seen. Rises seen in PTH and urinary cAMP confirmed the physiologic significance of the biochemical effect. There were no significant changes in other serum and urine laboratory or clinical assessments. Reported significant symptoms included bloating, cramps, abdominal pain, and nausea. Significant hypocalcemia and hyperphosphatemia after oral sodium phosphate raises concern about its use in normal individuals. Oral sodium phosphate should not be administered in patients with cardiopulmonary, renal, or hepatic disease.

  11. Biochemical basis for the biological clock

    NASA Technical Reports Server (NTRS)

    Morre, D. James; Chueh, Pin-Ju; Pletcher, Jake; Tang, Xiaoyu; Wu, Lian-Ying; Morre, Dorothy M.

    2002-01-01

    NADH oxidases at the external surface of plant and animal cells (ECTO-NOX proteins) exhibit stable and recurring patterns of oscillations with potentially clock-related, entrainable, and temperature-compensated period lengths of 24 min. To determine if ECTO-NOX proteins might represent the ultradian time keepers (pacemakers) of the biological clock, COS cells were transfected with cDNAs encoding tNOX proteins having a period length of 22 min or with C575A or C558A cysteine to alanine replacements having period lengths of 36 or 42 min. Here we demonstrate that such transfectants exhibited 22, 36, or 40 to 42 h circadian patterns in the activity of glyceraldehyde-3-phosphate dehydrogenase, a common clock-regulated protein, in addition to the endogenous 24 h circadian period length. The fact that the expression of a single oscillatory ECTO-NOX protein determines the period length of a circadian biochemical marker (60 X the ECTO-NOX period length) provides compelling evidence that ECTO-NOX proteins are the biochemical ultradian drivers of the cellular biological clock.

  12. Development of histopathological indices in the digestive gland and gonad of mussels: integration with contamination levels and effects of confounding factors.

    PubMed

    Cuevas, Nagore; Zorita, Izaskun; Costa, Pedro M; Franco, Javier; Larreta, Joana

    2015-05-01

    Bivalve histopathology has become an important tool in aquatic toxicology, having been implemented in many biomonitoring programmes worldwide. However, there are various gaps in the knowledge of many sentinel organisms and the interference of confounding factors. This work aimed (i) to develop a detailed semi-quantitative histopathological index of the digestive gland and gonad of the Mytilus galloprovincialis mussel collected from five sites contaminated with distinct patterns of organic and inorganic toxicants along the Basque coast (SE Bay of Biscay) and (ii) to investigate whether seasonal variability and parasitosis act as confounding factors. A total of twenty-three histopathological alterations were analysed in the digestive gland and gonad following a weighed condition index approach. The alterations were integrated into a single value for a better understanding of the mussels' health status. The digestive gland was consistently more damaged than the gonad. Mussels from the most impacted sites endured the most significant deleterious effects showing inflammation-related alterations together with digestive tubule atrophy and necrosis. Neoplastic diseases were scarce, with only a few cases of fibromas (benign neoplasia). In contrast, in moderately or little impacted sites, contamination levels did not cause significant tissue damage. However, parasites contributed to overestimating the values of histopathological indices (i.e. more severe tissue damage) in mussels from little impacted sites, whilst the opposite occurred in mussels from highly polluted sites. Accordingly, inter-site differences were more pronounced in autumn when natural physiological responses of advanced maturation stages did not interfere in the histological response. In conclusion, although seasonal variability and parasitosis mask the response of histopathological indices, this biomonitoring approach may provide good sensitivity for assessing the health status of mussels if fluctuations

  13. Use of Self-Matching to Control for Stable Patient Characteristics While Addressing Time-Varying Confounding on Treatment Effect: A Case Study of Older Intensive Care Patients.

    PubMed

    Han, Ling; Pisani, M A; Araujo, K L B; Allore, Heather G

    Exposure-crossover design offers a non-experimental option to control for stable baseline confounding through self-matching while examining causal effect of an exposure on an acute outcome. This study extends this approach to longitudinal data with repeated measures of exposure and outcome using data from a cohort of 340 older medical patients in an intensive care unit (ICU). The analytic sample included 92 patients who received ≥1 dose of haloperidol, an antipsychotic medication often used for patients with delirium. Exposure-crossover design was implemented by sampling the 3-day time segments prior (Induction) and posterior (Subsequent) to each treatment episode of receiving haloperidol. In the full cohort, there was a trend of increasing delirium severity scores (Mean±SD: 4.4±1.7) over the course of the ICU stay. After exposure-crossover sampling, the delirium severity score decreased from the Induction (4.9) to the Subsequent (4.1) intervals, with the treatment episode falling in-between (4.5). Based on a GEE Poisson model accounting for self-matching and within-subject correlation, the unadjusted mean delirium severity scores was -0.55 (95% CI: -1.10, -0.01) points lower for the Subsequent than the Induction intervals. The association diminished by 32% (-0.38, 95%CI: -0.99, 0.24) after adjusting only for ICU confounding, while being slightly increased by 7% (-0.60, 95%CI: -1.15, -0.04) when adjusting only for baseline characteristics. These results suggest that longitudinal exposure-crossover design is feasible and capable of partially removing stable baseline confounding through self-matching. Loss of power due to eliminating treatment-irrelevant person-time and uncertainty around allocating person-time to comparison intervals remain methodological challenges.

  14. Resolving Confounding Enrichment Kinetics Due to Overlapping Resonance Signals From 13C-Enriched Long Chain Fatty Acid Oxidation and Uptake Within Intact Hearts

    PubMed Central

    O'Donnell, J. Michael; Fasano, Matthew J.; Lewandowski, E. Douglas

    2014-01-01

    Purpose Long chain fatty acid (LCFA) oxidation measurements in the intact heart from 13C-NMR rely on detection of 13C-enriched glutamate. However, progressive increases in overlapping resonance signal from LCFA can confound detection of the glutamate 4-carbon (GLU-C4) signal. We evaluated alternative 13C labeling for exogenous LCFA and developed a simple scheme to distinguish kinetics of LCFA uptake and storage from oxidation. Methods Sequential 13C-NMR spectra were acquired from isolated rat hearts perfused with 13C LCFA and glucose. Spectra were evaluated from hearts supplied: U 13C LCFA, [2,4,6,8,10,12,14,16-13C8] palmitate, [2,4,6,8,10,12,14,16,18-13C9] oleate, [4,6,8,10,12,14,16-13C7] palmitate, or [4,6,8,10,12, 14,16,18-13C8] oleate. Results 13C signal reflected the progressive enrichment at 34.6 ppm from GLU-C4, confounded by additional signal with distinct kinetics attributed to 13C-enriched LCFA 2-carbon (34.0 ppm). Excluding 13C at the 2-carbon of both palmitate and oleate eliminated signal overlap and enabled detection of the exponential enrichment of GLU-C4 for assessing LCFA oxidation. Conclusion Eliminating enrichment at the 2-carbon of 13C LCFA resolved confounding kinetics between GLU-C4 and LCFA 2-carbon signals. With this enrichment scheme, oxidation of LCFA, the primary fuel for cardiac ATP synthesis, can now be more consistently examined in whole organs with dynamic mode, proton-decoupled 13C-NMR. PMID:25199499

  15. Methylenetetrahydrofolate reductase: biochemical characterization and medical significance.

    PubMed

    Trimmer, Elizabeth E

    2013-01-01

    Methylenetetrahydrofolate reductase (MTHFR) catalyzes the reduction of 5,10-methylenetetrahydofolate (CH2-H4folate) to 5-methyltetrahydrofolate (CH3-H4folate). The enzyme employs a noncovalently-bound flavin adenine dinucleotide (FAD), which accepts reducing equivalents from NAD(P)H and transfers them to CH2-H4folate. The reaction provides the sole source of CH3-H4folate, which is utilized by methionine synthase in the synthesis of methionine from homocysteine. MTHFR plays a key role in folate metabolism and in the homeostasis of homocysteine; mutations in the enzyme lead to hyperhomocyst(e)inemia. A common C677T polymorphism in MTHFR has been associated with an increased risk for the development of cardiovascular disease, Alzheimer's disease, and depression in adults, and of neural tube defects in the fetus. The mutation also confers protection for certain types of cancers. This review presents the current knowledge of the enzyme, its biochemical characterization, and medical significance.

  16. Optofluidics in bio-chemical analysis

    NASA Astrophysics Data System (ADS)

    Guo, Yunbo; Fan, Xudong

    2012-01-01

    Optofluidics organically integrates microfluidics and photonics and is an emerging technology in biological and chemical analysis. In this paper, we overview the recent studies in bio-chemical sensing applications of optofluidics. Particularly, we report the research progress in our lab in developing diverse optofluidic devices using two unique configurations: thin-walled capillary based optofluidic ring resonator (OFRR) and multi-hole capillary based optofluidic platforms. The first one has been developed to be OFRR-based label-free biosensor, microfluidic laser based intra-cavity sensors, and on-column optical detectors for micro-gas chromatography (μGC), while the second one has been developed to be optofluidic Fabry-Pérot based label-free biosensor and optofluidic Surface-Enhanced Raman Spectroscopy (SERS) biosensor. All of these devices take advantage of superior fluidic handling capability and high sensitivity, and have been used in detecting various biological and chemical analytes in either liquid or vapor phase.

  17. Droplet microfluidics in (bio)chemical analysis.

    PubMed

    Basova, Evgenia Yu; Foret, Frantisek

    2015-01-07

    Droplet microfluidics may soon change the paradigm of performing chemical analyses and related instrumentation. It can improve not only the analysis scale, possibility for sensitivity improvement, and reduced consumption of chemical and biological reagents, but also the speed of performing a variety of unit operations. At present, microfluidic platforms can reproducibly generate monodisperse droplet populations at kHz or higher rates with droplet sizes suitable for high-throughput experiments, single-cell detection or even single molecule analysis. In addition to being used as microreactors with volume in the micro- to femtoliter range, droplet based systems have also been used to directly synthesize particles and encapsulate biological entities for biomedicine and biotechnology applications. This minireview summarizes various droplet microfluidics operations and applications for (bio)chemical assays described in the literature during the past few years.

  18. Highly valuable microalgae: biochemical and topological aspects.

    PubMed

    Pignolet, Olivier; Jubeau, Sébastien; Vaca-Garcia, Carlos; Michaud, Philippe

    2013-08-01

    The past decade has seen a surge in the interest in microalgae culture for biodiesel production and other applications as renewable biofuels as an alternative to petroleum transport fuels. The development of new technologies for the culture of these photosynthetic microorganisms and improved knowledge of their biochemical composition has spurred innovation in the field of high-value biomolecules. These developments are only economically viable if all the microalgae fractions are valorized in a biorefinery strategy. Achieving this objective requires an understanding of microalgae content and the cellular localization of the main biomolecular families in order to develop efficient harvest and sequential recovery technologies. This review summarizes the state of the art in microalgae compositions and topologies using some examples of the main industrially farmed microalgae.

  19. Thin membrane sensor with biochemical switch

    NASA Technical Reports Server (NTRS)

    Case, George D. (Inventor); Worley, III, Jennings F. (Inventor)

    1994-01-01

    A modular biosensor system for chemical or biological agent detection utilizes electrochemical measurement of an ion current across a gate membrane triggered by the reaction of the target agent with a recognition protein conjugated to a channel blocker. The sensor system includes a bioresponse simulator or biochemical switch module which contains the recognition protein-channel blocker conjugate, and in which the detection reactions occur, and a transducer module which contains a gate membrane and a measuring electrode, and in which the presence of agent is sensed electrically. In the poised state, ion channels in the gate membrane are blocked by the recognition protein-channel blocker conjugate. Detection reactions remove the recognition protein-channel blocker conjugate from the ion channels, thus eliciting an ion current surge in the gate membrane which subsequently triggers an output alarm. Sufficiently large currents are generated that simple direct current electronics are adequate for the measurements. The biosensor has applications for environmental, medical, and industrial use.

  20. The biochemical basis of hereditary fructose intolerance.

    PubMed

    Bouteldja, Nadia; Timson, David J

    2010-04-01

    Hereditary fructose intolerance is a rare, but potentially lethal, inherited disorder of fructose metabolism, caused by mutation of the aldolase B gene. Treatment currently relies solely on dietary restriction of problematic sugars. Biochemical study of defective aldolase B enzymes is key to revealing the molecular basis of the disease and providing a stronger basis for improved treatment and diagnosis. Such studies have revealed changes in enzyme activity, stability and oligomerisation. However, linking these changes to disease phenotypes has not always been straightforward. This review gives a general overview of the features of hereditary fructose intolerance, then concentrates on the biochemistry of the AP variant (Ala149Pro variant of aldolase B) and molecular pathological consequences of mutation of the aldolase B gene.

  1. Hydrophobic hydrophilic phenomena in biochemical processes.

    PubMed

    Ben-Naim, Arieh

    2003-09-01

    The evolution of concepts developed in the study of the hydrophobic affect is surveyed, within the more general context of solvent-induced effects. A systematic analysis of the solvent-induced contribution to the driving force for the process of protein folding has led to two important modifications in our understanding of these effects. First, the conventional concepts of hydrophobic solvation and hydrophobic interactions had to be replaced by their respective conditional effects. Second, each of the hydrophobic effects has also a corresponding hydrophilic counterpart. Some of the latter effects could contribute significantly to the total driving force for the process of protein folding, and perhaps even dominate the driving force for biochemical processes.

  2. 'Bigger data' on scale-dependent effects of invasive species on biodiversity cannot overcome confounded analyses: a comment on Stohlgren & Rejmánek (2014).

    PubMed

    Chase, Jonathan M; Powell, Kristin I; Knight, Tiffany M

    2015-08-01

    A recent study by Stohlgren & Rejmánek (SR: Stohlgren TJ, Rejmánek M. 2014 Biol. Lett. 10. (doi:10.1098/rsbl.2013.0939)) purported to test the generality of a recent finding of scale-dependent effects of invasive plants on native diversity; dominant invasive plants decreased the intercept and increased the slope of the species-area relationship. SR (2014) find little correlation between invasive species cover and the slopes and intercepts of SARs across a diversity of sites. We show that the analyses of SR (2014) are inappropriate because of confounding causality.

  3. Psychological and Biochemical Effects of a Stress Management Program,

    DTIC Science & Technology

    risk factors for cardiovascular disease . We wanted to sample emotional, behavioral, physical and biochemical measures which might be sensitive to the changes of an effective stress management program.

  4. Biochemically enhanced methane production from coal

    NASA Astrophysics Data System (ADS)

    Opara, Aleksandra

    For many years, biogas was connected mostly with the organic matter decomposition in shallow sediments (e.g., wetlands, landfill gas, etc.). Recently, it has been realized that biogenic methane production is ongoing in many hydrocarbon reservoirs. This research examined microbial methane and carbon dioxide generation from coal. As original contributions methane production from various coal materials was examined in classical and electro-biochemical bench-scale reactors using unique, developed facultative microbial consortia that generate methane under anaerobic conditions. Facultative methanogenic populations are important as all known methanogens are strict anaerobes and their application outside laboratory would be problematic. Additional testing examined the influence of environmental conditions, such as pH, salinity, and nutrient amendments on methane and carbon dioxide generation. In 44-day ex-situ bench-scale batch bioreactor tests, up to 300,000 and 250,000 ppm methane was generated from bituminous coal and bituminous coal waste respectively, a significant improvement over 20-40 ppm methane generated from control samples. Chemical degradation of complex hydrocarbons using environmentally benign reagents, prior to microbial biodegradation and methanogenesis, resulted in dissolution of up to 5% bituminous coal and bituminous coal waste and up to 25% lignite in samples tested. Research results confirm that coal waste may be a significant underutilized resource that could be converted to useful fuel. Rapid acidification of lignite samples resulted in low pH (below 4.0), regardless of chemical pretreatment applied, and did not generate significant methane amounts. These results confirmed the importance of monitoring and adjusting in situ and ex situ environmental conditions during methane production. A patented Electro-Biochemical Reactor technology was used to supply electrons and electron acceptor environments, but appeared to influence methane generation in a

  5. Pattern Selection by Dynamical Biochemical Signals

    PubMed Central

    Palau-Ortin, David; Formosa-Jordan, Pau; Sancho, José M.; Ibañes, Marta

    2015-01-01

    The development of multicellular organisms involves cells to decide their fate upon the action of biochemical signals. This decision is often spatiotemporally coordinated such that a spatial pattern arises. The dynamics that drive pattern formation usually involve genetic nonlinear interactions and positive feedback loops. These complex dynamics may enable multiple stable patterns for the same conditions. Under these circumstances, pattern formation in a developing tissue involves a selection process: why is a certain pattern formed and not another stable one? Herein we computationally address this issue in the context of the Notch signaling pathway. We characterize a dynamical mechanism for developmental selection of a specific pattern through spatiotemporal changes of the control parameters of the dynamics, in contrast to commonly studied situations in which initial conditions and noise determine which pattern is selected among multiple stable ones. This mechanism can be understood as a path along the parameter space driven by a sequence of biochemical signals. We characterize the selection process for three different scenarios of this dynamical mechanism that can take place during development: the signal either 1) acts in all the cells at the same time, 2) acts only within a cluster of cells, or 3) propagates along the tissue. We found that key elements for pattern selection are the destabilization of the initial pattern, the subsequent exploration of other patterns determined by the spatiotemporal symmetry of the parameter changes, and the speeds of the path compared to the timescales of the pattern formation process itself. Each scenario enables the selection of different types of patterns and creates these elements in distinct ways, resulting in different features. Our approach extends the concept of selection involved in cellular decision-making, usually applied to cell-autonomous decisions, to systems that collectively make decisions through cell

  6. Do predisposing and family background characteristics modify or confound the relationship between drinking frequency and alcohol-related aggression? A study of late adolescent and young adult drinkers.

    PubMed

    Wells, Samantha; Graham, Kathryn; Speechley, Mark; Koval, John J

    2006-04-01

    The present study examined whether predisposing and family background characteristics confounded (common cause/general deviance theory) or modified (conditional/interactive theory) the association between drinking frequency and alcohol-related aggression. A secondary analysis of the US National Longitudinal Survey of Youth was conducted using a composite sample of drinkers, ages 17 to 21, from the 1994, 1996, and 1998 Young Adult surveys (n=602). No evidence of confounding of the relationship between drinking frequency and alcohol-related aggression was found. In addition, predisposing characteristics did not modify the association between drinking frequency and alcohol-related aggression. However, family background variables (mother's education and any poverty) were important explanatory variables for alcohol-related aggression among males, whereas recent aggression (fights at school or work) was an important predictor for females. Overall, lack of support for the conditional/interactive and common cause theories of the alcohol and aggression relationship suggests that alcohol has an independent explanatory role in alcohol-related aggression. In addition, the gender differences found in the present study highlight the need for more gender-focussed research on predictors of alcohol-related aggression, especially among adolescents and young adults.

  7. fMRI measurements of amygdala activation are confounded by stimulus correlated signal fluctuation in nearby veins draining distant brain regions

    PubMed Central

    Boubela, Roland N.; Kalcher, Klaudius; Huf, Wolfgang; Seidel, Eva-Maria; Derntl, Birgit; Pezawas, Lukas; Našel, Christian; Moser, Ewald

    2015-01-01

    Imaging the amygdala with functional MRI is confounded by multiple averse factors, notably signal dropouts due to magnetic inhomogeneity and low signal-to-noise ratio, making it difficult to obtain consistent activation patterns in this region. However, even when consistent signal changes are identified, they are likely to be due to nearby vessels, most notably the basal vein of rosenthal (BVR). Using an accelerated fMRI sequence with a high temporal resolution (TR = 333 ms) combined with susceptibility-weighted imaging, we show how signal changes in the amygdala region can be related to a venous origin. This finding is confirmed here in both a conventional fMRI dataset (TR = 2000 ms) as well as in information of meta-analyses, implying that “amygdala activations” reported in typical fMRI studies are likely confounded by signals originating in the BVR rather than in the amygdala itself, thus raising concerns about many conclusions on the functioning of the amygdala that rely on fMRI evidence alone. PMID:25994551

  8. A Biochemical Approach to the Problem of Dyslexia.

    ERIC Educational Resources Information Center

    Baker, Sidney McDonald

    1985-01-01

    The paper presents the case of a sixth-grade boy, labeled dyslexic, who responded positively to a biochemical approach. Remedy of iron, zinc, and Vitamin B-6 deficiencies as well as an imbalance of fatty acids resulted in improvements in hair and skin and also in reading. A biochemical approach to behavior problems is proposed. (Author/CL)

  9. Biochemical Education in Thailand: Past, Present, and Future.

    ERIC Educational Resources Information Center

    Svasti, Jisnuson; Surarit, Rudee

    1991-01-01

    Traces the history of Thailand's biochemical education from its initial evolution from medicine to modern day. Discusses the following aspects of Thailand's modern biochemical education: biochemistry teaching at Thai schools, university departments and biochemistry courses, textbooks, degree programs, interplay between research and teaching, and…

  10. Editorial: ESBES - European Society of Biochemical Engineering Sciences.

    PubMed

    Ferreira, Guilherme; Jungbauer, Alois

    2013-06-01

    The latest ESBES special issue on "Biochemical Engineering Sciences" is edited by Prof. Guilherme Ferreira (Chairman, ESBES) and Prof. Alois Jungbauer (co-Editor-in-Chief, Biotechnology Journal). This special issue comprises the latest research in biochemical engineering science presented at the 9(th) ESBES Conference held in Istanbul, Turkey in 2012.

  11. Model-Based Design of Biochemical Microreactors

    PubMed Central

    Elbinger, Tobias; Gahn, Markus; Neuss-Radu, Maria; Hante, Falk M.; Voll, Lars M.; Leugering, Günter; Knabner, Peter

    2016-01-01

    Mathematical modeling of biochemical pathways is an important resource in Synthetic Biology, as the predictive power of simulating synthetic pathways represents an important step in the design of synthetic metabolons. In this paper, we are concerned with the mathematical modeling, simulation, and optimization of metabolic processes in biochemical microreactors able to carry out enzymatic reactions and to exchange metabolites with their surrounding medium. The results of the reported modeling approach are incorporated in the design of the first microreactor prototypes that are under construction. These microreactors consist of compartments separated by membranes carrying specific transporters for the input of substrates and export of products. Inside the compartments of the reactor multienzyme complexes assembled on nano-beads by peptide adapters are used to carry out metabolic reactions. The spatially resolved mathematical model describing the ongoing processes consists of a system of diffusion equations together with boundary and initial conditions. The boundary conditions model the exchange of metabolites with the neighboring compartments and the reactions at the surface of the nano-beads carrying the multienzyme complexes. Efficient and accurate approaches for numerical simulation of the mathematical model and for optimal design of the microreactor are developed. As a proof-of-concept scenario, a synthetic pathway for the conversion of sucrose to glucose-6-phosphate (G6P) was chosen. In this context, the mathematical model is employed to compute the spatio-temporal distributions of the metabolite concentrations, as well as application relevant quantities like the outflow rate of G6P. These computations are performed for different scenarios, where the number of beads as well as their loading capacity are varied. The computed metabolite distributions show spatial patterns, which differ for different experimental arrangements. Furthermore, the total output of G6P

  12. Model-Based Design of Biochemical Microreactors.

    PubMed

    Elbinger, Tobias; Gahn, Markus; Neuss-Radu, Maria; Hante, Falk M; Voll, Lars M; Leugering, Günter; Knabner, Peter

    2016-01-01

    Mathematical modeling of biochemical pathways is an important resource in Synthetic Biology, as the predictive power of simulating synthetic pathways represents an important step in the design of synthetic metabolons. In this paper, we are concerned with the mathematical modeling, simulation, and optimization of metabolic processes in biochemical microreactors able to carry out enzymatic reactions and to exchange metabolites with their surrounding medium. The results of the reported modeling approach are incorporated in the design of the first microreactor prototypes that are under construction. These microreactors consist of compartments separated by membranes carrying specific transporters for the input of substrates and export of products. Inside the compartments of the reactor multienzyme complexes assembled on nano-beads by peptide adapters are used to carry out metabolic reactions. The spatially resolved mathematical model describing the ongoing processes consists of a system of diffusion equations together with boundary and initial conditions. The boundary conditions model the exchange of metabolites with the neighboring compartments and the reactions at the surface of the nano-beads carrying the multienzyme complexes. Efficient and accurate approaches for numerical simulation of the mathematical model and for optimal design of the microreactor are developed. As a proof-of-concept scenario, a synthetic pathway for the conversion of sucrose to glucose-6-phosphate (G6P) was chosen. In this context, the mathematical model is employed to compute the spatio-temporal distributions of the metabolite concentrations, as well as application relevant quantities like the outflow rate of G6P. These computations are performed for different scenarios, where the number of beads as well as their loading capacity are varied. The computed metabolite distributions show spatial patterns, which differ for different experimental arrangements. Furthermore, the total output of G6P

  13. [Biochemical tests for identifying Pasteurella multocida].

    PubMed

    Karaivanov, L

    1984-01-01

    Studied was the biochemical activity of a total of 168 strains of Pasteurella--73 isolated from birds (48 from cases of acute fowl cholera, and 25--of chronic cholera), and 95 isolated from mammals (3 from lambs, 24 from pigs, 36 from cattle, and 32 from rabbits) with regard to the tests determining the hemolytic activity, production of indol, reduction of nitrates, breakdown of urea, beta galactosidase activity, production of hydrogen sulfide, ornitin-, arginine-, lysine-decarboxylase-, and phosphatase activity, and the fermentation of substrates such as manite, glucose, galactose, saccharose, manose, levulose, dulcite, lactose, maltose, rafinose, trechalose, salicin, melobiose, icelobiose, arabinose, xylose, and sorbite. To differentiate Pasteurella multocida strains isolated from mamals from those isolated from birds the phosphatase activity test on solid media with sodium phenolphtalein diphosphate had to be employed Pasteurella organisms isolated from mammals showed positive phosphatase activity, while those isolated from birds exhibited a negative one. Arabinose and xylose fermentation tests could simultaneously be used. Pasteurellae isolated in cases of acute fowl cholera showed positive reaction for arabinose and a negative one for xylose, while the strains isolated from mammals showed the reverse activity. The strains isolated in cases of chronic fowl cholera were shown to belong to this group.

  14. Biochemical indicators of hepatotoxic effects of pesticides.

    PubMed

    Dahamna, S; Sekfali, N; Walker, C H

    2004-01-01

    Pesticides can cause damage to man and beneficial organisms. Some sub-lethal effects of pesticides were studied in birds with a view to identifying characteristic biochemical responses that may be useful for the monitoring of exposure to sub-lethal levels in the field. Pesticides were used: demeton-S-methyl, (DSM), chlorpyriphos, chlorfenviphos, triazophos, pirimicarb, methiocarb and permethrin. Blood was collected before dosing, and 2, 6, 24, 48 and 72 hours after the treatment from the brachial vein of birds. Enzyme activities were assayed in the plasma or serum samples obtained. The assays used were GOT, MDH, GDH, SDH, GAMMA GT and ChE. The results showed an increase in plasma and serum GOT and gamma-GT levels were found in all animals treated with the previous pesticides. The level of ChE increased in birds after treatment with permethrin. It was concluded that the pesticides cause structural and functional changes in the liver and also, the measurement of the previous parameter activities may be useful for assessing exposure and sub-lethal effects of pesticides on the wildlife.

  15. Reaction networks and kinetics of biochemical systems.

    PubMed

    Arceo, Carlene Perpetua P; Jose, Editha C; Lao, Angelyn R; Mendoza, Eduardo R

    2017-01-01

    This paper further develops the connection between Chemical Reaction Network Theory (CRNT) and Biochemical Systems Theory (BST) that we recently introduced [1]. We first use algebraic properties of kinetic sets to study the set of complex factorizable kinetics CFK(N) on a CRN, which shares many characteristics with its subset of mass action kinetics. In particular, we extend the Theorem of Feinberg-Horn [9] on the coincidence of the kinetic and stoichiometric subsets of a mass action system to CF kinetics, using the concept of span surjectivity. We also introduce the branching type of a network, which determines the availability of kinetics on it and allows us to characterize the networks for which all kinetics are complex factorizable: A "Kinetics Landscape" provides an overview of kinetics sets, their algebraic properties and containment relationships. We then apply our results and those (of other CRNT researchers) reviewed in [1] to fifteen BST models of complex biological systems and discover novel network and kinetic properties that so far have not been widely studied in CRNT. In our view, these findings show an important benefit of connecting CRNT and BST modeling efforts.

  16. Biochemical studies of the tracheobronchial epithelium

    SciTech Connect

    Mass, M.J.; Kaufman, D.G.

    1984-06-01

    Tracheobronchial epithelium has been a focus of intense investigation in the field of chemical carcinogenesis. We have reviewed some biochemical investigations that have evolved through linkage with carcinogenesis research. These areas of investigation have included kinetics of carcinogen metabolism, identification of carcinogen metabolites, levels of carcinogen binding to DNA, and analysis of carcinogen-DNA adducts. Such studies appear to have provided a reasonable explanation for the susceptibilities of the respiratory tracts of rats and hamsters to carcinogenesis by benzo(a)pyrene. Coinciding with the attempts to understand the initiation of carcinogenesis in the respiratory tract has also been a major thrust aimed at effecting its prevention both in humans and in animal models for human bronchogenic carcinoma. These studies have concerned the effects of derivatives of vitamin A (retinoids) and their influence on normal cell biology and biochemistry of this tissue. Recent investigations have included the effects of retinoid deficiency on the synthesis of RNA and the identification of RNA species associated with this biological state, and also have included the effects of retinoids on the synthesis of mucus-related glycoproteins. Tracheal organ cultures from retinoid-deficient hamsters have been used successfully to indicate the potency of synthetic retinoids by monitoring the reversal of squamous metaplasia. Techniques applied to this tissue have also served to elucidate features of the metabolism of retinoic acid using high pressure liquid chromatography. 94 references, 9 figures, 2 tables.

  17. [Cystinuria update: clinical, biochemical and genetic aspects].

    PubMed

    Orts Costa, J A; Zúñiga Cabrera, A; Martínez de la Cára y Salmerón, J

    2003-06-01

    Cystinuria is an autosomal recessive disorder with an estimated incidence of 1 case in 7000 live births, that results in elevated urinary excretion of cystine and dibasic aminoacids: ornithine, lysine and arginine. Discussed by Sir Archibald Edward Garrod, in 1908, as one of the four first known inborn errors of metabolism, it is characterized by a defect in transport of cystine and dibasic aminoacids, that affects their reabsortion in both renal tubule and gastrointestinal tract. To date, according to the recent molecular findings, two genes have been identified as responsible for this disease: SLC3A1 and SLC7A9. A more accurate pheno/genotyping identification of cystinuric patients will allow to improve prophilaxis and therapy for this illness. Cystinuria only causes recurrent urolithiasis (about 1-2 / of renal calculi in adults) and its associated complications as clinical feature because of poor cystine solubility at low pH. An accurate control over prohylaxis (based on high water intake and potassium citrate treatment, on first line, and tiol-derivatives treatment, on second line) must be taken in patients -like homozygous type I- with high lithiasis risk. However, approximately one half of patients under prophylaxis control will develop recurrent lithiasis; in this case, only urology or surgical approaches would be possible. 474 Updated knowledge about biochemical, genetic, clinical, diagnosis, prevention, treatment and prognosis aspects of this, relatively unusual, disease has been reviewed in this article.

  18. Applied spectrophotometry: analysis of a biochemical mixture.

    PubMed

    Trumbo, Toni A; Schultz, Emeric; Borland, Michael G; Pugh, Michael Eugene

    2013-01-01

    Spectrophotometric analysis is essential for determining biomolecule concentration of a solution and is employed ubiquitously in biochemistry and molecular biology. The application of the Beer-Lambert-Bouguer Lawis routinely used to determine the concentration of DNA, RNA or protein. There is however a significant difference in determining the concentration of a given species (RNA, DNA, protein) in isolation (a contrived circumstance) as opposed to determining that concentration in the presence of other species (a more realistic situation). To present the student with a more realistic laboratory experience and also to fill a hole that we believe exists in student experience prior to reaching a biochemistry course, we have devised a three week laboratory experience designed so that students learn to: connect laboratory practice with theory, apply the Beer-Lambert-Bougert Law to biochemical analyses, demonstrate the utility and limitations of example quantitative colorimetric assays, demonstrate the utility and limitations of UV analyses for biomolecules, develop strategies for analysis of a solution of unknown biomolecular composition, use digital micropipettors to make accurate and precise measurements, and apply graphing software.

  19. Multiple capillary biochemical analyzer with barrier member

    DOEpatents

    Dovichi, Norman J.; Zhang, Jian Z.

    1996-01-01

    A multiple capillary biochemical analyzer for sequencing DNA and performing other analyses, in which a set of capillaries extends from wells in a microtiter plate into a cuvette. In the cuvette the capillaries are held on fixed closely spaced centers by passing through a sandwich construction having a pair of metal shims which squeeze between them a rubber gasket, forming a leak proof seal for an interior chamber in which the capillary ends are positioned. Sheath fluid enters the chamber and entrains filament sample streams from the capillaries. The filament sample streams, and sheath fluid, flow through aligned holes in a barrier member spaced close to the capillary ends, into a collection chamber having a lower glass window. The filament streams are illuminated above the barrier member by a laser, causing them to fluoresce. The fluorescence is viewed end-on by a CCD camera chip located below the glass window. The arrangement ensures an equal optical path length from all fluorescing spots to the CCD chip and also blocks scattered fluorescence illumination, providing more uniform results and an improved signal to noise ratio.

  20. Multiple capillary biochemical analyzer with barrier member

    DOEpatents

    Dovichi, N.J.; Zhang, J.Z.

    1996-10-22

    A multiple capillary biochemical analyzer is disclosed for sequencing DNA and performing other analyses, in which a set of capillaries extends from wells in a microtiter plate into a cuvette. In the cuvette the capillaries are held on fixed closely spaced centers by passing through a sandwich construction having a pair of metal shims which squeeze between them a rubber gasket, forming a leak proof seal for an interior chamber in which the capillary ends are positioned. Sheath fluid enters the chamber and entrains filament sample streams from the capillaries. The filament sample streams, and sheath fluid, flow through aligned holes in a barrier member spaced close to the capillary ends, into a collection chamber having a lower glass window. The filament streams are illuminated above the barrier member by a laser, causing them to fluoresce. The fluorescence is viewed end-on by a CCD camera chip located below the glass window. The arrangement ensures an equal optical path length from all fluorescing spots to the CCD chip and also blocks scattered fluorescence illumination, providing more uniform results and an improved signal-to-noise ratio. 12 figs.

  1. Robustness analysis of stochastic biochemical systems.

    PubMed

    Ceska, Milan; Safránek, David; Dražan, Sven; Brim, Luboš

    2014-01-01

    We propose a new framework for rigorous robustness analysis of stochastic biochemical systems that is based on probabilistic model checking techniques. We adapt the general definition of robustness introduced by Kitano to the class of stochastic systems modelled as continuous time Markov Chains in order to extensively analyse and compare robustness of biological models with uncertain parameters. The framework utilises novel computational methods that enable to effectively evaluate the robustness of models with respect to quantitative temporal properties and parameters such as reaction rate constants and initial conditions. We have applied the framework to gene regulation as an example of a central biological mechanism where intrinsic and extrinsic stochasticity plays crucial role due to low numbers of DNA and RNA molecules. Using our methods we have obtained a comprehensive and precise analysis of stochastic dynamics under parameter uncertainty. Furthermore, we apply our framework to compare several variants of two-component signalling networks from the perspective of robustness with respect to intrinsic noise caused by low populations of signalling components. We have successfully extended previous studies performed on deterministic models (ODE) and showed that stochasticity may significantly affect obtained predictions. Our case studies demonstrate that the framework can provide deeper insight into the role of key parameters in maintaining the system functionality and thus it significantly contributes to formal methods in computational systems biology.

  2. A biochemically structured model for Saccharomyces cerevisiae.

    PubMed

    Lei, F; Rotbøll, M; Jørgensen, S B

    2001-07-12

    A biochemically structured model for the aerobic growth of Saccharomyces cerevisiae on glucose and ethanol is presented. The model focuses on the pyruvate and acetaldehyde branch points where overflow metabolism occurs when the growth changes from oxidative to oxido-reductive. The model is designed to describe the onset of aerobic alcoholic fermentation during steady-state as well as under dynamical conditions, by triggering an increase in the glycolytic flux using a key signalling component which is assumed to be closely related to acetaldehyde. An investigation of the modelled process dynamics in a continuous cultivation revealed multiple steady states in a region of dilution rates around the transition between oxidative and oxido-reductive growth. A bifurcation analysis using the two external variables, the dilution rate, D, and the inlet concentration of glucose, S(f), as parameters, showed that a fold bifurcation occurs close to the critical dilution rate resulting in multiple steady-states. The region of dilution rates within which multiple steady states may occur depends strongly on the substrate feed concentration. Consequently a single steady state may prevail at low feed concentrations, whereas multiple steady states may occur over a relatively wide range of dilution rates at higher feed concentrations.

  3. Induced biochemical interactions in crude oils

    SciTech Connect

    Premuzic, E.T.; Lin, M.S.

    1996-08-01

    In the evolution of oil from sedimentary to reservoir conditions, the hydrogen to carbon ratios decrease while the oxygen, nitrogen, and sulfur to carbon ratios increase. During this process, the oils become heavier and richer in asphaltenes. In terms of chemical composition, the oils become enriched in resins, asphaltenes, and polar compounds containing the heteroatoms and metals. Over the geological periods of time, the chemical and physical changes have been brought about by chemical, biological (biochemical) and physical (temperature and pressure) means as well as by the catalytic effects of the sedimentary matrices, migration, flooding, and other physical processes. Therefore, different types of oils are the end products of a given set of such interactions which were brought about by multiple and simultaneous physicochemical processes involving electron transfer, free radical, and chemical reactions. A biocatalyst introduced into a reaction mixture of the type produced by such reactions will seek available chemical reaction sites and react at the most favorable ones. The rates and the chemical pathways by which the biocatalytic reactions will proceed will depend on the oil type and the biocatalyst(s). Some of the possible reaction pathways that may occur in such complex mixtures are discussed.

  4. The role of thermodynamics in biochemical engineering

    NASA Astrophysics Data System (ADS)

    von Stockar, Urs

    2013-09-01

    This article is an adapted version of the introductory chapter of a book whose publication is imminent. It bears the title "Biothermodynamics - The role of thermodynamics in biochemical engineering." The aim of the paper is to give a very short overview of the state of biothermodynamics in an engineering context as reflected in this book. Seen from this perspective, biothermodynamics may be subdivided according to the scale used to formalize the description of the biological system into three large areas: (i) biomolecular thermodynamics (most fundamental scale), (ii) thermodynamics of metabolism (intermediary scale), and (iii) whole-cell thermodynamics ("black-box" description of living entities). In each of these subareas, the main available theoretical approaches and the current and the potential applications are discussed. Biomolecular thermodynamics (i) is especially well developed and is obviously highly pertinent for the development of downstream processing. Its use ought to be encouraged as much as possible. The subarea of thermodynamics of live cells (iii), although scarcely applied in practice, is also expected to enhance bioprocess research and development, particularly in predicting culture performances, for understanding the driving forces for cellular growth, and in developing, monitoring, and controlling cellular cultures. Finally, there is no question that thermodynamic analysis of cellular metabolism (ii) is a promising tool for systems biology and for many other applications, but quite a large research effort is still needed before it may be put to practical use.

  5. Familial Confounding of the Association Between Maternal Smoking during Pregnancy and Offspring Substance Use and Problems: Converging Evidence Across Samples and Measures

    PubMed Central

    D’Onofrio, Brian M.; Rickert, Martin E.; Långström, Niklas; Donahue, Kelly L.; Coyne, Claire A.; Larsson, Henrik; Ellingson, Jarrod M.; Van Hulle, Carol A.; Iliadou, Anastasia N.; Rathouz, Paul J.; Lahey, Benjamin B.; Lichtenstein, Paul

    2013-01-01

    Context Previous epidemiological, animal, and human cognitive neuroscience research suggests that maternal smoking during pregnancy causes increased risk of offspring substance use/problems. Objective To determine the extent to which the association between SDP and offspring substance use/problems depends on confounded familial background factors by using a quasi-experimental design. Design We used two separate samples, from the United States and from Sweden, respectively. The analyses prospectively predicted multiple indices of substance use and problems while controlling for statistical covariates and comparing differentially exposed siblings to minimize confounding. Setting Sample 1: Offspring of a representative sample of women in the United States. Sample 2: The total Swedish population born over 13 years. Patients or Other Participants Sample 1: Adolescent offspring of the women in the National Longitudinal Survey of Youth 1979 (n=6,094). Sample 2: All offspring born in Sweden from 1983 through 1995 (n=1,187,360). Main Outcome Measures Sample 1: Self-reported adolescent alcohol, cigarette, and marijuana use, and early onset (before age 14 years) of each substance. Sample 2: Substance-related convictions and hospitalizations for an alcohol- or drug-related problem. Results The same pattern emerged for each index of substance use/problems across the two samples. At the population level maternal smoking during pregnancy predicted every measure of offspring substance use/problems in both samples, ranging from adolescent alcohol use (HRmoderate=1.32, CI=1.22–1.43; HRhigh=1.33, CI=1.17=1.53) to a narcotic convictions (HRmoderate=2.23, CI=2.14–2.31; HRhigh=2.97, CI=2.86–3.09). When comparing differentially exposed siblings to minimize genetic and environmental confounds, however, the association between SDP and each measure of substance use/problems was minimal and not statistically significant. Conclusions The association between maternal smoking during

  6. Estimated effect of weight loss on risk of coronary heart disease and mortality in middle-aged or older women: sensitivity analysis for unmeasured confounding by undiagnosed disease

    PubMed Central

    Danaei, Goodarz; Robins, James M.; Young, Jessica; Hu, Frank B.; Manson, JoAnn E; Hernán, Miguel A.

    2016-01-01

    Background The evidence on the effect of weight loss on coronary heart disease (CHD) or mortality has been mixed. The effect estimates can be confounded due to undiagnosed diseases that may affect weight loss. Methods We used data from the Nurses’ Health Study to estimate the 26-year risk of CHD under several hypothetical weight loss interventions (e.g. maintain baseline weight, lose 5% of weight every 2 years if overweight/obese). We applied the parametric g-formula and implemented a novel sensitivity analysis for unmeasured confounding due to undiagnosed disease by imposing a lag time for the effect of weight loss on chronic disease. Sensitivity analyses were conducted by using only the first 16 years of follow-up, restricting the analysis to women who had reported intentional weight loss, those who were younger (<49 years old at baseline), and those who never smoked. Results The 26-year risk of CHD under no weight loss intervention was 5.0% (95% Confidence Interval 4.9, 5.3). The estimated risk did not change under hypothetical weight loss interventions using lag times from 0 to 18 years. For a 6-year lag time, the risk ratios of CHD for weight loss compared with no intervention ranged from 1.00 (0.99, 1.02) to 1.02 (0.99, 1.05) for different degrees of weight loss with and without restricting the intervention to participants with no major chronic disease. Similarly, no protective effect of weight loss was estimated for mortality risk. In contrast, we estimated a protective effect of weight loss on risk of type 2 diabetes. The estimated effect of weight loss on CHD and mortality remained null in all sensitivity analyses. Conclusion We estimated that maintaining weight or losing weight after becoming overweight or obese does not reduce the risk of CHD or death in this cohort of middle-aged US women. Unmeasured confounding, measurement error, and model misspecification are possible explanations but they did not prevent us from estimating a beneficial effect of

  7. Pure and Confounded Effects of Causal SNPs on Longevity: Insights for Proper Interpretation of Research Findings in GWAS of Populations with Different Genetic Structures

    PubMed Central

    Yashin, Anatoliy I.; Zhbannikov, Ilya; Arbeeva, Liubov; Arbeev, Konstantin G.; Wu, Deqing; Akushevich, Igor; Yashkin, Arseniy; Kovtun, Mikhail; Kulminski, Alexander M.; Stallard, Eric; Kulminskaya, Irina; Ukraintseva, Svetlana

    2016-01-01

    This paper shows that the effects of causal SNPs on lifespan, estimated through GWAS, may be confounded and the genetic structure of the study population may be responsible for this effect. Simulation experiments show that levels of linkage disequilibrium (LD) and other parameters of the population structure describing connections between two causal SNPs may substantially influence separate estimates of the effect of the causal SNPs on lifespan. This study suggests that differences in LD levels between two causal SNP loci within two study populations may contribute to the failure to replicate previous GWAS findings. The results of this paper also show that successful replication of the results of genetic association studies does not necessarily guarantee proper interpretation of the effect of a causal SNP on lifespan. PMID:27877192

  8. Pellagra and alcoholism: a biochemical perspective.

    PubMed

    Badawy, Abdulla A-B

    2014-01-01

    Historical and clinical aspects of pellagra and its relationship to alcoholism are reviewed from a biochemical perspective. Pellagra is caused by deficiency of niacin (nicotinic acid) and/or its tryptophan (Trp) precursor and is compounded by B vitamin deficiencies. Existence on maize or sorghum diets and loss of or failure to isolate niacin from them led to pellagra incidence in India, South Africa, Southern Europe in the 18th century and the USA following the civil war. Pellagra is also induced by drugs inhibiting the conversion of Trp to niacin and by conditions of gastrointestinal dysfunction. Skin photosensitivity in pellagra may be due to decreased synthesis of the Trp metabolite picolinic acid → zinc deficiency → decreased skin levels of the histidine metabolite urocanic acid and possibly also increased levels of the haem precursor 5-aminolaevulinic acid (5-ALA) and photo-reactive porphyrins. Depression in pellagra may be due to a serotonin deficiency caused by decreased Trp availability to the brain. Anxiety and other neurological disturbances may be caused by 5-ALA and the Trp metabolite kynurenic acid. Pellagra symptoms are resolved by niacin, but aggravated mainly by vitamin B6. Alcohol dependence can induce or aggravate pellagra by inducing malnutrition, gastrointestinal disturbances and B vitamin deficiencies, inhibiting the conversion of Trp to niacin and promoting the accumulation of 5-ALA and porphyrins. Alcoholic pellagra encephalopathy should be managed with niacin, other B vitamins and adequate protein nutrition. Future studies should explore the potential role of 5-ALA and also KA in the skin and neurological disturbances in pellagra.

  9. Historical cohort study of US man-made vitreous fiber production workers: VI. Respiratory system cancer standardized mortality ratios adjusted for the confounding effect of cigarette smoking.

    PubMed

    Marsh, G M; Buchanich, J M; Youk, A O

    2001-09-01

    To date, the US cohort study of man-made vitreous fiber workers has provided no consistent evidence of a relationship between man-made vitreous fiber exposure and mortality from malignant or non-malignant respiratory disease. Nevertheless, there have been small, overall excesses in respiratory system cancer (RSC) among workers from the fiberglass and rock/slag wool production plants included in the study that were unexplained by estimated worker exposures to respirable fiber or other agents present in the plants. The present investigation was designed to provide a quantitative estimate of the extent to which the overall excess in RSC mortality observed at the total cohort level among male fiberglass and rock/slag wool workers is a result of the positive confounding effects of cigarette smoking. Because cigarette-smoking data were neither available nor obtainable at the individual level for all members of the fiberglass and rock/slag wool cohorts, we used the "indirect" method to adjust RSC standardized mortality ratios (SMRs) at the group (cohort and plant) level. Our adjustment suggested that cigarette smoking accounts for all of the 7% and 24% excesses in RSC observed, respectively, for the male fiberglass and rock/slag wool cohorts in the latest mortality updates. The same conclusion was reached regardless of which of several alternative formulations were used to adjust local rate-based RSC SMRs. We found that our smoking adjustments were robust with respect to several alternative characterizations and (with the exception of one fiberglass plant) produced adjusted RSC SMRs that were lower than their unadjusted counterparts. Further, all statistically significantly elevated unadjusted SMRs were reduced to not statistically significant levels. These results reaffirm that RSC SMRs based on US and local rates must take into account the potential confounding effects of cigarette smoking. They also suggest that the use of local county mortality rate-based SMRs may not

  10. Polymorphisms in DNA-Repair Genes in a Cohort of Prostate Cancer Patients from Different Areas in Spain: Heterogeneity between Populations as a Confounding Factor in Association Studies

    PubMed Central

    Henríquez-Hernández, Luis Alberto; Valenciano, Almudena; Foro-Arnalot, Palmira; Álvarez-Cubero, María Jesús; Cozar, José Manuel; Suárez-Novo, José Francisco; Castells-Esteve, Manel; Ayala-Gil, Adriana; Fernández-Gonzalo, Pablo; Ferrer, Montse; Guedea, Ferrán; Sancho-Pardo, Gemma; Craven-Bartle, Jordi; Ortiz-Gordillo, María José; Cabrera-Roldán, Patricia; Herrera-Ramos, Estefanía; Lara, Pedro C.

    2013-01-01

    Background Differences in the distribution of genotypes between individuals of the same ethnicity are an important confounder factor commonly undervalued in typical association studies conducted in radiogenomics. Objective To evaluate the genotypic distribution of SNPs in a wide set of Spanish prostate cancer patients for determine the homogeneity of the population and to disclose potential bias. Design, Setting, and Participants A total of 601 prostate cancer patients from Andalusia, Basque Country, Canary and Catalonia were genotyped for 10 SNPs located in 6 different genes associated to DNA repair: XRCC1 (rs25487, rs25489, rs1799782), ERCC2 (rs13181), ERCC1 (rs11615), LIG4 (rs1805388, rs1805386), ATM (rs17503908, rs1800057) and P53 (rs1042522). The SNP genotyping was made in a Biotrove OpenArray® NT Cycler. Outcome Measurements and Statistical Analysis Comparisons of genotypic and allelic frequencies among populations, as well as haplotype analyses were determined using the web-based environment SNPator. Principal component analysis was made using the SnpMatrix and XSnpMatrix classes and methods implemented as an R package. Non-supervised hierarchical cluster of SNP was made using MultiExperiment Viewer. Results and Limitations We observed that genotype distribution of 4 out 10 SNPs was statistically different among the studied populations, showing the greatest differences between Andalusia and Catalonia. These observations were confirmed in cluster analysis, principal component analysis and in the differential distribution of haplotypes among the populations. Because tumor characteristics have not been taken into account, it is possible that some polymorphisms may influence tumor characteristics in the same way that it may pose a risk factor for other disease characteristics. Conclusion Differences in distribution of genotypes within different populations of the same ethnicity could be an important confounding factor responsible for the lack of validation of

  11. A population-based study of edentulism in the US: does depression and rural residency matter after controlling for potential confounders?

    PubMed Central

    2014-01-01

    Background Oral health is an integral component of general health and well-being. While edentulism has been examined in relation to socioeconomic status, rural residency, chronic disease and mental health, no study that we know of has examined edentulism and these factors together. The objective of this study was to determine whether depression and rural residency were significantly associated with partial and full edentulism in US adults after controlling for potential confounders. Methods 2006 Behavioral Risk Factor Surveillance Survey (BRFSS) data were analyzed to identify factors associated with increased odds of partial or full edentulism. This year of BRFSS data was chosen for analysis because in this year the standardized and validated Personal Health Questionnaire-8 (PHQ-8) was used to measure current depression. This measure was part of the optional questions BRFSS asks, and in 2006 33 states and/or territories included them in their annual surveillance data collection. Bivariate and logistic regression analyses were performed on weighted BRFSS data. Results Logistic regression analysis using either full or partial edentulism as the dependent variable yielded that rural residency or living in a rural locale, low and/or middle socioeconomic status (SES), depression as measured by the PHQ-8, and African American race/ethnicity were all independent risk factors when controlling for these and a number of additional covariates. Conclusions This study adds to the epidemiological literature by assessing partial and full edentulism in the US utilizing data from the CDC’s Behavioral Risk Factor Surveillance System (BRFSS). Examining data collected through a large national surveillance system such as BRFSS allows for an analysis that incorporates an array of covariates not available from clinically-based data alone. This study demonstrated that current depression and rural residency are important factors related to partial and full edentulism after controlling for

  12. Associations of Milk Consumption and Vitamin B2 and Β12 Derived from Milk with Fitness, Anthropometric and Biochemical Indices in Children. The Healthy Growth Study

    PubMed Central

    Moschonis, George; van den Heuvel, Ellen G. H. M.; Mavrogianni, Christina; Singh-Povel, Cécile M.; Leotsinidis, Michalis; Manios, Yannis

    2016-01-01

    The benefits of dairy consumption seem to extend beyond its significant contribution to ensuring nutrient intake adequacy as indicated by the favourable associations with several health outcomes reported by different studies. The aims of the present study were to examine the associations of milk consumption with fitness, anthropometric and biochemical indices in children and further explore whether the observed associations are attributed to vitamins B2 and B12 derived from milk. A representative subsample of 600 children aged 9–13 years participating in the Healthy Growth Study was examined. Data were collected on children’s dietary intake, using 24 h recalls, as well as on fitness, anthropometric and biochemical indices. Regression analyses were performed for investigating the research hypothesis, adjusting for potential confounders and for B-vitamin status indices (i.e., plasma riboflavin, methylmalonic acid and total homocysteine concentrations), dietary calcium intake and plasma zinc concentrations that could possibly act as effect modifiers. Milk consumption was positively associated with the number of stages performed in the endurance run test (ERT) (β = 0.10; p = 0.017) and negatively with body mass index (BMI) (β = −0.10; p = 0.014), after adjusting for several potential confounders and effect modifiers. Dietary intakes of vitamin B2 and B12 derived from milk were also positively associated with the number of ERT stages (β = 0.10; p = 0.015 and β = 0.10; p = 0.014 respectively). In conclusion, higher intake of milk as well as vitamin B2 and B12 derived from milk were independently associated with higher cardiorespiratory fitness in Greek preadolescents. The key roles of these B-vitamins in substrate oxidation, energy production, haemoglobin synthesis and erythropoiesis could provide a basis for interpreting these associations. However, further research is needed to confirm this potential interpretation. PMID:27754376

  13. Associations of Milk Consumption and Vitamin B₂ and Β12 Derived from Milk with Fitness, Anthropometric and Biochemical Indices in Children. The Healthy Growth Study.

    PubMed

    Moschonis, George; van den Heuvel, Ellen G H M; Mavrogianni, Christina; Singh-Povel, Cécile M; Leotsinidis, Michalis; Manios, Yannis

    2016-10-13

    The benefits of dairy consumption seem to extend beyond its significant contribution to ensuring nutrient intake adequacy as indicated by the favourable associations with several health outcomes reported by different studies. The aims of the present study were to examine the associations of milk consumption with fitness, anthropometric and biochemical indices in children and further explore whether the observed associations are attributed to vitamins B₂ and B12 derived from milk. A representative subsample of 600 children aged 9-13 years participating in the Healthy Growth Study was examined. Data were collected on children's dietary intake, using 24 h recalls, as well as on fitness, anthropometric and biochemical indices. Regression analyses were performed for investigating the research hypothesis, adjusting for potential confounders and for B-vitamin status indices (i.e., plasma riboflavin, methylmalonic acid and total homocysteine concentrations), dietary calcium intake and plasma zinc concentrations that could possibly act as effect modifiers. Milk consumption was positively associated with the number of stages performed in the endurance run test (ERT) (β = 0.10; p = 0.017) and negatively with body mass index (BMI) (β = -0.10; p = 0.014), after adjusting for several potential confounders and effect modifiers. Dietary intakes of vitamin B₂ and B12 derived from milk were also positively associated with the number of ERT stages (β = 0.10; p = 0.015 and β = 0.10; p = 0.014 respectively). In conclusion, higher intake of milk as well as vitamin B₂ and B12 derived from milk were independently associated with higher cardiorespiratory fitness in Greek preadolescents. The key roles of these B-vitamins in substrate oxidation, energy production, haemoglobin synthesis and erythropoiesis could provide a basis for interpreting these associations. However, further research is needed to confirm this potential interpretation.

  14. 40 CFR 158.2080 - Experimental use permit data requirements-biochemical pesticides.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... requirements-biochemical pesticides. 158.2080 Section 158.2080 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) PESTICIDE PROGRAMS DATA REQUIREMENTS FOR PESTICIDES Biochemical Pesticides § 158.2080 Experimental use permit data requirements—biochemical pesticides. (a) Sections...

  15. 40 CFR 158.2080 - Experimental use permit data requirements-biochemical pesticides.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... requirements-biochemical pesticides. 158.2080 Section 158.2080 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) PESTICIDE PROGRAMS DATA REQUIREMENTS FOR PESTICIDES Biochemical Pesticides § 158.2080 Experimental use permit data requirements—biochemical pesticides. (a) Sections...

  16. 40 CFR 158.2080 - Experimental use permit data requirements-biochemical pesticides.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... requirements-biochemical pesticides. 158.2080 Section 158.2080 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) PESTICIDE PROGRAMS DATA REQUIREMENTS FOR PESTICIDES Biochemical Pesticides § 158.2080 Experimental use permit data requirements—biochemical pesticides. (a) Sections...

  17. 40 CFR 158.2080 - Experimental use permit data requirements-biochemical pesticides.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... requirements-biochemical pesticides. 158.2080 Section 158.2080 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) PESTICIDE PROGRAMS DATA REQUIREMENTS FOR PESTICIDES Biochemical Pesticides § 158.2080 Experimental use permit data requirements—biochemical pesticides. (a) Sections...

  18. 40 CFR 158.2080 - Experimental use permit data requirements-biochemical pesticides.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... requirements-biochemical pesticides. 158.2080 Section 158.2080 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) PESTICIDE PROGRAMS DATA REQUIREMENTS FOR PESTICIDES Biochemical Pesticides § 158.2080 Experimental use permit data requirements—biochemical pesticides. (a) Sections...

  19. Nutritional status in pregnant adolescents: a systematic review of biochemical markers.

    PubMed

    Moran, Victoria Hall

    2007-04-01

    Adolescent pregnancy is a major public health challenge for many industrialized countries and is associated with significant medical, nutritional, social and economic risk for mothers and their infants. Despite this, relatively little is known about the nutritional status of this population. The aim of this paper was to conduct a systematic review of the current evidence relating to the biochemical markers of nutritional status of pregnant adolescents living in industrialized countries. Six papers were identified that fulfilled the inclusion criteria, the majority of which were conducted in the United States. The studies were of variable quality and most failed to control for potential confounders which may have strongly influenced the findings. Due to limited research, conclusions cannot be drawn about the zinc and calcium status of pregnant adolescents, and data on folate and vitamin B(12) status appeared conflicting. There was some consensus among studies, however, to suggest that indicators of anaemia and iron status were compromised in pregnant adolescents, particularly during the third trimester of pregnancy. Chronological age did not appear to influence nutritional status, although there was some evidence to suggest that increasing gynaecologic age may positively influence plasma ferritin levels. Current research is limited by sampling and measurement bias, and research is urgently required to address these limitations. Further consideration should also be made of the influence of the role of socio-economic support on pregnant adolescents' nutritional status. The achievement of improved nutrition in pregnancy among adolescents requires multidisciplinary collaborations of adolescent healthcare providers, academics, professional organizations, policymakers, industry and service users. Only once this is achieved can adolescent nutrition, and adolescent nutrition in pregnancy, be significantly and sustainably optimized.

  20. Biochemical investigation of cypermethrin toxicity in rabbits.

    PubMed

    Dahamna, S; Harzallah, D; Guemache, A; Sekfali, N

    2009-01-01

    cypermethrin on the erythropoiesis. An increase of plasma enzyme activities in GOT, GPT and CPK were recorded, explain a high energy-generating product. An increase, in the plasma enzyme activity in Alkaline phosphatase, related to their role in the cell permeability. The histopathological results showed lesions and morphological changes of hepato-cellular, fibrosis and appearance of inflammatory infiltrate, confirmed disturbances of the biochemical parameters. These changes were much underlines during the animal toxicity.

  1. Reduction, integration and emergence in biochemical networks.

    PubMed

    Ricard, Jacques

    2004-12-01

    Most studies of molecular cell biology are based upon a process of decomposition of complex biological systems into their components, followed by the study of these components. The aim of the present paper is to discuss, on a physical basis, the internal logic of this process of reduction. The analysis is performed on simple biological systems, namely protein and metabolic networks. A multi-sited protein that binds two ligands x and y can be considered the simplest possible biochemical network. The organization of this network can be described through a comparison of three systems, i.e. XY, X and Y. X and Y are component sub-systems that collect states x(i) and y(j), respectively, i.e. protein states that have bound either i molecules of x (whether or not these states have also bound y), or j molecules of y (whether or not these states have bound x). XY is a system made up of the specific association of X and Y that collects states x(i)y(j). One can define mean self-informations per node of the network, , and . Reduction of the system XY into its components is possible if, and only if, ,is equal to the sum of and . If is smaller than the sum of and , the system is integrated, for it has less self-information than the set of its components X and Y. It can also occur that , be larger than the sum of and . Hence, the system XY displays negative integration and emergence of self-information relative to its components X and Y. Such a system is defined as complex. Positive or negative integration of the system implies it cannot be reduced to its components. The degree of integration can be measured by a function , called mutual information of integration. In the case of enzyme networks, emergence of self-information is associated with emergence of catalytic activity. Moreover, if the enzyme reaction is part of a metabolic sequence, its mutual information of integration can be

  2. Biochemical observation during 28 days of space flight

    NASA Technical Reports Server (NTRS)

    Leach, C. S.; Kambaut, P. C.

    1975-01-01

    With the completion of the 28-day flight of Skylab 2, the sum of biochemical data on human reaction to the weightless environment was significantly extended both quantitatively and qualitatively. The biochemical studies were divided into two broad categories. One group included the more routine blood studies similar to those used in everyday medical practice. The second category encompassed those analyses used to investigate more thoroughly the endocrinological and fluid changes first seen in the crewmembers following the Gemini, Apollo, and Soviet missions. Significant biochemical changes were observed that varied in magnitude and direction, but all disappeared shortly after return to earth. Most of changes indicate successful adaptation by the body to the combined stresses of weightlessness. Results of the biochemical observation are presented in the form of data tables and graphs.

  3. Aquatic ecological biochemical investigations in the Lake Baikal region

    SciTech Connect

    Timofeeva, S.S.; Kozhova, O.M.

    1986-07-01

    The authors maintain that at the current level of investigations a constructive solution of the problem of protecting aquatic ecosystems is possible only on the basis of a thorough study of biochemical mechanisms of the interaction of biota and pollutants. They believe that in the program of investigations in the Baikal region, with consideration of the easy vulnerability of the aquatic ecosystems, ecological biochemical investigations should occupy one of the leading places. The authors suggest a method for the screening of xenobiotics, consisting of xenobiotics; chemical investigations; biochemical investigations of the properties of xenobiotics, and toxicological investigations of xenobiotics. The differences in the elimination of xenobiotics are considerable due to the species and biochemical characteristics of hydrophytes and chemical structure of the investigated toxicants. The results obtained in experiments with cyanide compounds are of considerable interest, since cyanides, the strongest poisons of animals, prove to be little toxic for higher aquatic plants and algae.

  4. 2011 Biomass Program Platform Peer Review: Biochemical Conversion

    SciTech Connect

    Pezzullo, Leslie

    2012-02-01

    This document summarizes the recommendations and evaluations provided by an independent external panel of experts at the 2011 U.S. Department of Energy Biomass Program’s Biochemical Conversion Platform Review meeting.

  5. A view of the history of biochemical engineering.

    PubMed

    Katzen, R; Tsao, G T

    2000-01-01

    The authors present a view of biochemical engineering by describing their personal interests and experience over the years involving mostly conversion of lignocellulosics into fuels and chemicals and the associated engineering subjects.

  6. Optical chemical and biochemical sensors: new trends (Invited Paper)

    NASA Astrophysics Data System (ADS)

    Baldini, F.; Giannetti, A.

    2005-06-01

    Chemical and biochemical sensing is under the extensive research all over the world and many chemical and biochemical sensors are finding increasing number of applications in industry, environmental monitoring, medicine, biomedicine and chemical analysis. This is evidenced by each-year-growing number of international scientific conferences, in which advances in the field of the sensors are reported. One of the main reason why only a few sensors reach the international market, notwithstanding the high number of laboratory prototype described in many peer reviewed papers, lies in the fact that a biochemical sensor is a highly interdisciplinary "object" the realization of which requires the team work of scientists coming from different areas such as chemistry, physics, optoelectronics, engineering, biochemistry, and medicine. And this peculiarity is not easily found in the research teams. In the present paper, the fundamental bases of chemical and biochemical optical sensing are summarised and the new trends are described.

  7. Why do thin people have elevated all-cause mortality? Evidence on confounding and reverse causality in the association of adiposity and COPD from the British Women's Heart and Health Study.

    PubMed

    Dale, Caroline; Nüesch, Eveline; Prieto-Merino, David; Choi, Minkyoung; Amuzu, Antoinette; Ebrahim, Shah; Casas, Juan P; Davey-Smith, George

    2015-01-01

    Low adiposity has been linked to elevated mortality from several causes including respiratory disease. However, this could arise from confounding or reverse causality. We explore the association between two measures of adiposity (BMI and WHR) with COPD in the British Women's Heart and Health Study including a detailed assessment of the potential for confounding and reverse causality for each adiposity measure. Low BMI was found to be associated with increased COPD risk while low WHR was not (OR = 2.2; 95% CI 1.3-3.1 versus OR = 1.2; 95% CI 0.7-1.6). Potential confounding variables (e.g. smoking) and markers of ill-health (e.g. unintentional weight loss) were found to be higher in low BMI but not in low WHR. Women with low BMI have a detrimental profile across a broad range of health markers compared to women with low WHR, and women with low WHR do not appear to have an elevated COPD risk, lending support to the hypothesis that WHR is a less confounded measure of adiposity than BMI. Low adiposity does not in itself appear to increase the risk of respiratory disease, and the apparent adverse consequences of low BMI may be due to reverse causation and confounding.

  8. Laetrile: A Study of Its Physicochemical and Biochemical Properties

    PubMed Central

    Levi, Leo; French, W. N.; Bickis, I. J.; Henderson, I. W. D.

    1965-01-01

    A study was made of the composition and biochemical behaviour of the drug, Laetrile, distributed for clinical trial in the United States and Canada. It was established that the Canadian and the American product are different pharmaceutical formulations, displaying different physicochemical and biochemical properties. The investigation demonstrated, furthermore, that neither preparation can be considered as a palliative in cancer therapy on the basis of the biological rationale advanced by their manufacturers. ImagesFig. 3 PMID:14281087

  9. Energy-based analysis of biochemical cycles using bond graphs.

    PubMed

    Gawthrop, Peter J; Crampin, Edmund J

    2014-11-08

    Thermodynamic aspects of chemical reactions have a long history in the physical chemistry literature. In particular, biochemical cycles require a source of energy to function. However, although fundamental, the role of chemical potential and Gibb's free energy in the analysis of biochemical systems is often overlooked leading to models which are physically impossible. The bond graph approach was developed for modelling engineering systems, where energy generation, storage and transmission are fundamental. The method focuses on how power flows between components and how energy is stored, transmitted or dissipated within components. Based on the early ideas of network thermodynamics, we have applied this approach to biochemical systems to generate models which automatically obey the laws of thermodynamics. We illustrate the method with examples of biochemical cycles. We have found that thermodynamically compliant models of simple biochemical cycles can easily be developed using this approach. In particular, both stoichiometric information and simulation models can be developed directly from the bond graph. Furthermore, model reduction and approximation while retaining structural and thermodynamic properties is facilitated. Because the bond graph approach is also modular and scaleable, we believe that it provides a secure foundation for building thermodynamically compliant models of large biochemical networks.

  10. Energy-based analysis of biochemical cycles using bond graphs

    PubMed Central

    Gawthrop, Peter J.; Crampin, Edmund J.

    2014-01-01

    Thermodynamic aspects of chemical reactions have a long history in the physical chemistry literature. In particular, biochemical cycles require a source of energy to function. However, although fundamental, the role of chemical potential and Gibb's free energy in the analysis of biochemical systems is often overlooked leading to models which are physically impossible. The bond graph approach was developed for modelling engineering systems, where energy generation, storage and transmission are fundamental. The method focuses on how power flows between components and how energy is stored, transmitted or dissipated within components. Based on the early ideas of network thermodynamics, we have applied this approach to biochemical systems to generate models which automatically obey the laws of thermodynamics. We illustrate the method with examples of biochemical cycles. We have found that thermodynamically compliant models of simple biochemical cycles can easily be developed using this approach. In particular, both stoichiometric information and simulation models can be developed directly from the bond graph. Furthermore, model reduction and approximation while retaining structural and thermodynamic properties is facilitated. Because the bond graph approach is also modular and scaleable, we believe that it provides a secure foundation for building thermodynamically compliant models of large biochemical networks. PMID:25383030

  11. [Fifty years of cooperation--FEBS and Polish Biochemical Society].

    PubMed

    Barańska, Jolanta

    2014-01-01

    This year, the Federation of European Biochemical Societies (FEBS) celebrates its 50th anniversary. The Polish Biochemical Society, represented by the Society's President, Kazimierz Zakrzewski, was a founding member of the organization. The text presents a history of collaboration between FEBS and Polish Biochemical Society, the participation of Polish Biochemical Society members in different FEBS activities, as well as the role they played in running the Federation. Author describes FEBS Congresses which taken place in Warsaw, the first 3rd FEBS Meeting in 1966 and then 29th Congress in 2004. The profiles of Jakub Karol Parnas, the founding father of the Polish biochemistry and some crucial Presidents of the Society, are also presented. The text describes Parnas Conferences, organized jointly by Polish and Ukrainian Biochemical Societies from 1996, and growing from 2011 into three-nation event with participation of Ukrainian, Israeli and Polish scientists, largely due to significant help from FEBS. Summarizing the last few years, author judge the cooperation between the Federation and the Polish Biochemical Society as optimal.

  12. Drug resistance confounding prion therapeutics

    PubMed Central

    Berry, David B.; Lu, Duo; Geva, Michal; Watts, Joel C.; Bhardwaj, Sumita; Oehler, Abby; Renslo, Adam R.; DeArmond, Stephen J.; Prusiner, Stanley B.; Giles, Kurt

    2013-01-01

    There is not a single pharmaceutical that halts or even slows any neurodegenerative disease. Mounting evidence shows that prions cause many neurodegenerative diseases, and arguably, scrapie and Creutzfeldt–Jakob disease prions represent the best therapeutic targets. We report here that the previously identified 2-aminothiazoles IND24 and IND81 doubled the survival times of scrapie-infected, wild-type mice. However, mice infected with Rocky Mountain Laboratory (RML) prions, a scrapie-derived strain, and treated with IND24 eventually exhibited neurological dysfunction and died. We serially passaged their brain homogenates in mice and cultured cells. We found that the prion strain isolated from IND24-treated mice, designated RML[IND24], emerged during a single passage in treated mice. Although RML prions infect both the N2a and CAD5 cell lines, RML[IND24] prions could only infect CAD5 cells. When passaged in CAD5 cells, the prions remained resistant to high concentrations of IND24. However, one passage of RML[IND24] prions in untreated mice restored susceptibility to IND24 in CAD5 cells. Although IND24 treatment extended the lives of mice propagating different prion strains, including RML, another scrapie-derived prion strain ME7, and chronic wasting disease, it was ineffective in slowing propagation of Creutzfeldt–Jakob disease prions in transgenic mice. Our studies demonstrate that prion strains can acquire resistance upon exposure to IND24 that is lost upon passage in mice in the absence of IND24. These data suggest that monotherapy can select for resistance, thus intermittent therapy with mixtures of antiprion compounds may be required to slow or stop neurodegeneration. PMID:24128760

  13. Cord Blood Methylmercury and Fetal Growth Outcomes in Baltimore Newborns: Potential Confounding and Effect Modification by Omega-3 Fatty Acids, Selenium, and Sex

    PubMed Central

    Wells, Ellen M.; Herbstman, Julie B.; Lin, Yu Hong; Jarrett, Jeffery; Verdon, Carl P.; Ward, Cynthia; Caldwell, Kathleen L.; Hibbeln, Joseph R.; Witter, Frank R.; Halden, Rolf U.; Goldman, Lynn R.

    2015-01-01

    Background Methylmercury (MeHg) may affect fetal growth; however, prior research often lacked assessment of mercury speciation, confounders, and interactions. Objective Our objective was to assess the relationship between MeHg and fetal growth as well as the potential for confounding or interaction of this relationship from speciated mercury, fatty acids, selenium, and sex. Methods This cross-sectional study includes 271 singletons born in Baltimore, Maryland, 2004–2005. Umbilical cord blood was analyzed for speciated mercury, serum omega-3 highly unsaturated fatty acids (n-3 HUFAs), and selenium. Multivariable linear regression models controlled for gestational age, birth weight, maternal age, parity, prepregnancy body mass index, smoking, hypertension, diabetes, selenium, n-3 HUFAs, and inorganic mercury (IHg). Results Geometric mean cord blood MeHg was 0.94 μg/L (95% CI: 0.84, 1.07). In adjusted models for ponderal index, βln(MeHg) = –0.045 (g/cm3) × 100 (95% CI: –0.084, –0.005). There was no evidence of a MeHg × sex interaction with ponderal index. Contrastingly, there was evidence of a MeHg × n-3 HUFAs interaction with birth length [among low n-3 HUFAs, βln(MeHg) = 0.40 cm, 95% CI: –0.02, 0.81; among high n-3 HUFAs, βln(MeHg) = –0.15, 95% CI: –0.54, 0.25; p-interaction = 0.048] and head circumference [among low n-3 HUFAs, βln(MeHg) = 0.01 cm, 95% CI: –0.27, 0.29; among high n-3 HUFAs, βln(MeHg) = –0.37, 95% CI: –0.63, –0.10; p-interaction = 0.042]. The association of MeHg with birth weight and ponderal index was affected by n-3 HUFAs, selenium, and IHg. For birth weight, βln(MeHg) without these variables was –16.8 g (95% CI: –75.0, 41.3) versus –29.7 (95% CI: –93.9, 34.6) with all covariates. Corresponding values for ponderal index were –0.030 (g/cm3) × 100 (95% CI: –0.065, 0.005) and –0.045 (95% CI: –0.084, –0005). Conclusion We observed an association of increased MeHg with decreased ponderal index. There is

  14. Commentary: How can family-based quasi-experimental designs and national registers be used to address confounding in risk factor studies of psychopathology? A reflection on Obel et al. (2016).

    PubMed

    Larsson, Henrik

    2016-04-01

    Standard observational studies have reported a robust correlation between maternal smoking during pregnancy and risk of ADHD in offspring. In the accompanying article, Obel et al. used sibling-comparisons to explore the extent to which unmeasured familial confounding explains this association. This commentary highlights three important implications of the study. At a general level, Obel et al. illustrates how (1) family-based quasi-experimental designs and (2) national registers can be used to address confounding in risk factor studies of psychopathology. At a more specific level, the study suggests that maternal smoking during pregnancy is probably not a causal risk factor for ADHD.

  15. Confounding Factors Affecting the National Institutes of Health (NIH) Chronic Graft-Versus-Host Disease Organ-Specific Score and Global Severity

    PubMed Central

    Aki, Sahika Zeynep; Inamoto, Yoshihiro; Carpenter, Paul A.; Storer, Barry E.; Sandmaier, Brenda M.; Lee, Stephanie J.; Martin, Paul J.; Flowers, Mary E.D.

    2016-01-01

    The 2005 NIH chronic graft-versus-host disease (cGVHD) organ severity is based on the assessment of current status regardless of whether abnormalities are due to GVHD. The score assignment does not require knowledge of past manifestations, attribution, or whether cGVHD is still active. The aim of this study is to describe confounding factors affecting organ scores in patients with cGVHD. The study included 189 consecutive cGVHD patients evaluated at our center in 2013. Providers completed the NIH 0–3 organ-specific scoring evaluation with two questions added for each organ to identify abnormalities that were 1) not attributed to cGVHD, or 2) attributed to cGVHD plus other causes. Abnormalities attributed to causes other than GVHD were recorded. Eighty (14%) abnormalities were not attributed to cGVHD in at least one organ, and 41 (7%) abnormalities were attributed to cGVHD plus other causes in at least one organ. A total of 436 (78%) abnormalities were attributed only to cGVHD. Abnormalities not attributed to cGVHD were observed most frequently in the lung, gastrointestinal tract and skin. Most common abnormalities included pre-transplant condition, sequelae from GVHD, deconditioning, infections and medications. Our results support the the 2014 NIH consensus recommendation to consider attribution when scoring organ abnormalities. PMID:27214071

  16. Diffuse large B-cell lymphoma in colon confounded by prior history of colorectal cancer: A case report and literature review.

    PubMed

    Ren, Yanling; Chen, Zhilu; Su, Chuanyong; Tong, Hongyan; Qian, Wenbin

    2016-02-01

    A 66-year-old male underwent left hemicolectomy for rectal adenocarcinoma in 2008. Five years later he was admitted to hospital with abdominal pain. A computed tomography scan revealed notable thickening of the middle of the ascending colon wall, and colonoscopy revealed an ulcerofungating mass of 3×3 cm in the cecum and extending to the ascending colon. Under the consideration of cancer recurrence, laparoscopic right hemicolectomy was performed directly. Surgical specimens revealed sheets of large pleomorphic lymphoid cells with nuclei of different sizes, nucleoli and mitotic phases visible in most cells. These tested positive for CD45, CD20 and CD79a diffusely, but negative for CD3, CD5, Bcl-2, Bcl-6 and ALK. The Ki-67 proliferation index was 40%. Epstein-Barr virus in situ hybridization did not reveal any positive signals in any of the tumor cells. Based on these findings, the recurrent tumor was diagnosed as diffuse large B-cell lymphoma. The patient could have avoided surgery and received chemotherapy only; however, the case was confounded by the patient's prior history of colorectal cancer due to the rarity of colon lymphoma following rectal cancer in the same patient. It is therefore essential to investigate carefully and differentiate between potential lesions during routine postoperative colonoscopy following colorectal cancer surgery, as patients may present with rare colon lymphoma, which may be confused with a recurrence of colorectal cancer.

  17. The association between whole body vibration exposure and musculoskeletal disorders in the Swedish work force is confounded by lifting and posture

    NASA Astrophysics Data System (ADS)

    Hagberg, Mats; Burström, Lage; Ekman, Anna; Vilhelmsson, Rebecka

    2006-12-01

    This was a cross-sectional study based on material representing the Swedish work-force from a survey conducted in 1999, 2001 and 2003 by Statistics Sweden. Exposure to whole body vibration (WBV) was prevalent among agricultural, forestry, fishery workers and among plant and machinery operators based on a sample of 40,000 employed persons. Approximately 70% responders, that are 9798 persons answered both the interview and the questionnaire for the analysis of exposure-response. Exposure to WBV at least half the working time was associated with prevalence ratios above two for musculoskeletal symptoms in the low back, neck, shoulder/arm and hand among workers. When the exposure factors lifting and frequent bending were added to a multivariate analysis, surprisingly the magnitude of association was low between low back symptoms and WBV exposure. Interestingly, the relation between WBV exposure and symptoms in the neck, shoulder/arm and hand had the same or higher magnitude of association even when the possible confounders were in the model. For the neck, low back and shoulder/arm there was a visible increase in prevalence ratio (as high as 5 times) when combined exposures of WBV, lifting, frequent bending, twisted posture and noise were included in the analysis.

  18. Management of a Septic Open Abdomen Patient with Spontaneous Jejunal Perforation after Emergent C/S with Confounding Factor of Mild Acute Pancreatitis

    PubMed Central

    Yetisir, Fahri; Sarer, Akgün Ebru; Acar, Hasan Zafer; Osmanoglu, Gokhan; Özer, Mehmet; Yaylak, Faik

    2016-01-01

    Introduction. We report the management of a septic Open Abdomen (OA) patient by the help of negative pressure therapy (NPT) and abdominal reapproximation anchor (ABRA) system in pregnant woman with spontaneous jejunal perforation after emergent cesarean section (C/S) with confounding factor of mild acute pancreatitis (AP). Presentation of Case. A 29-year-old and 34-week pregnant woman with AP underwent C/S. She was arrested after anesthesia induction and responded to cardiopulmonary resuscitation (CPR). There were only ash-colored serosanguinous fluid within abdomen during C/S. After C/S, she was transferred to intensive care unit (ICU) with vasopressor support. On postoperative 1st day, she underwent reoperation due to fecal fluid coming near the drainage. Leakage point could not be identified exactly and operation had to be deliberately abbreviated due to hemodynamic instability. NPT was applied. Two days later source control was provided by conversion of enteroatmospheric fistula (EAF) to jejunostomy. ABRA was added and OA was closed. No hernia developed at 10-month follow-up period. Conclusion. NPT application in septic OA patient may gain time to patient until adequate source control could be achieved. Using ABRA in conjunction with NPT increases the fascial closure rate in infected OA patient. PMID:27006853

  19. Conditions for duality between fluxes and concentrations in biochemical networks.

    PubMed

    Fleming, Ronan M T; Vlassis, Nikos; Thiele, Ines; Saunders, Michael A

    2016-11-21

    Mathematical and computational modelling of biochemical networks is often done in terms of either the concentrations of molecular species or the fluxes of biochemical reactions. When is mathematical modelling from either perspective equivalent to the other? Mathematical duality translates concepts, theorems or mathematical structures into other concepts, theorems or structures, in a one-to-one manner. We present a novel stoichiometric condition that is necessary and sufficient for duality between unidirectional fluxes and concentrations. Our numerical experiments, with computational models derived from a range of genome-scale biochemical networks, suggest that this flux-concentration duality is a pervasive property of biochemical networks. We also provide a combinatorial characterisation that is sufficient to ensure flux-concentration duality.The condition prescribes that, for every two disjoint sets of molecular species, there is at least one reaction complex that involves species from only one of the two sets. When unidirectional fluxes and molecular species concentrations are dual vectors, this implies that the behaviour of the corresponding biochemical network can be described entirely in terms of either concentrations or unidirectional fluxes.

  20. Biochemical diagnosis in 3040 kidney stone formers in Argentina.

    PubMed

    Spivacow, Francisco Rodolfo; del Valle, Elisa Elena; Negri, Armando Luis; Fradinger, Erich; Abib, Anabella; Rey, Paula

    2015-08-01

    Nephrolithiasis is a frequent condition in urology that has an important recurrence and high impact in health economy. Knowing the biochemical abnormalities implicated in its pathogenesis is mandatory to establish therapeutic aims. Our objectives are to present the results in 3040 kidney stone formers in Argentina. All patients were selected after completing an ambulatory metabolic protocol with diagnostic purposes. There were 1717 men, (56.48%), with a mean age of 45±12 years, and 1323 women, (43.52%), mean age 44±12 years. 2781 patients had biochemical abnormalities, (91.49%), and were arbitrarily divided in two groups: those who had only one (single) biochemical abnormality (n=2156) and those who had associated abnormalities (n=625). No biochemical abnormalities were found in 259 patients (8.51%). The abnormalities present, single and associated, in order of frequency, were idiopathic hypercalciuria, (56.88%), hyperuricosuria (21.08%), unduly acidic urine (10.95%), hypocitraturia (10.55%), hypomagnesuria (7.9%), primary hyperparathyroidism (3.01%), hyperoxaluria (2.6%), and cystinuria (0.32%). We performed in 484 patient's stone composition and found calcium oxalate stones related to idiopathic hypercalciuria predominantly while uric acid stones to unduly acidic urine. In conclusion, the biochemical abnormalities described are similar to those found in a previous series of our own and to those reported in the literature. Its diagnosis is important to therapeutic purposes to avoid eventual recurrence.

  1. Hematologic and plasma biochemical values of hyacinth macaws (Anodorhynchus hyacinthinus).

    PubMed

    Kolesnikovas, Cristiane K M; Niemeyer, Claudia; Teixeira, Rodrigo H F; Nunes, Adauto L V; Rameh-de-Albuquerque, Luciana C; Sant'Anna, Sávio S; Catão-Dias, José L

    2012-09-01

    The hyacinth macaw (Anodorhyncus hyacinthinus), considered the largest psittacine bird species in the world, is an endangered species, with a remaining population of approximately 6500 birds in the wild. To establish hematologic and plasma biochemical reference ranges and to verify differences related to sex, samples from 29 hyacinth macaws (14 males, 15 females) were obtained from birds apprehended from illegal wildlife trade and subsequently housed at the Sorocaba Zoo, Brazil. No significant differences in hematologic or plasma biochemical values were found between females and males. Compared with published reference values, differences were found in mean concentrations of total red blood cell count, corpuscular volume, corpuscular hemoglobin level, total white blood cell count, aspartate aminotransferase level, creatine kinase concentration, alkaline phosphatase concentration, and phosphorus level. Baseline hematologic and plasma biochemical ranges were established, which may be useful as reference values for clinicians working with this endangered species in captivity or rehabilitation centers.

  2. Hematologic and plasma biochemical values of Spix's macaws (Cyanopsitta spixii).

    PubMed

    Foldenauer, Ulrike; Borjal, Raffy Jim; Deb, Amrita; Arif, Abdi; Taha, Abid Sharif; Watson, Ryan William; Steinmetz, Hanspeter; Bürkle, Marcellus; Hammer, Sven

    2007-12-01

    The Spix's macaw (Cyanopsitta spixii) is considered the world's most endangered parrot, with the last wild bird disappearing in 2001 and only 74 birds in captivity. To establish hematologic and plasma biochemical reference ranges and to look for differences relative to sex, age, and season, we obtained blood samples from 46 captive Spix's macaws (23 male, 23 female) housed in aviaries at the Al Wabra Wildlife Preservation in the State of Qatar. No significant differences in hematologic or plasma biochemical values were found between females and males. Adult and juvenile birds differed in mean concentrations of glucose, total protein, amylase, cholesterol, and phosphorus; in percentages of heterophils and lymphocytes; and in the absolute lymphocyte count. Total protein, cholesterol, and phosphorus concentrations; hematocrit; and heterophil and lymphocyte counts differed significantly by season. Baseline hematologic and plasma biochemical ranges were established, which may be useful as reference values for clinicians working with this highly endangered species.

  3. Click Chemistry-Mediated Nanosensors for Biochemical Assays

    PubMed Central

    Chen, Yiping; Xianyu, Yunlei; Wu, Jing; Yin, Binfeng; Jiang, Xingyu

    2016-01-01

    Click chemistry combined with functional nanoparticles have drawn increasing attention in biochemical assays because they are promising in developing biosensors with effective signal transformation/amplification and straightforward signal readout for clinical diagnostic assays. In this review, we focus on the latest advances of biochemical assays based on Cu (I)-catalyzed 1, 3-dipolar cycloaddition of azides and alkynes (CuAAC)-mediated nanosensors, as well as the functionalization of nanoprobes based on click chemistry. Nanoprobes including gold nanoparticles, quantum dots, magnetic nanoparticles and carbon nanomaterials are covered. We discuss the advantages of click chemistry-mediated nanosensors for biochemical assays, and give perspectives on the development of click chemistry-mediated approaches for clinical diagnosis and other biomedical applications. PMID:27217831

  4. Click Chemistry-Mediated Nanosensors for Biochemical Assays.

    PubMed

    Chen, Yiping; Xianyu, Yunlei; Wu, Jing; Yin, Binfeng; Jiang, Xingyu

    2016-01-01

    Click chemistry combined with functional nanoparticles have drawn increasing attention in biochemical assays because they are promising in developing biosensors with effective signal transformation/amplification and straightforward signal readout for clinical diagnostic assays. In this review, we focus on the latest advances of biochemical assays based on Cu (I)-catalyzed 1, 3-dipolar cycloaddition of azides and alkynes (CuAAC)-mediated nanosensors, as well as the functionalization of nanoprobes based on click chemistry. Nanoprobes including gold nanoparticles, quantum dots, magnetic nanoparticles and carbon nanomaterials are covered. We discuss the advantages of click chemistry-mediated nanosensors for biochemical assays, and give perspectives on the development of click chemistry-mediated approaches for clinical diagnosis and other biomedical applications.

  5. Cloning and characterization of a maize cytochrome-b5 reductase with Fe3+-chelate reduction capability.

    PubMed

    Bagnaresi, P; Thoiron, S; Mansion, M; Rossignol, M; Pupillo, P; Briat, J F

    1999-03-01

    We previously purified an NADH-dependent Fe3+-chelate reductase (NFR) from maize roots with biochemical features of a cytochrome-b5 reductase (b5R) [Sparla, Bagnaresi, Scagliarini and Trost (1997) FEBS Lett. 414, 571-575]. We have now cloned a maize root cDNA that, on the basis of sequence information, calculated parameters and functional assay, codes for NFR. Maize NFR has 66% and 65% similarity to mammal and yeast b5R respectively. It has a deduced molecular mass of 31.17 kDa and a pI of 8.53. An uncharged region is observed at its N-terminus but no myristoylation consensus site is present. Taken together, these results, coupled with previous biochemical evidence, prove that NFR belongs to the b5R class and document b5R from a plant at the molecular level for the first time. We have also identified a putative Arabidopsis thaliana NFR gene. Its organization (nine exons) closely resembles mammalian b5Rs. Several NFR isoforms are expected to exist in maize. They are probably not produced by alternative translational mechanisms as occur in mammals, because of specific constraints observed in the maize NFR cDNA sequence. In contrast with yeast and mammals, tissue-specific and various subcellular localizations of maize b5R isoforms could result from differential expression of the various members of a multigene family. The first molecular characterization of a plant b5R indicates an overall remarkable evolutionary conservation for these versatile reductase systems. In addition, the well-characterized Fe3+-chelate reduction capabilities of NFR, in addition to known Fe3+-haemoglobin reduction roles for mammal b5R isoforms, suggest further and more generalized roles for the b5R class in endocellular iron reduction.

  6. Overview of the DOE/SERI Biochemical Conversion Program

    SciTech Connect

    Wright, J D

    1986-09-01

    The Solar Energy Research Institute manages a program of research and development on the biochemical conversion of renewable lignocellulosic materials to liquid fuels for the Department of Energy's Biofuels and Municipal Waste Technology Division. The Biochemical Conversion Program is mission oriented so effort is concentrated on technologies which appear to have the greatest potential for being adopted by the private sector to economically convert lignocellulosic materials into high value liquid transportation fuels such as ethanol. The program is structured to supply the technology for such fuels to compete economically first as an octane booster or fuel additive, and, with additional improvements, as a neat fuel. 18 refs., 3 figs., 1 tab.

  7. [Biochemical differentiation of proteus strains from various clinical materials].

    PubMed

    Józefowicz-Piatkowska, H; Woch, G

    1993-01-01

    The material consisted of 729 strain of Proteus isolated from clinical samples in three microbiological laboratories of city of Lódź region. Our of these strains, 466 were Proteus mirabilis, and remaining represented: P. penneri-13 strains, P. vulgaris (II biogroup)-56 and 54 strains which were not classifiable on the basis of biochemical properties and scheme elaborated by Hickman et al. for biogroups of P. vulgaris. The authors indicate feasibility of differentiation of P. vulgaris basing on biochemical tests as a supplementary method to other tests of intracellular differentiation of Proteus.

  8. A high prevalence of biochemical evidence of vitamin B12 or folate deficiency does not translate into a comparable prevalence of anemia.

    PubMed

    Metz, Jack

    2008-06-01

    Based on biochemical evidence, a high prevalence of biochemical evidence of vitamin B12 or folate deficiency has been reported in a number of areas in the world. The evidence that these biochemical abnormalities lead to a comparable prevalence of anemia is reviewed. The overall contribution of vitamin B12 deficiency to the global burden of anemia is probably not significant, except perhaps in women and their infants and children in vegetarian communities. In developed countries, folate-deficiency anemia is uncommon. In some developing countries, this anemia is still seen, but there are no comprehensive data on the relative prevalence compared with anemia due to malaria, iron-deficiency, hemoglobinopathy, and HIV disease. It seems unlikely that folate deficiency makes a major contribution to the burden of anemia in developing countries. Iron-deficiency anemia may coexist with vitamin B12 and especially folate deficiency, and may confound the hematological features of the vitamin deficiencies whose prevalence would then be underestimated. Supplementation of the diet of pregnant women with folic acid can virtually eliminate folate-deficiency anemia in these women. There are very few data on the hematological effect of vitamin B12 supplementation or fortification at the population level. The addition of vitamin B12 to the supplementation of the diet of pregnant women with iron and folic acid does not produce an increased hematological response, at least in nonvegetarian populations. There are numerous reports of the effect of folic acid fortification of food on tests of folate status, but only a single published report on the hematological response was found.

  9. The relationship between motor performance and parent-rated executive functioning in 3- to 5-year-old children: What is the role of confounding variables?

    PubMed

    Houwen, Suzanne; van der Veer, Gerda; Visser, Jan; Cantell, Marja

    2017-01-30

    It is generally agreed that motor performance and executive functioning (EF) are intertwined. As the literature on this issue concerning preschool children is scarce, we examined the relationship between motor performance and parent-rated EF in a sample of 3- to 5-year-old children with different levels of motor skill proficiency, while controlling for age, gender, socio-economic status (SES), and attention-deficit-hyperactivity disorder (ADHD) symptomatology. EF was reported by parents of 153 children (mean age 4years 1months, SD 8months; 75 male) by means of the Behaviour Rating Inventory of Executive Function-Preschool version (BRIEF-P). Parent-reported ADHD symptoms were assessed using the Hyperactivity-Inattention subscale of the Strengths and Difficulties Questionnaire3-4. In addition, the children performed the Movement Assessment Battery for Children-2 (MABC-2). Several weak to moderate relationships were found between the MABC-2 Total Score and the EF subscales. Once other variables such as age, gender, SES, and ADHD symptomatology were taken into account, the only BRIEF-P subscale that was associated with the MABC-2 Total Score was the Working Memory subscale. Compared to their typically developing peers, children who are at risk for motor coordination difficulties (⩽the 16th percentile on the MABC-2) performed poorly on the Working Memory subscale, which confirms the results of the regression analyses. The at risk group also performed significantly worse on the Planning/Organize subscale, however. This is one of the first studies investigating the relationship between motor performance and parent-rated EF in such a young age group. It shows that the relationship between motor performance and EF in young children is complex and may be influenced by the presence of confounding variables such as ADHD symptomatology.

  10. Observed effects of “distributional learning” may not relate to the number of peaks. A test of “dispersion” as a confounding factor

    PubMed Central

    Wanrooij, Karin; Boersma, Paul; Benders, Titia

    2015-01-01

    Distributional learning of speech sounds is learning from simply being exposed to frequency distributions of speech sounds in one’s surroundings. In laboratory settings, the mechanism has been reported to be discernible already after a few minutes of exposure, in both infants and adults. These “effects of distributional training” have traditionally been attributed to the difference in the number of peaks between the experimental distribution (two peaks) and the control distribution (one or zero peaks). However, none of the earlier studies fully excluded a possibly confounding effect of the dispersion in the distributions. Additionally, some studies with a non-speech control condition did not control for a possible difference between processing speech and non-speech. The current study presents an experiment that corrects both imperfections. Spanish listeners were exposed to either a bimodal distribution encompassing the Dutch contrast /ɑ/∼/a/ or a unimodal distribution with the same dispersion. Before and after training, their accuracy of categorization of [ɑ]- and [a]-tokens was measured. A traditionally calculated p-value showed no significant difference in categorization improvement between bimodally and unimodally trained participants. Because of this null result, a Bayesian method was used to assess the odds in favor of the null hypothesis. Four different Bayes factors, each calculated on a different belief in the truth value of previously found effect sizes, indicated the absence of a difference between bimodally and unimodally trained participants. The implication is that “effects of distributional training” observed in the lab are not induced by the number of peaks in the distributions. PMID:26441719

  11. Distance to High-Voltage Power Lines and Risk of Childhood Leukemia – an Analysis of Confounding by and Interaction with Other Potential Risk Factors

    PubMed Central

    Pedersen, Camilla; Bräuner, Elvira V.; Rod, Naja H.; Albieri, Vanna; Andersen, Claus E.; Ulbak, Kaare; Hertel, Ole; Johansen, Christoffer; Schüz, Joachim; Raaschou-Nielsen, Ole

    2014-01-01

    We investigated whether there is an interaction between distance from residence at birth to nearest power line and domestic radon and traffic-related air pollution, respectively, in relation to childhood leukemia risk. Further, we investigated whether adjusting for potential confounders alters the association between distance to nearest power line and childhood leukemia. We included 1024 cases aged <15, diagnosed with leukemia during 1968–1991, from the Danish Cancer Registry and 2048 controls randomly selected from the Danish childhood population and individually matched by gender and year of birth. We used geographical information systems to determine the distance between residence at birth and the nearest 132–400 kV overhead power line. Concentrations of domestic radon and traffic-related air pollution (NOx at the front door) were estimated using validated models. We found a statistically significant interaction between distance to nearest power line and domestic radon regarding risk of childhood leukemia (p = 0.01) when using the median radon level as cut-off point but not when using the 75th percentile (p = 0.90). We found no evidence of an interaction between distance to nearest power line and traffic-related air pollution (p = 0.73). We found almost no change in the estimated association between distance to power line and risk of childhood leukemia when adjusting for socioeconomic status of the municipality, urbanization, maternal age, birth order, domestic radon and traffic-related air pollution. The statistically significant interaction between distance to nearest power line and domestic radon was based on few exposed cases and controls and sensitive to the choice of exposure categorization and might, therefore, be due to chance. PMID:25259740

  12. Distance to high-voltage power lines and risk of childhood leukemia--an analysis of confounding by and interaction with other potential risk factors.

    PubMed

    Pedersen, Camilla; Bräuner, Elvira V; Rod, Naja H; Albieri, Vanna; Andersen, Claus E; Ulbak, Kaare; Hertel, Ole; Johansen, Christoffer; Schüz, Joachim; Raaschou-Nielsen, Ole

    2014-01-01

    We investigated whether there is an interaction between distance from residence at birth to nearest power line and domestic radon and traffic-related air pollution, respectively, in relation to childhood leukemia risk. Further, we investigated whether adjusting for potential confounders alters the association between distance to nearest power line and childhood leukemia. We included 1024 cases aged <15, diagnosed with leukemia during 1968-1991, from the Danish Cancer Registry and 2048 controls randomly selected from the Danish childhood population and individually matched by gender and year of birth. We used geographical information systems to determine the distance between residence at birth and the nearest 132-400 kV overhead power line. Concentrations of domestic radon and traffic-related air pollution (NOx at the front door) were estimated using validated models. We found a statistically significant interaction between distance to nearest power line and domestic radon regarding risk of childhood leukemia (p = 0.01) when using the median radon level as cut-off point but not when using the 75th percentile (p = 0.90). We found no evidence of an interaction between distance to nearest power line and traffic-related air pollution (p = 0.73). We found almost no change in the estimated association between distance to power line and risk of childhood leukemia when adjusting for socioeconomic status of the municipality, urbanization, maternal age, birth order, domestic radon and traffic-related air pollution. The statistically significant interaction between distance to nearest power line and domestic radon was based on few exposed cases and controls and sensitive to the choice of exposure categorization and might, therefore, be due to chance.

  13. Chemical and biochemical thermodynamics: Is it time for a reunification?

    PubMed

    Iotti, Stefano; Raff, Lionel; Sabatini, Antonio

    2017-02-01

    The thermodynamics of chemical reactions in which all species are explicitly considered with atoms and charge balanced is compared with the transformed thermodynamics generally used to treat biochemical reactions where atoms and charges are not balanced. The transformed thermodynamic quantities suggested by Alberty are obtained by execution of Legendre transformation of the usual thermodynamic potentials. The present analysis demonstrates that the transformed values for ΔrG'(0) and ΔrH'(0)can be obtained directly without performing Legendre transformations by simply writing the chemical reactions with all the pseudoisomers explicitly included and charges balanced. The appropriate procedures for computing the stoichiometric coefficients for the pseudoisomers are fully explained by means of an example calculation for the biochemical ATP hydrolysis reaction. It is concluded that the analysis has reunited the "two separate worlds" of conventional thermodynamics and transformed thermodynamics. In addition, it is also shown that the value of the conditional Gibbs energy of reaction, ΔrG', for a biochemical reaction is the same of the value of ΔrG for any chemical reaction involving pseudoisomers of the biochemical reagents.

  14. Biochemical and physiological consequences of the Apollo flight diet.

    NASA Technical Reports Server (NTRS)

    Hander, E. W.; Leach, C. S.; Fischer, C. L.; Rummel, J.; Rambaut, P.; Johnson, P. C.

    1971-01-01

    Six male subjects subsisting on a typical Apollo flight diet for five consecutive days were evaluated for changes in biochemical and physiological status. Laboratory examinations failed to demonstrate any significant changes of the kind previously attributed to weightlessness, such as in serum electrolytes, endocrine values, body fluid, or hematologic parameters.

  15. MATLAB-Based Teaching Modules in Biochemical Engineering

    ERIC Educational Resources Information Center

    Lee, Kilho; Comolli, Noelle K.; Kelly, William J.; Huang, Zuyi

    2015-01-01

    Mathematical models play an important role in biochemical engineering. For example, the models developed in the field of systems biology have been used to identify drug targets to treat pathogens such as Pseudomonas aeruginosa in biofilms. In addition, competitive binding models for chromatography processes have been developed to predict expanded…

  16. Biochemical markers of spontaneous preterm birth in asymptomatic women.

    PubMed

    Chan, Ronna L

    2014-01-01

    Preterm birth is a delivery that occurs at less than 37 completed weeks of gestation and it is associated with perinatal morbidity and mortality. Spontaneous preterm birth accounts for up to 75% of all preterm births. A number of maternal or fetal characteristics have been associated with preterm birth, but the use of individual or group biochemical markers have advanced some of the understanding on the mechanisms leading to spontaneous preterm birth. This paper provides a summary on the current literature on the use of biochemical markers in predicting spontaneous preterm birth in asymptomatic women. Evidence from the literature suggests fetal fibronectin, cervical interleukin-6, and α-fetoprotein as promising biochemical markers in predicting spontaneous preterm birth in asymptomatic women. The role of gene-gene and gene-environment interactions, as well as epigenetics, has the potential to further elucidate and improve understanding of the underlying mechanisms or pathways of spontaneous preterm birth. Refinement in study design and methodology is needed in future research for the development and validation of individual or group biochemical marker(s) for use independently or in conjunction with other potential risk factors such as genetic variants and environmental and behavioral factors in predicting spontaneous preterm birth across diverse populations.

  17. Solving the differential biochemical Jacobian from metabolomics covariance data.

    PubMed

    Nägele, Thomas; Mair, Andrea; Sun, Xiaoliang; Fragner, Lena; Teige, Markus; Weckwerth, Wolfram

    2014-01-01

    High-throughput molecular analysis has become an integral part in organismal systems biology. In contrast, due to a missing systematic linkage of the data with functional and predictive theoretical models of the underlying metabolic network the understanding of the resulting complex data sets is lacking far behind. Here, we present a biomathematical method addressing this problem by using metabolomics data for the inverse calculation of a biochemical Jacobian matrix, thereby linking computer-based genome-scale metabolic reconstruction and in vivo metabolic dynamics. The incongruity of metabolome coverage by typical metabolite profiling approaches and genome-scale metabolic reconstruction was solved by the design of superpathways to define a metabolic interaction matrix. A differential biochemical Jacobian was calculated using an approach which links this metabolic interaction matrix and the covariance of metabolomics data satisfying a Lyapunov equation. The predictions of the differential Jacobian from real metabolomic data were found to be correct by testing the corresponding enzymatic activities. Moreover it is demonstrated that the predictions of the biochemical Jacobian matrix allow for the design of parameter optimization strategies for ODE-based kinetic models of the system. The presented concept combines dynamic modelling strategies with large-scale steady state profiling approaches without the explicit knowledge of individual kinetic parameters. In summary, the presented strategy allows for the identification of regulatory key processes in the biochemical network directly from metabolomics data and is a fundamental achievement for the functional interpretation of metabolomics data.

  18. Study on color difference estimation method of medicine biochemical analysis

    NASA Astrophysics Data System (ADS)

    Wang, Chunhong; Zhou, Yue; Zhao, Hongxia; Sun, Jiashi; Zhou, Fengkun

    2006-01-01

    The biochemical analysis in medicine is an important inspection and diagnosis method in hospital clinic. The biochemical analysis of urine is one important item. The Urine test paper shows corresponding color with different detection project or different illness degree. The color difference between the standard threshold and the test paper color of urine can be used to judge the illness degree, so that further analysis and diagnosis to urine is gotten. The color is a three-dimensional physical variable concerning psychology, while reflectance is one-dimensional variable; therefore, the estimation method of color difference in urine test can have better precision and facility than the conventional test method with one-dimensional reflectance, it can make an accurate diagnose. The digital camera is easy to take an image of urine test paper and is used to carry out the urine biochemical analysis conveniently. On the experiment, the color image of urine test paper is taken by popular color digital camera and saved in the computer which installs a simple color space conversion (RGB -> XYZ -> L *a *b *)and the calculation software. Test sample is graded according to intelligent detection of quantitative color. The images taken every time were saved in computer, and the whole illness process will be monitored. This method can also use in other medicine biochemical analyses that have relation with color. Experiment result shows that this test method is quick and accurate; it can be used in hospital, calibrating organization and family, so its application prospect is extensive.

  19. The use of biochemical methods in extraterrestrial life detection

    NASA Astrophysics Data System (ADS)

    McDonald, Gene

    2006-08-01

    Instrument development for in situ extraterrestrial life detection focuses primarily on the ability to distinguish between biological and non-biological material, mostly through chemical analysis for potential biosignatures (e.g., biogenic minerals, enantiomeric excesses). In constrast, biochemical analysis techniques commonly applied to Earth life focus primarily on the exploration of cellular and molecular processes, not on the classification of a given system as biological or non-biological. This focus has developed because of the relatively large functional gap between life and non-life on Earth today. Life on Earth is very diverse from an environmental and physiological point of view, but is highly conserved from a molecular point of view. Biochemical analysis techniques take advantage of this similarity of all terrestrial life at the molecular level, particularly through the use of biologically-derived reagents (e.g., DNA polymerases, antibodies), to enable analytical methods with enormous sensitivity and selectivity. These capabilities encourage consideration of such reagents and methods for use in extraterrestrial life detection instruments. The utility of this approach depends in large part on the (unknown at this time) degree of molecular compositional differences between extraterrestrial and terrestrial life. The greater these differences, the less useful laboratory biochemical techniques will be without significant modification. Biochemistry and molecular biology methods may need to be "de-focused" in order to produce instruments capable of unambiguously detecting a sufficiently wide range of extraterrestrial biochemical systems. Modern biotechnology tools may make that possible in some cases.

  20. Solving the Differential Biochemical Jacobian from Metabolomics Covariance Data

    PubMed Central

    Nägele, Thomas; Mair, Andrea; Sun, Xiaoliang; Fragner, Lena; Teige, Markus; Weckwerth, Wolfram

    2014-01-01

    High-throughput molecular analysis has become an integral part in organismal systems biology. In contrast, due to a missing systematic linkage of the data with functional and predictive theoretical models of the underlying metabolic network the understanding of the resulting complex data sets is lacking far behind. Here, we present a biomathematical method addressing this problem by using metabolomics data for the inverse calculation of a biochemical Jacobian matrix, thereby linking computer-based genome-scale metabolic reconstruction and in vivo metabolic dynamics. The incongruity of metabolome coverage by typical metabolite profiling approaches and genome-scale metabolic reconstruction was solved by the design of superpathways to define a metabolic interaction matrix. A differential biochemical Jacobian was calculated using an approach which links this metabolic interaction matrix and the covariance of metabolomics data satisfying a Lyapunov equation. The predictions of the differential Jacobian from real metabolomic data were found to be correct by testing the corresponding enzymatic activities. Moreover it is demonstrated that the predictions of the biochemical Jacobian matrix allow for the design of parameter optimization strategies for ODE-based kinetic models of the system. The presented concept combines dynamic modelling strategies with large-scale steady state profiling approaches without the explicit knowledge of individual kinetic parameters. In summary, the presented strategy allows for the identification of regulatory key processes in the biochemical network directly from metabolomics data and is a fundamental achievement for the functional interpretation of metabolomics data. PMID:24695071

  1. Metabolic decompensation in methylmalonic aciduria: which biochemical parameters are discriminative?

    PubMed

    Zwickler, Tamaris; Haege, Gisela; Riderer, Alina; Hörster, Friederike; Hoffmann, Georg F; Burgard, Peter; Kölker, Stefan

    2012-09-01

    Recurrent, life-threatening metabolic decompensations often occur in patients with methylmalonic aciduria (MMAuria). Our study evaluated (impending) metabolic decompensations in these patients aiming to identify the most frequent and reliable clinical and biochemical abnormalities that could be helpful for decision-making on when to start an emergency treatment. Seventy-six unscheduled and 179 regular visits of 10 patients with confirmed MMAuria continuously followed by our metabolic centre between 1975 and 2009 were analysed. The most frequent symptom of an impending acute metabolic decompensation was vomiting (90% of episodes), whereas symptoms of intercurrent infectious disease (29%) or other symptoms (such as food refusal and impaired consciousness) were found less often. Thirty-five biochemical parameters were included in the analysis. Among them, pathological changes of acid-base balance reflecting metabolic acidosis with partial respiratory compensation (decreased pH, pCO(2), standard bicarbonate, and base excess) and elevated ammonia were the most reliable biochemical parameters for the identification of a metabolic decompensation and the estimation of its severity. In contrast, analyses of organic acids, acylcarnitines and carnitine status were less discriminative. In conclusion, careful history taking and identification of suspicious symptoms in combination with a small number of rapidly available biochemical parameters are helpful to differentiate compensated metabolic condition and (impending) metabolic crisis and to decide when to start an emergency treatment.

  2. Classic and contemporary approaches to modeling biochemical reactions

    PubMed Central

    Chen, William W.; Niepel, Mario; Sorger, Peter K.

    2010-01-01

    Recent interest in modeling biochemical networks raises questions about the relationship between often complex mathematical models and familiar arithmetic concepts from classical enzymology, and also about connections between modeling and experimental data. This review addresses both topics by familiarizing readers with key concepts (and terminology) in the construction, validation, and application of deterministic biochemical models, with particular emphasis on a simple enzyme-catalyzed reaction. Networks of coupled ordinary differential equations (ODEs) are the natural language for describing enzyme kinetics in a mass action approximation. We illustrate this point by showing how the familiar Briggs-Haldane formulation of Michaelis-Menten kinetics derives from the outer (or quasi-steady-state) solution of a dynamical system of ODEs describing a simple reaction under special conditions. We discuss how parameters in the Michaelis-Menten approximation and in the underlying ODE network can be estimated from experimental data, with a special emphasis on the origins of uncertainty. Finally, we extrapolate from a simple reaction to complex models of multiprotein biochemical networks. The concepts described in this review, hitherto of interest primarily to practitioners, are likely to become important for a much broader community of cellular and molecular biologists attempting to understand the promise and challenges of “systems biology” as applied to biochemical mechanisms. PMID:20810646

  3. Biosensors and bioelectronics on smartphone for portable biochemical detection.

    PubMed

    Zhang, Diming; Liu, Qingjun

    2016-01-15

    Smartphone has been widely integrated with sensors, such as test strips, sensor chips, and hand-held detectors, for biochemical detections due to its portability and ubiquitous availability. Utilizing built-in function modules, smartphone is often employed as controller, analyzer, and displayer for rapid, real-time, and point-of-care monitoring, which can significantly simplify design and reduce cost of the detecting systems. This paper presents a review of biosensors and bioelectronics on smartphone for portable biochemical detections. The biosensors and bioelectronics based on smartphone can mainly be classified into biosensors using optics, surface plasmon resonance, electrochemistry, and near-field communication. The developments of these biosensors and bioelectronics on smartphone are reviewed along with typical biochemical detecting cases. Sensor strategies, detector attachments, and coupling methods are highlighted to show designs of the compact, lightweight, and low-cost sensor systems. The performances and advantages of these designs are introduced with their applications in healthcare diagnosis, environment monitoring, and food evaluation. With advances in micro-manufacture, sensor technology, and miniaturized electronics, biosensor and bioelectronic devices on smartphone can be used to perform biochemical detections as common and convenient as electronic tag readout in foreseeable future.

  4. The biochemical properties of antibodies and their fragments

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Immunoglobulins (Ig) or antibodies are a powerful molecular recognition tools that can be used to identify minute quantities of a given target analyte. Their antigen binding properties define both the sensitivity and selectivity of an immunoassay. Understanding the biochemical properties of this c...

  5. A MULTILAYER BIOCHEMICAL DRY DEPOSITION MODEL 1. MODEL FORMULATION

    EPA Science Inventory

    A multilayer biochemical dry deposition model has been developed based on the NOAA Multilayer Model (MLM) to study gaseous exchanges between the soil, plants, and the atmosphere. Most of the parameterizations and submodels have been updated or replaced. The numerical integration ...

  6. A MULTILAYER BIOCHEMICAL DRY DEPOSITION MODEL 2. MODEL EVALUATION

    EPA Science Inventory

    The multilayer biochemical dry deposition model (MLBC) described in the accompanying paper was tested against half-hourly eddy correlation data from six field sites under a wide range of climate conditions with various plant types. Modeled CO2, O3, SO2<...

  7. Physiologic and biochemical aspects of skeletal muscle denervation and reinnervation

    NASA Technical Reports Server (NTRS)

    Max, S. R.; Mayer, R. F.

    1984-01-01

    Some of the physiologic and biochemical changes that occur in mammalian skeletal muscle following denervation and reinnervation are considered and some comparisons are made with changes observed following altered motor function. The nature of the trophic influence by which nerves control muscle properties are discussed, including the effects of choline acetyltransferase and acetylcholinesterase and the role of the acetylcholine receptor.

  8. Metstoich--Teaching Quantitative Metabolism and Energetics in Biochemical Engineering

    ERIC Educational Resources Information Center

    Wong, Kelvin W. W.; Barford, John P.

    2010-01-01

    Metstoich, a metabolic calculator developed for teaching, can provide a novel way to teach quantitative metabolism to biochemical engineering students. It can also introduce biochemistry/life science students to the quantitative aspects of life science subjects they have studied. Metstoich links traditional biochemistry-based metabolic approaches…

  9. [Strategies for diagnosis and biochemical control of porphyrias].

    PubMed

    Brock, Axel; Rasmussen, Lars Melholt; Hertz, Jens Michael

    2014-02-17

    Porphyrias are rare, distinct and well characterized diseases due to impairment of one of the eight steps in the biosynthesis of haem, which is the functional group of haemoglobin, myoglobin and cytochromes, including the cytochrome P-450 family. The actual strategies for diagnosis and biochemical control of the five most common porphyrias are described.

  10. Development of a new first-aid biochemical detector

    NASA Astrophysics Data System (ADS)

    Hu, Jingfei; Liao, Haiyang; Su, Shilin; Ding, Hao; Liu, Suquan

    2016-10-01

    The traditional biochemical detector exhibits poor adaptability, inconvenient carrying and slow detection, which can't meet the needs of first-aid under field condition like natural or man-made disasters etc. Therefore a scheme of first-aid biochemical detector based on MOMES Micro Spectrometer, UV LED and Photodiode was proposed. An optical detection structure combined continuous spectrum sweep with fixed wavelength measurement was designed, which adopted mobile detection optical path consisting of Micro Spectrometer and Halogen Lamp to detect Chloride (Cl-), Creatinine (Cre), Glucose (Glu), Hemoglobin (Hb). The UV LED and Photodiode were designed to detect Potassium (K-), Carbon dioxide (CO2), Sodium (Na+). According to the field diagnosis and treatment requirements, we designed the embedded control hardware circuit and software system, the prototype of first-aid biochemical detector was developed and the clinical trials were conducted. Experimental results show that the sample's absorbance repeatability is less than 2%, the max coefficient of variation (CV) in the batch repeatability test of all 7 biochemical parameters in blood samples is 4.68%, less than the clinical requirements 10%, the correlation coefficient (R2) in the clinical contrast test with AU5800 is almost greater than 0.97. To sum up, the prototype meets the requirements of clinical application.

  11. [Experiments using rats on Kosmos biosatellites: morphologic and biochemical studies].

    PubMed

    Il'in, E A; Kaplanskiĭ, A S; Savina, E A

    1989-01-01

    Results of morphological and biochemical investigations of rats flown on Cosmos biosatellites are discussed. It is emphasized that most changes occurring during exposure to microgravity are directly or indirectly related to lower musculoskeletal loads which in turn produce deconditioning of different physiological systems and organism as a whole. It is concluded that this deconditioning is associated with both metabolic and structural changes.

  12. Biochemical Markers of Brain Injury: Applications to Combat Casualty Care

    DTIC Science & Technology

    2004-09-01

    these failures [6]. Unlike other organ-based diseases where rapid diagnosis employing biomarkers (usually involving blood tests) prove invaluable...implementation of appropriate triage and medical management. Criteria For Biochemical/Surrogate Markers: In the course of research on biomarkers ...our laboratories have developed criteria for biomarker development. As reflected in the present proposal, useful biomarkers should employ readily

  13. Biochemical Parameters of Orienteers Competing in a Long Distance Race.

    ERIC Educational Resources Information Center

    Mikan, Vladimir; And Others

    1992-01-01

    Measured important biochemical parameters in a group of orienteers two hours before beginning and immediately after an orienteering marathon. Found levels of dehydration. Suggests a drinking regimen which is designed for orienteering races. Concludes that no runner having kidney or liver abnormalities or changes in the urine should be allowed to…

  14. Biochemical and Structural Studies of RNA Modification and Repair

    ERIC Educational Resources Information Center

    Chan, Chio Mui

    2009-01-01

    RNA modification, RNA interference, and RNA repair are important events in the cell. This thesis presents three projects related to these three fields. By using both biochemical and structural methods, we characterized enzymatic activities of pseudouridine synthase TruD, solved the structure of "A. aeolicus" GidA, and reconstituted a novel…

  15. The Stereochemistry of Biochemical Molecules: A Subject to Revisit

    ERIC Educational Resources Information Center

    Centelles, Josep J.; Imperial, Santiago

    2005-01-01

    Although Fischer's convention for stereoisomers is useful for simple molecules, the stereochemistry of complex biochemical molecules is often poorly indicated in textbooks. This article reports on errors in stereochemistry of complex hydrosoluble vitamin B12 molecule. Twenty-five popular biochemistry textbooks were examined for their treatment of…

  16. BIOCHEMICAL INDICES OF EXPOSURE TO ENVIRONMENTAL ESTROGENS: A SPECIES COMPARISON

    EPA Science Inventory

    Existence of endocrine active substances in the aquatic environment has been clearly established in several studies. Exposure of organisms to both natural and synthetic xenoestrogens have been found to alter biochemical homeostatis and, in some cases, result in reproductive and d...

  17. Biochemical correlates in an animal model of depression

    SciTech Connect

    Johnson, J.O.

    1986-01-01

    A valid animal model of depression was used to explore specific adrenergic receptor differences between rats exhibiting aberrant behavior and control groups. Preliminary experiments revealed a distinct upregulation of hippocampal beta-receptors (as compared to other brain regions) in those animals acquiring a response deficit as a result of exposure to inescapable footshock. Concurrent studies using standard receptor binding techniques showed no large changes in the density of alpha-adrenergic, serotonergic, or dopaminergic receptor densities. This led to the hypothesis that the hippocampal beta-receptor in responses deficient animals could be correlated with the behavioral changes seen after exposure to the aversive stimulus. Normalization of the behavior through the administration of antidepressants could be expected to reverse the biochemical changes if these are related to the mechanism of action of antidepressant drugs. This study makes three important points: (1) there is a relevant biochemical change in the hippocampus of response deficient rats which occurs in parallel to a well-defined behavior, (2) the biochemical and behavioral changes are normalized by antidepressant treatments exhibiting both serotonergic and adrenergic mechanisms of action, and (3) the mode of action of antidepressants in this model is probably a combination of serotonergic and adrenergic influences modulating the hippocampal beta-receptor. These results are discussed in relation to anatomical and biochemical aspects of antidepressant action.

  18. Physiological, biochemical and transcriptional analysis of onion bulbs during storage

    PubMed Central

    Chope, Gemma A.; Cools, Katherine; Hammond, John P.; Thompson, Andrew J.; Terry, Leon A.

    2012-01-01

    Background and Aims During the transition from endo-dormancy to eco-dormancy and subsequent growth, the onion bulb undergoes the transition from sink organ to source, to sustain cell division in the meristematic tissue. The mechanisms controlling these processes are not fully understood. Here, a detailed analysis of whole onion bulb physiological, biochemical and transcriptional changes in response to sprouting is reported, enabling a better knowledge of the mechanisms regulating post-harvest onion sprout development. Methods Biochemical and physiological analyses were conducted on different cultivars (‘Wellington’, ‘Sherpa’ and ‘Red Baron’) grown at different sites over 3 years, cured at different temperatures (20, 24 and 28 °C) and stored under different regimes (1, 3, 6 and 6 → 1 °C). In addition, the first onion oligonucleotide microarray was developed to determine differential gene expression in onion during curing and storage, so that transcriptional changes could support biochemical and physiological analyses. Key Results There were greater transcriptional differences between samples at harvest and before sprouting than between the samples taken before and after sprouting, with some significant changes occurring during the relatively short curing period. These changes are likely to represent the transition from endo-dormancy to sprout suppression, and suggest that endo-dormancy is a relatively short period ending just after curing. Principal component analysis of biochemical and physiological data identified the ratio of monosaccharides (fructose and glucose) to disaccharide (sucrose), along with the concentration of zeatin riboside, as important factors in discriminating between sprouting and pre-sprouting bulbs. Conclusions These detailed analyses provide novel insights into key regulatory triggers for sprout dormancy release in onion bulbs and provide the potential for the development of biochemical or transcriptional markers for sprout

  19. Accurate atom-mapping computation for biochemical reactions.

    PubMed

    Latendresse, Mario; Malerich, Jeremiah P; Travers, Mike; Karp, Peter D

    2012-11-26

    The complete atom mapping of a chemical reaction is a bijection of the reactant atoms to the product atoms that specifies the terminus of each reactant atom. Atom mapping of biochemical reactions is useful for many applications of systems biology, in particular for metabolic engineering where synthesizing new biochemical pathways has to take into account for the number of carbon atoms from a source compound that are conserved in the synthesis of a target compound. Rapid, accurate computation of the atom mapping(s) of a biochemical reaction remains elusive despite significant work on this topic. In particular, past researchers did not validate the accuracy of mapping algorithms. We introduce a new method for computing atom mappings called the minimum weighted edit-distance (MWED) metric. The metric is based on bond propensity to react and computes biochemically valid atom mappings for a large percentage of biochemical reactions. MWED models can be formulated efficiently as Mixed-Integer Linear Programs (MILPs). We have demonstrated this approach on 7501 reactions of the MetaCyc database for which 87% of the models could be solved in less than 10 s. For 2.1% of the reactions, we found multiple optimal atom mappings. We show that the error rate is 0.9% (22 reactions) by comparing these atom mappings to 2446 atom mappings of the manually curated Kyoto Encyclopedia of Genes and Genomes (KEGG) RPAIR database. To our knowledge, our computational atom-mapping approach is the most accurate and among the fastest published to date. The atom-mapping data will be available in the MetaCyc database later in 2012; the atom-mapping software will be available within the Pathway Tools software later in 2012.

  20. Students' Ability to Organize Biochemical and Biochemistry-Related Terms Correlates with Their Performance in a Biochemical Examination

    ERIC Educational Resources Information Center

    Nagata, Ryoichi

    2007-01-01

    Organization is believed to be related to understanding and memory. Whether this belief was applicable in biochemical education was examined about two years after students had experienced biochemistry classes in their first year. The ability of organizing information in biochemistry was judged from the number of correct links of 886 biochemical…

  1. Uroncor consensus statement: Management of biochemical recurrence after radical radiotherapy for prostate cancer: From biochemical failure to castration resistance.

    PubMed

    López Torrecilla, José; Hervás, Asunción; Zapatero, Almudena; Gómez Caamaño, Antonio; Macías, Victor; Herruzo, Ismael; Maldonado, Xavier; Gómez Iturriaga, Alfonso; Casas, Francesc; González San Segundo, Carmen

    2015-01-01

    Management of patients who experience biochemical failure after radical radiotherapy with or without hormonal therapy is highly challenging. The clinician must not only choose the type of treatment, but also the timing and optimal sequence of treatment administration. When biochemical failure occurs, numerous treatment scenarios are possible, thus making it more difficult to select the optimal approach. Moreover, rapid and ongoing advances in treatment options require that physicians make decisions that could impact both survival and quality of life. The aim of the present consensus statement, developed by the Urological Tumour Working Group (URONCOR) of the Spanish Society of Radiation Oncology (SEOR), is to provide cancer specialists with the latest, evidence-based information needed to make the best decisions for the patient under all possible treatment scenarios. The structure of this consensus statement follows the typical development of disease progression after biochemical failure, with the most appropriate treatment recommendations given for each stage. The consensus statement is organized into three separate chapters, as follows: biochemical failure with or without local recurrence and/or metastasis; progression after salvage therapy; and treatment of castration-resistant patients.

  2. Uroncor consensus statement: Management of biochemical recurrence after radical radiotherapy for prostate cancer: From biochemical failure to castration resistance

    PubMed Central

    López Torrecilla, José; Hervás, Asunción; Zapatero, Almudena; Gómez Caamaño, Antonio; Macías, Victor; Herruzo, Ismael; Maldonado, Xavier; Gómez Iturriaga, Alfonso; Casas, Francesc; González San Segundo, Carmen

    2015-01-01

    Management of patients who experience biochemical failure after radical radiotherapy with or without hormonal therapy is highly challenging. The clinician must not only choose the type of treatment, but also the timing and optimal sequence of treatment administration. When biochemical failure occurs, numerous treatment scenarios are possible, thus making it more difficult to select the optimal approach. Moreover, rapid and ongoing advances in treatment options require that physicians make decisions that could impact both survival and quality of life. The aim of the present consensus statement, developed by the Urological Tumour Working Group (URONCOR) of the Spanish Society of Radiation Oncology (SEOR), is to provide cancer specialists with the latest, evidence-based information needed to make the best decisions for the patient under all possible treatment scenarios. The structure of this consensus statement follows the typical development of disease progression after biochemical failure, with the most appropriate treatment recommendations given for each stage. The consensus statement is organized into three separate chapters, as follows: biochemical failure with or without local recurrence and/or metastasis; progression after salvage therapy; and treatment of castration-resistant patients. PMID:26109913

  3. Is the Association between Vitamin D and Cardiovascular Disease Risk Confounded by Obesity? Evidence from the Andhra Pradesh Children and Parents Study (APCAPS)

    PubMed Central

    Baker, Christopher Paul; Kulkarni, Bharati; Radhakrishna, K. V.; Charyulu, M. S.; Gregson, John; Matsuzaki, Mika; Taylor, Amy E.; Prabhakaran, Dorairaj; Mamidi, Raja Sriswan; Wells, Jonathan; Wilkinson, Ian; McEniery, Carmel; Yasmin; Davey Smith, George; Ben-Shlomo, Yoav; Kuper, Hannah; Kinra, Sanjay

    2015-01-01

    -causal. Instead, it may be attributable to confounding by lifestyle factors such as obesity and physical inactivity which may provide more fruitful targets for cardiovascular disease prevention. PMID:26079685

  4. National Bioenergy Center Biochemical Platform Integration Project: Quarterly Update #26, January - March 2010

    SciTech Connect

    Schell, D.

    2010-04-01

    January-March, 2010 edition of the National Bioenergy Center's Biochemical Platform Integration Project quarterly newsletter. Issue topics: understanding and improving sugar measurements in biomass hydrolysates; expansion of the NREL/DOE Biochemical Pilot Plant.

  5. ESTIMATING GASEOUS EXCHANGES BETWEEN THE ATMOSPHERE AND PLANTS USING A COUPLED BIOCHEMICAL DRY DEPOSITION MODEL

    EPA Science Inventory

    To study gaseous exchanges between the soil, biosphere and atmosphere, a biochemical model was coupled with the latest version of Meyers Multi-Layer Deposition Model. The biochemical model describes photosynthesis and respiration and their coupling with stomatal resistance for...

  6. Exploring and Understanding the Biochemical Diversity of the Human Microbiota.

    PubMed

    Koppel, Nitzan; Balskus, Emily P

    2016-01-21

    Recent studies have illuminated a remarkable diversity and abundance of microbes living on and within the human body. While we are beginning to appreciate associations of certain bacteria and genes with particular host physiological states, considerable information is lacking about the relevant functional activities of the human microbiota. The human gut microbiome encodes tremendous potential for the biosynthesis and transformation of compounds that are important for both microbial and host physiology. Implementation of chemical knowledge and techniques will be required to improve our understanding of the biochemical diversity of the human microbiota. Such efforts include the characterization of novel microbial enzymes and pathways, isolation of microbial natural products, and development of tools to modulate biochemical functions of the gut microbiota. Ultimately, a molecular understanding of gut microbial activities will be critical for elucidating and manipulating these organisms' contributions to human health and disease.

  7. Electrolyte-Gated Graphene Ambipolar Frequency Multipliers for Biochemical Sensing.

    PubMed

    Fu, Wangyang; Feng, Lingyan; Mayer, Dirk; Panaitov, Gregory; Kireev, Dmitry; Offenhäusser, Andreas; Krause, Hans-Joachim

    2016-04-13

    In this Letter, the ambipolar properties of an electrolyte-gated graphene field-effect transistor (GFET) have been explored to fabricate frequency-doubling biochemical sensor devices. By biasing the ambipolar GFETs in a common-source configuration, an input sinusoidal voltage at frequency f applied to the electrolyte gate can be rectified to a sinusoidal wave at frequency 2f at the drain electrode. The extraordinary high carrier mobility of graphene and the strong electrolyte gate coupling provide the graphene ambipolar frequency doubler an unprecedented unity gain, as well as a detection limit of ∼4 pM for 11-mer single strand DNA molecules in 1 mM PBS buffer solution. Combined with an improved drift characteristics and an enhanced low-frequency 1/f noise performance by sampling at doubled frequency, this good detection limit suggests the graphene ambipolar frequency doubler a highly promising biochemical sensing platform.

  8. The genetic and biochemical basis of FANCD2 monoubiquitination.

    PubMed

    Rajendra, Eeson; Oestergaard, Vibe H; Langevin, Frédéric; Wang, Meng; Dornan, Gillian L; Patel, Ketan J; Passmore, Lori A

    2014-06-05

    Fanconi anaemia (FA) is a cancer predisposition syndrome characterized by cellular sensitivity to DNA interstrand crosslinkers. The molecular defect in FA is an impaired DNA repair pathway. The critical event in activating this pathway is monoubiquitination of FANCD2. In vivo, a multisubunit FA core complex catalyzes this step, but its mechanism is unclear. Here, we report purification of a native avian FA core complex and biochemical reconstitution of FANCD2 monoubiquitination. This demonstrates that the catalytic FANCL E3 ligase subunit must be embedded within the complex for maximal activity and site specificity. We genetically and biochemically define a minimal subcomplex comprising just three proteins (FANCB, FANCL, and FAAP100) that functions as the monoubiquitination module. Residual FANCD2 monoubiquitination activity is retained in cells defective for other FA core complex subunits. This work describes the in vitro reconstitution and characterization of this multisubunit monoubiquitin E3 ligase, providing key insight into the conserved FA DNA repair pathway.

  9. Label-free optical resonant sensors for biochemical applications

    NASA Astrophysics Data System (ADS)

    Ciminelli, Caterina; Campanella, Clarissa Martina; Dell'Olio, Francesco; Campanella, Carlo Edoardo; Armenise, Mario Nicola

    2013-03-01

    For a number of years, the scientific community has been paying growing attention to the monitoring and enhancement of public health and the quality of life through the detection of all dangerous agents for the human body, including gases, proteins, virus, and bacterial agents. When these agents are detected through label-free biochemical sensors, the molecules are not modified structurally or functionally by adding fluorescent or radioactive dyes. This work focuses on label-free optical ring resonator-based configurations suited for bio-chemical sensing, highlighting their physical aspects and specific applications. Resonant wavelength shift and the modal splitting occurring when the analyte interacts with microresonant structures are the two major physical aspects analyzed in this paper. Competitive optical platforms proposed in the literature are also illustrated together with their properties and performance.

  10. Role and importance of biochemical markers in clinical cardiology.

    PubMed

    Panteghini, Mauro

    2004-07-01

    This paper reviews the current contribution of the biochemical marker determination to clinical cardiology and discusses some important developments in this field. Biochemical markers play a pivotal role in the diagnosis and management of patients with acute coronary syndrome (ACS), as witnessed by the incorporation of cardiac troponins into new international guidelines for patients with ACS and in the re-definition of myocardial infarction. Despite the success of cardiac troponins, there is still a need for the development of early markers that can reliably rule out ACS from the emergency room at presentation and also detect myocardial ischaemia in the absence of irreversible myocyte injury. Under investigation are two classes of indicators: markers of early injury/ischaemia and markers of inflammation and coronary plaque instability and disruption. Finally, with the characterisation of the cardiac natriuretic peptides, Laboratory Medicine is also assuming a role in the assessment of cardiac function.

  11. [Biochemical investigation for clinical diagnosis of drug dependence].

    PubMed

    Maeda, Hitoshi; Ishikawa, Takaki; Michiue, Tomomi

    2010-08-01

    Specific biochemical marker is not available for clinical diagnosis of drug dependence at present. However, drug abuse is accompanied by a decrease in serotonin and the derivative in cerebrospinal fluid, suggesting central serotonergic dysfunction, that is associated with cognitive deficits, alterations in sleep architecture and neuroendocrine function, and increased impulsivity as well as an increase in the risk for aggressive behavior toward the self involving suicide. For central stimulant abusers, elevated plasma catecholamine levels are associated with psychotic episodes and cardiovascular complications involving tachycardia and arrhythmias. Biochemical investigation is useful for predicting drug-induced mental disorders, complications and the prognosis, and also for differentiation from other mental disorders, e.g., secondary to metabolic and infectious diseases, or management of acute intoxication.

  12. [Biochemical evaluation of renal lesions produced by electrohydraulic shock waves].

    PubMed

    Rodriguez Vela, L; Abadia Bayona, T; Lazaro Castillo, J; Guallar Labrador, A; Rioja Sanz, C; Rioja Sanz, L A

    1995-01-01

    The authors present a biochemical study of the renal lesions produced during extracorporeal electrohydraulic shock wave lithotripsy (ESWL). The sequential variation (before and after ESWL) of various biochemical parameters of the blood and 24-hour urine was analysed in 50 patients. A significant increase of urinary N-Acetyl-Glucosaminidase (NAG), urinary NAG/urinary creatinine quotient, proteinuria, serum creatinine and potassium was detected during the 24 hours following ESWL. A significant fall in creatinine clearance, urinary osmolarity and uric acid clearance was also detected. A positive correlation was observed between these alterations, the number of shocks and the kilovoltage used. On the 7th and 15th days, no significant difference was observed compared to the baseline values before ESWL. This can be explained by the fact that the lesions caused by shock waves are already in the repair phase.

  13. Hematological and biochemical reference values for the endangered kiso horse.

    PubMed

    Takasu, Masaki; Nagatani, Nana; Tozaki, Teruaki; Kakoi, Hironaga; Maeda, Masami; Murase, Tetsuma; Mukoyama, Harutaka

    2013-01-01

    To establish blood and biochemical references for the endangered Kiso horse, blood samples were collected from 111 adult Kiso horses, 74.5% of the existing breed. The samples were analyzed for 23 hematological and biochemical parameters to determine their means and standard deviations (SD). We compared the mean ± 2SD with the reference values cited in one of the most commonly used veterinary textbooks in Japan. The hematology of Kiso horses is characterized by lower erythrocyte count and hematocrit and hemoglobin levels. In addition, their serum biochemistry showed lower levels of aspartate transaminase, alkaline phosphatase, and γ-glutamyl transferase. Whether these propensities are attributed to breed-specific factors or are acquired factors remains unclear. Nevertheless, this study provides useful diagnostic indices for the endangered Kiso horse.

  14. Self-organization in a biochemical-neuron network

    NASA Astrophysics Data System (ADS)

    Okamoto, Masahiro; Maki, Yukihiro; Sekiguchi, Tatsuya; Yoshida, Satoshi

    Mimicking the switching property of cyclic enzyme systems in metabolic pathways, we have proposed a different type of molecular switching device (post-synaptic neuron) whose mechanism can be represented by a threshold-logic function capable of storing short-term memory. We have named this system “biochemical-neuron” and have already developed the board-leveled analog circuit. In the present study, building the integrated artificial neural network system composed of biochemical-neurons, we have investigated the relationship between network responses and time-variant excited stimuli to the network, especially focusing on the examination of some neurophysiological experiments such as “selective elimination of synapses” and “associative long-term depression”. Furthermore we shall discuss the information processing where the time-variant external analog signals are received and transduced to impulse signals.

  15. FY 1987 biochemical conversion/alcohol fuels program: Annual report

    SciTech Connect

    Not Available

    1988-11-01

    Ethanol, a high-octane liquid fuel compatible with today's transportation system, can be produced by biological processes from lignocellulosic feedstocks. The Biochemical Conversion/Alcohol Fuels Research Program managed by the Solar Energy Research Institute (SERI) for the US Department of Energy's Biofuels and Municipal Waste Technology Division carries out a program of research and development with the goals of developing processes for converting lignocellulosic materials to ethanol and other fuels in an efficient and cost-effective manner, and facilitating the adoption of these processes by industry. This annual report for FY 1987 summarizes the state of the art and the research conducted by the Biochemical Conversion/Alcohol Fuels Research Program in the past year. The appendices contain detailed descriptions of the individual research projects, organized into the following categories: Acid Hydrolysis, Enzymatic Hydrolysis, Xylose Fermentation, and Lignin Conversion.

  16. [Progress in noninvasive biochemical examination by near infrared spectroscopy].

    PubMed

    Ding, Hai-quan; Lu, Qi-peng; Peng, Zhong-qi; Chen, Xing-dan

    2010-08-01

    In the early nineties of last century, great importance had been gradually attached to the potential of near-infrared spectroscopy (NIRS) in the human body noninvasive biochemical examination. However, the human body is extremely complex. Although research teams have made some achievements in experimental simulations and in-vitro analysis, there is still no substantive breakthrough in clinical application now. The present paper discusses the key problems which prevent NIRS from achieving human noninvasive clinical biochemical examination, such as weak signal, the interference of human tissue background and the problem of blood volume change. The thoughts of noninvasive biomedical examination using NIRS are divided into two categories in terms of analytical method, that is classical near-infrared analysis and issue background interference elimination analysis. This paper also introduces in detail the current status of the two categories in the world, and believes that the second category is more promising to be successful in clinical application under the existing conditions.

  17. Changes in biochemical and functional parameters for men during exercise

    PubMed Central

    Karanauskiene, Diana; Zaicenkoviene, Kristina; Stasiule, Loreta

    2015-01-01

    Benefits of physical activity are undeniable. The aim of the present research was to determine the effects of physical activity and age on cholesterol and glucose levels in the blood, as well as changes in the functional parameters of the cardiovascular system, during stepwise increases in physical load for men employed in the same place, but with different levels of physical activity. The subjects were 95 military officers who were divided into groups according to the level of physical activity of their occupation, with veloergometry used as physical load. Cholesterol and glucose levels in the blood were taken as biochemical indices. The results showed that occupational physical activity had a positive effect on biochemical and cardiovascular functional parameters before, during, and after the physical load. Only the cardiovascular rate (systolic blood pressure) in older subjects was significantly higher than that of the younger persons; for all other parameters, age had no effect at all. PMID:28352696

  18. Biochemical markers of neurodegeneration in hereditary diffuse leucoencephalopathy with spheroids

    PubMed Central

    Spitzer, Philipp; Kohl, Zacharias; Gölitz, Philipp; Coras, Roland; Blümcke, Ingmar; Brück, Wolfgang; Dörfler, Arnd; Maihöfner, Christian

    2014-01-01

    Hereditary diffuse leucoencephalopathy with spheroids (HDLS) is a rare autosomal dominantly inherited disease with unknown pathophysiology. Diagnosis of neurodegenerative diseases is increasingly based on biomarkers. Although lumbar puncture is routinely performed during the diagnostic workup of HDLS, reports on alterations of neurodegeneration-specific biochemical markers have not been documented so far. We report a 35-year-old woman with clinical, radiological and neuropathological signs of HDLS. She suffered from a rapidly progressive frontal lobe syndrome. Brain MRI revealed diffuse leucoencephalopathy with predominant involvement of the periventricular white matter and corpus callosum. Although she was severely impaired and leucoencephalopathy was prominent, only cerebrospinal fluid total-τ was moderately elevated. Other markers of neuronal (NSE) and astrocytic (S100B) damage were within normal range. Therefore, biochemical markers of central nervous system damage are not helpful in the diagnosis of HDLS. PMID:24891473

  19. Biochemical evidence for programmed cell death in rabbit uterine epithelium.

    PubMed Central

    Rotello, R. J.; Hocker, M. B.; Gerschenson, L. E.

    1989-01-01

    Uterine epithelial cell proliferation, differentiation, and death are known to be regulated by estrogen and progesterone. The authors investigated a specific pattern of cell death called apoptosis, or programmed cell death, which is biochemically characterized by a specific pattern of DNA degradation. DNA isolated from endometrium of ovariectomized pseudopregnant rabbits showed a pattern of DNA cleavage at internucleosomal locations. In comparison, DNA from the endometrium of non-ovariectomized animals, as well as several other organs, did not exhibit that pattern. This biochemical evidence supports previous and present morphologic data and correlates with it. Under the experimental conditions used, only the uterine epithelial compartment of the endometrium shows apoptotic cell death, which is absent in the stromal compartment. Images Figure 1 Figure 2 PMID:2923180

  20. The application of information theory to biochemical signaling systems.

    PubMed

    Rhee, Alex; Cheong, Raymond; Levchenko, Andre

    2012-08-01

    Cell signaling can be thought of fundamentally as an information transmission problem in which chemical messengers relay information about the external environment to the decision centers within a cell. Due to the biochemical nature of cellular signal transduction networks, molecular noise will inevitably limit the fidelity of any messages received and processed by a cell's signal transduction networks, leaving it with an imperfect impression of its environment. Fortunately, Shannon's information theory provides a mathematical framework independent of network complexity that can quantify the amount of information that can be transmitted despite biochemical noise. In particular, the channel capacity can be used to measure the maximum number of stimuli a cell can distinguish based upon the noisy responses of its signaling systems. Here, we provide a primer for quantitative biologists that covers fundamental concepts of information theory, highlights several key considerations when experimentally measuring channel capacity, and describes successful examples of the application of information theoretic analysis to biological signaling.

  1. Biochemical markers in the assessment of bone disease

    NASA Technical Reports Server (NTRS)

    Bikle, D. D.

    1997-01-01

    As the mean age of our population increases, increasing attention has been paid to the diseases associated with aging, including diseases of the skeleton such as osteoporosis. Effective means of treating and possibly preventing such skeletal disorders are emerging, making their early recognition an important goal for the primary care physician. Although bone density measurements and skeletal imaging studies remain of primary diagnostic importance in this regard, a large number of assays for biochemical markers of bone formation and resorption are being developed that promise to complement the densitometry measurements and imaging studies, providing an assessment of the rates of bone turnover and an earlier evaluation of the effects of therapy. In this review, emphasizing the recent literature, the major biochemical markers currently in use or under active investigation are described, and their application in a number of diseases of the skeleton including osteoporosis is evaluated.

  2. Biochemical functionalization of peptide nanotubes with phage displayed peptides

    NASA Astrophysics Data System (ADS)

    Swaminathan, Swathi; Cui, Yue

    2016-09-01

    The development of a general approach for the biochemical functionalization of peptide nanotubes (PNTs) could open up existing opportunities in both fundamental studies as well as a variety of applications. PNTs are spontaneously assembled organic nanostructures made from peptides. Phage display has emerged as a powerful approach for identifying selective peptide binding motifs. Here, we demonstrate for the first time the biochemical functionalization of PNTs via peptides identified from a phage display peptide library. The phage-displayed peptides are shown to recognize PNTs. These advances further allow for the development of bifunctional peptides for the capture of bacteria and the self-assembly of silver particles onto PNTs. We anticipate that these results could provide significant opportunities for using PNTs in both fundamental studies and practical applications, including sensors and biosensors nanoelectronics, energy storage devices, drug delivery, and tissue engineering.

  3. Biochemical responses of the Skylab crewmen: An overview

    NASA Technical Reports Server (NTRS)

    Leach, C. S.; Rambaut, P. C.

    1977-01-01

    Continuous metabolic and endocrinic monitoring of Skylab crewmen established significant biochemical changes that varied in magnitude and direction but disappeared shortly after return to earth. These changes indicate adaptation by the body to the combined stresses of weightlessness. Transient changes in fluid and electrolyte metabolisms lead to the conclusion that a homeostasis condition had been achieved. Unstable states persisted in the metabolisms of bone mineral, protein, and carbohydrates.

  4. Functional and biochemical modifications in skeletal muscles from malarial mice.

    PubMed

    Brotto, Marco A P; Marrelli, Mauro T; Brotto, Leticia S; Jacobs-Lorena, Marcelo; Nosek, Thomas M

    2005-05-01

    Although it is well established that patients suffering from malaria experience skeletal muscle problems (contracture, aches, fatigue, weakness), detailed studies have not been performed to investigate changes in the contractile function and biochemical properties of intact and skinned skeletal muscles of mammals infected with malaria. To this end, we investigated such features in the extensor digitorium longus (EDL, fast-twitch, glyocolytic) and in the soleus (SOL, slow-twitch, oxidative) muscles from mice infected with Plasmodium berghei. We first studied maximal tetanic force (T(max)) produced by intact control and malaria-infected muscles before, during and after fatigue. Triton-skinned muscle fibres were isolated from these muscles and used to determine isometric contractile features as well as a basic biochemical profile as analysed by silver-enhanced SDS-PAGE. We found that the T(max) of intact muscles and the maximal Ca2+-activated force (F(max)) of Triton-skinned muscle fibres were reduced by approximately 50% in malarial muscles. In addition, the contractile proteins of Triton-skinned muscle fibres from malarial muscles were significantly less sensitive to Ca2+. Biochemical analysis revealed that there was a significant loss of essential contractile proteins (e.g. troponins and myosin) in Triton-skinned muscle fibres from malarial muscles as compared to controls. The biochemical alterations (i.e., reduction of essential contractile proteins) seem to explain well the functional modifications resolved in both intact muscles and Triton-skinned muscle fibres and may provide a suitable paradigm for the aetiology of muscle symptoms associated with malaria.

  5. In Vitro Biochemical Characterization of Cytokinesis Actin-Binding Proteins.

    PubMed

    Zimmermann, Dennis; Morganthaler, Alisha N; Kovar, David R; Suarez, Cristian

    2016-01-01

    Characterizing the biochemical and biophysical properties of purified proteins is critical to understand the underlying molecular mechanisms that facilitate complicated cellular processes such as cytokinesis. Here we outline in vitro assays to investigate the effects of cytokinesis actin-binding proteins on actin filament dynamics and organization. We describe (1) multicolor single-molecule TIRF microscopy actin assembly assays, (2) "bulk" pyrene actin assembly/disassembly assays, and (3) "bulk" sedimentation actin filament binding and bundling assays.

  6. Biochemical properties of an intracellular serpin from Echinococcus multilocularis.

    PubMed

    Merckelbach, Armin; Ruppel, Andreas

    2007-11-01

    A serpin of the intracellular type from the tapeworm Echinococcus multilocularis was expressed in Escherichia coli, purified by ion exchange chromatography and tested for inhibitory activity against several proteinases. The recombinant protein, which after transcriptional induction, represents about 20 % of total cellular protein, is biochemically active and inhibits trypsin and the trypsin-like plasmin as well as pig pancreatic and human neutrophil elastase. Implications regarding its biochemistry and biological function are discussed.

  7. Nitrosonium cation in chemical and biochemical reactions: achievements and prospects

    NASA Astrophysics Data System (ADS)

    Borodkin, G. I.; Shubin, V. G.

    2017-01-01

    Data on the reactivity of nitrosonium cation in chemical reactions are systematized and integrated. The review demonstrates the structural diversity of nitrosonium complexes resulting from the specific features of the electronic structure of NO+. The use of nitrosonium salts in the synthesis of heterocyclic compounds and for the preparation of modern materials, including nanomaterials, is considered. The participation of NO+ in oxidative, catalytic and biochemical processes is discussed. The bibliography includes 332 references.

  8. Enzyme catalyzed biochemical production in a polydimethylsiloxane microreactor

    NASA Astrophysics Data System (ADS)

    Dickey, Cynthia K.; Elmore, Bill B.; Jones, Francis

    2000-08-01

    Study of an aqueous-phase reaction in an enzyme- catalyzedpolydimethylsiloxane (PDMS) microreactor is underway. In the present work, urease - an enzyme that catalyzes urea to ammonia and carbon dioxide has been immobilized within open microchannels of 450 micrometers (micrometers ) in diameter or less. Microchannels are templated within PDMS. Preliminary results demonstrate the proof of concept for conversion biochemicals via a PDMS-based microreactor system.

  9. Scalable Parameter Estimation for Genome-Scale Biochemical Reaction Networks

    PubMed Central

    Kaltenbacher, Barbara; Hasenauer, Jan

    2017-01-01

    Mechanistic mathematical modeling of biochemical reaction networks using ordinary differential equation (ODE) models has improved our understanding of small- and medium-scale biological processes. While the same should in principle hold for large- and genome-scale processes, the computational methods for the analysis of ODE models which describe hundreds or thousands of biochemical species and reactions are missing so far. While individual simulations are feasible, the inference of the model parameters from experimental data is computationally too intensive. In this manuscript, we evaluate adjoint sensitivity analysis for parameter estimation in large scale biochemical reaction networks. We present the approach for time-discrete measurement and compare it to state-of-the-art methods used in systems and computational biology. Our comparison reveals a significantly improved computational efficiency and a superior scalability of adjoint sensitivity analysis. The computational complexity is effectively independent of the number of parameters, enabling the analysis of large- and genome-scale models. Our study of a comprehensive kinetic model of ErbB signaling shows that parameter estimation using adjoint sensitivity analysis requires a fraction of the computation time of established methods. The proposed method will facilitate mechanistic modeling of genome-scale cellular processes, as required in the age of omics. PMID:28114351

  10. Identification of biochemical features of defective Coffea arabica L. beans.

    PubMed

    Casas, María I; Vaughan, Michael J; Bonello, Pierluigi; McSpadden Gardener, Brian; Grotewold, Erich; Alonso, Ana P

    2017-05-01

    Coffee organoleptic properties are based in part on the quality and chemical composition of coffee beans. The presence of defective beans during processing and roasting contribute to off flavors and reduce overall cup quality. A multipronged approach was undertaken to identify specific biochemical markers for defective beans. To this end, beans were split into defective and non-defective fractions and biochemically profiled in both green and roasted states. A set of 17 compounds in green beans, including organic acids, amino acids and reducing sugars; and 35 compounds in roasted beans, dominated by volatile compounds, organic acids, sugars and sugar alcohols, were sufficient to separate the defective and non-defective fractions. Unsorted coffee was examined for the presence of the biochemical markers to test their utility in detecting defective beans. Although the green coffee marker compounds were found in all fractions, three of the roasted coffee marker compounds (1-methylpyrrole, 5-methyl- 2-furfurylfuran, and 2-methylfuran) were uniquely present in defective fractions.

  11. Design of a biochemical circuit motif for learning linear functions

    PubMed Central

    Lakin, Matthew R.; Minnich, Amanda; Lane, Terran; Stefanovic, Darko

    2014-01-01

    Learning and adaptive behaviour are fundamental biological processes. A key goal in the field of bioengineering is to develop biochemical circuit architectures with the ability to adapt to dynamic chemical environments. Here, we present a novel design for a biomolecular circuit capable of supervised learning of linear functions, using a model based on chemical reactions catalysed by DNAzymes. To achieve this, we propose a novel mechanism of maintaining and modifying internal state in biochemical systems, thereby advancing the state of the art in biomolecular circuit architecture. We use simulations to demonstrate that the circuit is capable of learning behaviour and assess its asymptotic learning performance, scalability and robustness to noise. Such circuits show great potential for building autonomous in vivo nanomedical devices. While such a biochemical system can tell us a great deal about the fundamentals of learning in living systems and may have broad applications in biomedicine (e.g. autonomous and adaptive drugs), it also offers some intriguing challenges and surprising behaviours from a machine learning perspective. PMID:25401175

  12. Human choline dehydrogenase: medical promises and biochemical challenges.

    PubMed

    Salvi, Francesca; Gadda, Giovanni

    2013-09-15

    Human choline dehydrogenase (CHD) is located in the inner membrane of mitochondria primarily in liver and kidney and catalyzes the oxidation of choline to glycine betaine. Its physiological role is to regulate the concentrations of choline and glycine betaine in the blood and cells. Choline is important for regulation of gene expression, the biosynthesis of lipoproteins and membrane phospholipids and for the biosynthesis of the neurotransmitter acetylcholine; glycine betaine plays important roles as a primary intracellular osmoprotectant and as methyl donor for the biosynthesis of methionine from homocysteine, a required step for the synthesis of the ubiquitous methyl donor S-adenosyl methionine. Recently, CHD has generated considerable medical attention due to its association with various human pathologies, including male infertility, homocysteinuria, breast cancer and metabolic syndrome. Despite the renewed interest, the biochemical characterization of the enzyme has lagged behind due to difficulties in the obtainment of purified, active and stable enzyme. This review article summarizes the medical relevance and the physiological roles of human CHD, highlights the biochemical knowledge on the enzyme, and provides an analysis based on the comparison of the protein sequence with that of bacterial choline oxidase, for which structural and biochemical information is available.

  13. Collecting and measuring wound exudate biochemical mediators in surgical wounds.

    PubMed

    Carvalho, Brendan; Clark, David J; Yeomans, David; Angst, Martin S

    2012-10-20

    We describe a methodology by which we are able to collect and measure biochemical inflammatory and nociceptive mediators at the surgical wound site. Collecting site-specific biochemical markers is important to understand the relationship between levels in serum and surgical wound, determine any associations between mediator release, pain, analgesic use and other outcomes of interest, and evaluate the effect of systemic and peripheral drug administration on surgical wound biochemistry. This methodology has been applied to healthy women undergoing elective cesarean delivery with spinal anesthesia. We have measured wound exudate and serum mediators at the same time intervals as patient's pain scores and analgesics consumption for up to 48 hours post-cesarean delivery. Using this methodology we have been able to detect various biochemical mediators including nerve growth factor (NGF), prostaglandin E2 (PG-E2) substance P, IL-1β, IL-2, IL-4, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-17, TNFα, INFγ, G-CSF, GM-CSF, MCP-1 and MIP-1β. Studies applying this human surgical wound bioassay have found no correlations between wound and serum cytokine concentrations or their time-release profile (J Pain. 2008; 9(7):650-7).(1) We also documented the utility of the technique to identify drug-mediated changes in wound cytokine content.

  14. Collecting And Measuring Wound Exudate Biochemical Mediators In Surgical Wounds

    PubMed Central

    Carvalho, Brendan; Clark, David J; Yeomans, David; Angst, Martin S

    2012-01-01

    We describe a methodology by which we are able to collect and measure biochemical inflammatory and nociceptive mediators at the surgical wound site. Collecting site-specific biochemical markers is important to understand the relationship between levels in serum and surgical wound, determine any associations between mediator release, pain, analgesic use and other outcomes of interest, and evaluate the effect of systemic and peripheral drug administration on surgical wound biochemistry. This methodology has been applied to healthy women undergoing elective cesarean delivery with spinal anesthesia. We have measured wound exudate and serum mediators at the same time intervals as patient's pain scores and analgesics consumption for up to 48 hours post-cesarean delivery. Using this methodology we have been able to detect various biochemical mediators including nerve growth factor (NGF), prostaglandin E2 (PG-E2) substance P, IL-1β, IL-2, IL-4, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-17, TNFα, INFγ, G-CSF, GM-CSF, MCP-1 and MIP-1β. Studies applying this human surgical wound bioassay have found no correlations between wound and serum cytokine concentrations or their time-release profile (J Pain. 2008; 9(7):650-7).1 We also documented the utility of the technique to identify drug-mediated changes in wound cytokine content (Anesth Analg 2010; 111:1452-9).2 PMID:23117346

  15. Complete integrability of information processing by biochemical reactions

    NASA Astrophysics Data System (ADS)

    Agliari, Elena; Barra, Adriano; Dello Schiavo, Lorenzo; Moro, Antonio

    2016-11-01

    Statistical mechanics provides an effective framework to investigate information processing in biochemical reactions. Within such framework far-reaching analogies are established among (anti-) cooperative collective behaviors in chemical kinetics, (anti-)ferromagnetic spin models in statistical mechanics and operational amplifiers/flip-flops in cybernetics. The underlying modeling – based on spin systems – has been proved to be accurate for a wide class of systems matching classical (e.g. Michaelis–Menten, Hill, Adair) scenarios in the infinite-size approximation. However, the current research in biochemical information processing has been focusing on systems involving a relatively small number of units, where this approximation is no longer valid. Here we show that the whole statistical mechanical description of reaction kinetics can be re-formulated via a mechanical analogy – based on completely integrable hydrodynamic-type systems of PDEs – which provides explicit finite-size solutions, matching recently investigated phenomena (e.g. noise-induced cooperativity, stochastic bi-stability, quorum sensing). The resulting picture, successfully tested against a broad spectrum of data, constitutes a neat rationale for a numerically effective and theoretically consistent description of collective behaviors in biochemical reactions.

  16. Endothelial cells and cathepsins: biochemical and biomechanical regulation

    PubMed Central

    Platt, Manu O.; Shockey, W. Andrew

    2015-01-01

    Cathepsins are mechanosensitive proteases that are regulated not only by biochemical factors, but are also responsive to biomechanical forces in the cardiovascular system that regulate their expression and activity to participate in cardiovascular tissue remodeling. Their elastinolytic and collagenolytic activity have been implicated in atherosclerosis, abdominal aortic aneurysms, and in heart valve disease, all of which are lined by endothelial cells that are the mechanosensitive monolayer of cells that sense and respond to fluid shear stress as the blood flows across the surfaces of the arteries and valve leaflets. Inflammatory cytokine signaling is integrated with biomechanical signaling pathways by the endothelial cells to transcribe, translate, and activate either the cysteine cathepsins to remodel the tissue or to express their inhibitors to maintain healthy cardiovascular tissue structure. Other cardiovascular diseases should now be included in the study of the cysteine cathepsin activation because of the additional biochemical cues they provide that merges with the already existing hemodynamics driving cardiovascular disease. Sickle cell disease causes a chronic inflammation including elevated TNFα and increased numbers of circulating monocytes that alter the biochemical stimulation while the more viscous red blood cells due to the sickling of hemoglobin alters the hemodynamics and is associated with accelerated elastin remodeling causing pediatric strokes. HIV-mediated cardiovascular disease also occurs earlier in than the broader population and the influence of HIV-proteins and antiretrovirals on endothelial cells must be considered to understand these accelerated mechanisms in order to identify new therapeutic targets for prevention. PMID:26458976

  17. Complete integrability of information processing by biochemical reactions

    PubMed Central

    Agliari, Elena; Barra, Adriano; Dello Schiavo, Lorenzo; Moro, Antonio

    2016-01-01

    Statistical mechanics provides an effective framework to investigate information processing in biochemical reactions. Within such framework far-reaching analogies are established among (anti-) cooperative collective behaviors in chemical kinetics, (anti-)ferromagnetic spin models in statistical mechanics and operational amplifiers/flip-flops in cybernetics. The underlying modeling – based on spin systems – has been proved to be accurate for a wide class of systems matching classical (e.g. Michaelis–Menten, Hill, Adair) scenarios in the infinite-size approximation. However, the current research in biochemical information processing has been focusing on systems involving a relatively small number of units, where this approximation is no longer valid. Here we show that the whole statistical mechanical description of reaction kinetics can be re-formulated via a mechanical analogy – based on completely integrable hydrodynamic-type systems of PDEs – which provides explicit finite-size solutions, matching recently investigated phenomena (e.g. noise-induced cooperativity, stochastic bi-stability, quorum sensing). The resulting picture, successfully tested against a broad spectrum of data, constitutes a neat rationale for a numerically effective and theoretically consistent description of collective behaviors in biochemical reactions. PMID:27812018

  18. Effect of Different Psychoactive Substances on Serum Biochemical Parameters

    PubMed Central

    Sanli, Dilek Beker; Bilici, Rabia; Suner, Ozgur; Citak, Serhat; Kartkaya, Kazim; Mutlu, Fezan Sahin

    2015-01-01

    Background: Psychoactive substances affect mainly central nervous system and brain function causing changes in behavior. Objectives: The purpose of this study was to determine the effects of different psychoactive substances on serum biochemical parameters. Patients and Methods: The study included 324 drug dependents, and 69 controls. The patient group was determined according to DSM-IV (The diagnostic and statistical manual of mental disorders, fourth edition) criteria. All patients and control subjects were tested for routine biochemical parameters and urine toxicology parameters for psychoactive substance use. Cases and controls with accompanying diseases like diabetes, cancer, metabolic disorders etc. are excluded from the study. Moreover, an association between urine toxicology results and changes in biochemical parameters was evaluated for statistical significance. Results: There was a statistically significant difference in the Gamma-Glutamyl Transferase (GGT), uric acid, creatinine, urea, albumin, Aspartate Aminotransferase (AST) medians between the dependent and control groups (P < 0.05). We found a statistically significant difference in sodium and albumin levels between the opium-dependent and control groups (P < 0.05). In the benzodiazepin dependent group, we found a significant difference in GGT, urea, glucose, sodium, T protein, and AST levels (P < 0.05). Moreover, a statistically significant difference was observed in triglyceride and GGT levels between the ethyl glucuronide and control groups (P < 0.05). Conclusions: In psychoactive substance dependents, serum routine biochemistry parameters can be used to predict the need for intensive monitoring and treatment programs. PMID:26405680

  19. Biochemical typing of hyperlipoproteinemia. The development of a nomogram.

    PubMed

    Gustafson, A; Abrahamsson, H; Wiklund, O

    1975-08-18

    The accurate biochemical typing of hyperlipoproteinemia would require quantification of lipoprotein fractions. At present, typing is frequently based on the lipoprotein electrophoresis pattern together with serum lipid analyses. Lack of facilities for lipoprotein electrophoresis has however focused the clinical interest for classification of hyperlipoproteinemia into other means of a simple biochemical typing. In the present study a nomogram was developed to allow biochemical typing of hyperlipoproteinemia from serum cholesterol and triglyceride values. Serum cholesterol was determined according to a Liebermann-Burchard reaction by the method of Cramer and Isaksson [1], serum triglycerides by the determination of glyceride glycerol according to Carlson [2], and serum lipoprotein electrophoresis was performed on agarose gel [3]. Cholesterol content [4] of alpha-lipoproteins ("alpha-LP cholesterol") was obtained in serum after the precipitation of very-low-density lipoproteins(VLDL) and low-density lipoproteins(LDL) by manganese chloride and heparin [5]. Preparative ultracentrifugation was performed in a one-step, gradient procedure [6] isolating VLDL, d less than 1.006, LDL, d 1.006--1.063 g/ml and high-density lipoprotein (HDL) including very-high-density lipoproteins, d greater than 1.063 g/ml, or alternatively at d 1.006 g/ml according to the procedure by Gustafson et al. [7].

  20. Modelling biochemical reaction systems by stochastic differential equations with reflection.

    PubMed

    Niu, Yuanling; Burrage, Kevin; Chen, Luonan

    2016-05-07

    In this paper, we gave a new framework for modelling and simulating biochemical reaction systems by stochastic differential equations with reflection not in a heuristic way but in a mathematical way. The model is computationally efficient compared with the discrete-state Markov chain approach, and it ensures that both analytic and numerical solutions remain in a biologically plausible region. Specifically, our model mathematically ensures that species numbers lie in the domain D, which is a physical constraint for biochemical reactions, in contrast to the previous models. The domain D is actually obtained according to the structure of the corresponding chemical Langevin equations, i.e., the boundary is inherent in the biochemical reaction system. A variant of projection method was employed to solve the reflected stochastic differential equation model, and it includes three simple steps, i.e., Euler-Maruyama method was applied to the equations first, and then check whether or not the point lies within the domain D, and if not perform an orthogonal projection. It is found that the projection onto the closure D¯ is the solution to a convex quadratic programming problem. Thus, existing methods for the convex quadratic programming problem can be employed for the orthogonal projection map. Numerical tests on several important problems in biological systems confirmed the efficiency and accuracy of this approach.

  1. How special is the biochemical function of native proteins?

    PubMed

    Skolnick, Jeffrey; Gao, Mu; Zhou, Hongyi

    2016-01-01

    Native proteins perform an amazing variety of biochemical functions, including enzymatic catalysis, and can engage in protein-protein and protein-DNA interactions that are essential for life. A key question is how special are these functional properties of proteins. Are they extremely rare, or are they an intrinsic feature? Comparison to the properties of compact conformations of artificially generated compact protein structures selected for thermodynamic stability but not any type of function, the artificial (ART) protein library, demonstrates that a remarkable number of the properties of native-like proteins are recapitulated. These include the complete set of small molecule ligand-binding pockets and most protein-protein interfaces. ART structures are predicted to be capable of weakly binding metabolites and cover a significant fraction of metabolic pathways, with the most enriched pathways including ancient ones such as glycolysis. Native-like active sites are also found in ART proteins. A small fraction of ART proteins are predicted to have strong protein-protein and protein-DNA interactions. Overall, it appears that biochemical function is an intrinsic feature of proteins which nature has significantly optimized during evolution. These studies raise questions as to the relative roles of specificity and promiscuity in the biochemical function and control of cells that need investigation.

  2. Design of a biochemical circuit motif for learning linear functions.

    PubMed

    Lakin, Matthew R; Minnich, Amanda; Lane, Terran; Stefanovic, Darko

    2014-12-06

    Learning and adaptive behaviour are fundamental biological processes. A key goal in the field of bioengineering is to develop biochemical circuit architectures with the ability to adapt to dynamic chemical environments. Here, we present a novel design for a biomolecular circuit capable of supervised learning of linear functions, using a model based on chemical reactions catalysed by DNAzymes. To achieve this, we propose a novel mechanism of maintaining and modifying internal state in biochemical systems, thereby advancing the state of the art in biomolecular circuit architecture. We use simulations to demonstrate that the circuit is capable of learning behaviour and assess its asymptotic learning performance, scalability and robustness to noise. Such circuits show great potential for building autonomous in vivo nanomedical devices. While such a biochemical system can tell us a great deal about the fundamentals of learning in living systems and may have broad applications in biomedicine (e.g. autonomous and adaptive drugs), it also offers some intriguing challenges and surprising behaviours from a machine learning perspective.

  3. Mapping biochemical networks with protein fragment complementation assays.

    PubMed

    Remy, Ingrid; Michnick, Stephen W

    2015-01-01

    Cellular biochemical machineries, what we call pathways, consist of dynamically assembling and disassembling macromolecular complexes. Although our models for the organization of biochemical machines are derived largely from in vitro experiments, do they reflect their organization in intact, living cells? We have developed a general experimental strategy that addresses this question by allowing the quantitative probing of molecular interactions in intact, living cells. The experimental strategy is based on Protein fragment Complementation Assays (PCA), a method whereby protein interactions are coupled to refolding of enzymes from cognate fragments where reconstitution of enzyme activity acts as the detector of a protein interaction. A biochemical machine or pathway is defined by grouping interacting proteins into those that are perturbed in the same way by common factors (hormones, metabolites, enzyme inhibitors, etc.). In this chapter we review some of the essential principles of PCA and provide details and protocols for applications of PCA, particularly in mammalian cells, based on three PCA reporters, dihydrofolate reductase, green fluorescent protein, and β-lactamase.

  4. Biochemical and biomedical applications of multifunctional magnetic nanoparticles: a review

    NASA Astrophysics Data System (ADS)

    Huang, Shih-Hung; Juang, Ruey-Shin

    2011-10-01

    Nanotechnology offers tremendous potential for future medical diagnosis and therapy. Various types of nanoparticles have been extensively studied for numerous biochemical and biomedical applications. Magnetic nanoparticles are well-established nanomaterials that offer controlled size, ability to be manipulated by an external magnetic field, and enhancement of contrast in magnetic resonance imaging. As a result, these nanoparticles could have many applications including bacterial detection, protein purification, enzyme immobilization, contamination decorporation, drug delivery, hyperthermia, etc. All these biochemical and biomedical applications require that these nanoparticles should satisfy some prerequisites including high magnetization, good stability, biocompatibility, and biodegradability. Because of the potential benefits of multimodal functionality in biomedical applications, in this account highlights some general strategies to generate magnetic nanoparticle-based multifunctional nanostructures. After these magnetic nanoparticles are conjugated with proper ligands (e.g., nitrilotriacetate), polymers (e.g., polyacrylic acid, chitosan, temperature- and pH-sensitive polymers), antibodies, enzymes, and inorganic metals (e.g., gold), such biofunctional magnetic nanoparticles exhibit many advantages in biomedical applications. In addition, the multifunctional magnetic nanoparticles have been widely applied in biochemical fields including enzyme immobilization and protein purification.

  5. [Biochemical changes in apoptosis and methods for their determination (review)].

    PubMed

    Sedláková, A; Kohút, A; Kalina, I

    1999-08-01

    Apoptosis or programmed cell death is a physiological process which occurs at different biological states as well as at disease process. Morphologically it is characterized by the chromatine condensation and other changes with preserved integrity of plasmatic membrane. The major and most frequently studied biochemical characteristic of apoptosis is a DNA fragmentation. In our paper attention is directed to the early biochemical changes in cell membranes, i.g., the externalization of phosphatidylserine, hydrolysis of sphingomyeline on the ceramide and activation of phospholipases especially phospholipase A2. In one part we described the changes of cysteine proteases (caspases), which play a key role in the execution of apoptosis. These biochemical changes are associated with ceramide signalization of apoptosis. Briefly are presented also some dates about apoptosis induction with reactive oxygen radicals and the role of the arachidonic acid metabolites in this process. We consider the investigation and determination of these changes as important parameters of apoptosis at some diseases, e.g., cancer or degenerative diseases, and of their treatment.

  6. 40 CFR 158.2070 - Biochemical pesticides product performance data requirements.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 23 2010-07-01 2010-07-01 false Biochemical pesticides product... AGENCY (CONTINUED) PESTICIDE PROGRAMS DATA REQUIREMENTS FOR PESTICIDES Biochemical Pesticides § 158.2070 Biochemical pesticides product performance data requirements. Product performance data must be developed...

  7. 40 CFR 158.2070 - Biochemical pesticides product performance data requirements.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 25 2012-07-01 2012-07-01 false Biochemical pesticides product... AGENCY (CONTINUED) PESTICIDE PROGRAMS DATA REQUIREMENTS FOR PESTICIDES Biochemical Pesticides § 158.2070 Biochemical pesticides product performance data requirements. Product performance data must be developed...

  8. 40 CFR 158.2070 - Biochemical pesticides product performance data requirements.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 24 2011-07-01 2011-07-01 false Biochemical pesticides product... AGENCY (CONTINUED) PESTICIDE PROGRAMS DATA REQUIREMENTS FOR PESTICIDES Biochemical Pesticides § 158.2070 Biochemical pesticides product performance data requirements. Product performance data must be developed...

  9. 40 CFR 158.2070 - Biochemical pesticides product performance data requirements.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 24 2014-07-01 2014-07-01 false Biochemical pesticides product... AGENCY (CONTINUED) PESTICIDE PROGRAMS DATA REQUIREMENTS FOR PESTICIDES Biochemical Pesticides § 158.2070 Biochemical pesticides product performance data requirements. Product performance data must be developed...

  10. 40 CFR 158.2070 - Biochemical pesticides product performance data requirements.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 25 2013-07-01 2013-07-01 false Biochemical pesticides product... AGENCY (CONTINUED) PESTICIDE PROGRAMS DATA REQUIREMENTS FOR PESTICIDES Biochemical Pesticides § 158.2070 Biochemical pesticides product performance data requirements. Product performance data must be developed...

  11. 40 CFR 158.2040 - Biochemical pesticides residue data requirements table.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 24 2011-07-01 2011-07-01 false Biochemical pesticides residue data... (CONTINUED) PESTICIDE PROGRAMS DATA REQUIREMENTS FOR PESTICIDES Biochemical Pesticides § 158.2040 Biochemical pesticides residue data requirements table. (a) General. Sections 158.100 through 158.130 describe how to...

  12. 40 CFR 158.2040 - Biochemical pesticides residue data requirements table.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 25 2013-07-01 2013-07-01 false Biochemical pesticides residue data... (CONTINUED) PESTICIDE PROGRAMS DATA REQUIREMENTS FOR PESTICIDES Biochemical Pesticides § 158.2040 Biochemical pesticides residue data requirements table. (a) General. Sections 158.100 through 158.130 describe how to...

  13. 40 CFR 158.2040 - Biochemical pesticides residue data requirements table.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 23 2010-07-01 2010-07-01 false Biochemical pesticides residue data... (CONTINUED) PESTICIDE PROGRAMS DATA REQUIREMENTS FOR PESTICIDES Biochemical Pesticides § 158.2040 Biochemical pesticides residue data requirements table. (a) General. Sections 158.100 through 158.130 describe how to...

  14. 40 CFR 158.2040 - Biochemical pesticides residue data requirements table.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 25 2012-07-01 2012-07-01 false Biochemical pesticides residue data... (CONTINUED) PESTICIDE PROGRAMS DATA REQUIREMENTS FOR PESTICIDES Biochemical Pesticides § 158.2040 Biochemical pesticides residue data requirements table. (a) General. Sections 158.100 through 158.130 describe how to...

  15. 40 CFR 158.2040 - Biochemical pesticides residue data requirements table.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 24 2014-07-01 2014-07-01 false Biochemical pesticides residue data... (CONTINUED) PESTICIDE PROGRAMS DATA REQUIREMENTS FOR PESTICIDES Biochemical Pesticides § 158.2040 Biochemical pesticides residue data requirements table. (a) General. Sections 158.100 through 158.130 describe how to...

  16. Discovering Reliable Sources of Biochemical Thermodynamic Data to Aid Students' Understanding

    ERIC Educational Resources Information Center

    Me´ndez, Eduardo; Cerda´, María F.

    2016-01-01

    Students of physical chemistry in biochemical disciplines need biochemical examples to capture the need, not always understood, of a difficult area in their studies. The use of thermodynamic data in the chemical reference state may lead to incorrect interpretations in the analysis of biochemical examples when the analysis does not include relevant…

  17. 40 CFR 158.2050 - Biochemical pesticides human health assessment data requirements table.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 23 2010-07-01 2010-07-01 false Biochemical pesticides human health... § 158.2050 Biochemical pesticides human health assessment data requirements table. (a) General. (1) Sections 158.100 through 158.130 describe how to use this table to determine the biochemical human...

  18. 40 CFR 158.2050 - Biochemical pesticides human health assessment data requirements table.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 24 2011-07-01 2011-07-01 false Biochemical pesticides human health... § 158.2050 Biochemical pesticides human health assessment data requirements table. (a) General. (1) Sections 158.100 through 158.130 describe how to use this table to determine the biochemical human...

  19. Effects of isolation and inbreeding on human quantitative traits: an example of biochemical markers of hemostasis and inflammation.

    PubMed

    Pulanić, Drazen; Polasek, Ozren; Petrovecki, Mladen; Vorko-Jović, Ariana; Pericić, Marijana; Lauc, Lovorka Barać; Klarić, Irena Martinović; Biloglav, Zrinka; Kolcić, Ivana; Zgaga, Lina; Carothers, Andrew D; Ramić, Senad; Setić, Mia; Janićijević, Branka; Narancić, Nina Smolej; Bućan, Kajo; Rudan, Diana; Lowe, Gordon; Rumley, Ann; Rudan, Pavao; Campbell, Harry; Rudan, Igor

    2008-10-01

    Isolation is a known force in evolutionary biology and one of the main factors in speciation. One of the main consequences of severe isolation is reduced mate choice, which results in the occurrence of inbreeding as a result of isolation. We investigated the effects of individual genome-wide heterozygosity measured as the multilocus heterozygosity (MLH) on biochemical markers of hemostasis and inflammation in 1,041 individuals from the island of Vis, Croatia, where inbreeding is prevalent and a wide range of variation in the genome-wide heterozygosity is expected. Assessment of individual genome-wide heterozygosity was based on genome-wide scans using 800 microsatellite (STR) and 317,503 single nucleotide (SNP) polymorphic markers in each examinee. In addition, for each examinee we defined a personal genetic history (PGH) based on genealogical records. The association between PGH and MLH and fibrinogen, D-dimer (Dd), von Willebrand factor (vWF), tissue plasminogen activator (tPA), and C-reactive protein (CRP) was performed with a mixed model, controlling for possible confounding effects. PGH was a significant predictor only for tPA (P < 0.001), whereas neither of the two MLH measures exhibited significant association with any of the investigated traits. The effects of individual genome-wide heterozygosity are most likely expressed in highly polygenically determined traits or in traits that are mediated by rare and recessive genetic variants. Weak associations between PGH and MLH and markers of hemostasis and inflammation suggest that their genetic control may not be highly polygenic and that they could be promising targets for genetic association studies.

  20. Simulation of Biochemical Pathway Adaptability Using Evolutionary Algorithms

    SciTech Connect

    Bosl, W J

    2005-01-26

    The systems approach to genomics seeks quantitative and predictive descriptions of cells and organisms. However, both the theoretical and experimental methods necessary for such studies still need to be developed. We are far from understanding even the simplest collective behavior of biomolecules, cells or organisms. A key aspect to all biological problems, including environmental microbiology, evolution of infectious diseases, and the adaptation of cancer cells is the evolvability of genomes. This is particularly important for Genomes to Life missions, which tend to focus on the prospect of engineering microorganisms to achieve desired goals in environmental remediation and climate change mitigation, and energy production. All of these will require quantitative tools for understanding the evolvability of organisms. Laboratory biodefense goals will need quantitative tools for predicting complicated host-pathogen interactions and finding counter-measures. In this project, we seek to develop methods to simulate how external and internal signals cause the genetic apparatus to adapt and organize to produce complex biochemical systems to achieve survival. This project is specifically directed toward building a computational methodology for simulating the adaptability of genomes. This project investigated the feasibility of using a novel quantitative approach to studying the adaptability of genomes and biochemical pathways. This effort was intended to be the preliminary part of a larger, long-term effort between key leaders in computational and systems biology at Harvard University and LLNL, with Dr. Bosl as the lead PI. Scientific goals for the long-term project include the development and testing of new hypotheses to explain the observed adaptability of yeast biochemical pathways when the myosin-II gene is deleted and the development of a novel data-driven evolutionary computation as a way to connect exploratory computational simulation with hypothesis