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Sample records for biochemical confounders nfr

  1. Association of blood lead to blood pressure in men aged 55 to 75 years: effect of selected social and biochemical confounders. NFR Study Group.

    PubMed Central

    Menditto, A; Morisi, G; Spagnolo, A; Menotti, A

    1994-01-01

    The association of blood lead (B-Pb) concentration to blood pressure was investigated in men aged 55 to 75 years living in the Rome area, who had no history of exposure to lead in the workplace and who participated between 1989 and 1990 in an epidemiologic survey for coronary heart disease (New Risk Factor Project). Of the 1856 individuals eligible for the study, 59 were excluded from analyses because not all relevant data were available; and 478 were excluded because they were treated for hypertension. In the remaining subjects (n = 1319) the median B-Pb concentration was 113 micrograms/l (range: 40-442 micrograms/l). Systolic blood pressure (SBP) averaged 140 +/- 18 (standard deviation) mm Hg (range 98-220) and diastolic blood pressure (DBP) 84 +/- 9 mm Hg (range 56-118). Median B-Pb values increased significantly from 111 micrograms/l in subjects with normal blood pressure (n = 668) to 113.5 micrograms/l in subjects with borderline high blood pressure (n = 373) and to 120 micrograms/l in subjects with increased blood pressure (n = 278). After log-normal conversion of B-Pb, the linear correlation coefficient between In[B-Pb(ug/l)] and both SBP and DBP was statistically significant (r = 0.1332, p < 0.001 and r = 0.0737, p = 0.007, respectively). The linear regression coefficient was 6.8 mm Hg/In(micrograms/l) for SBP and 1.8 mm Hg/In(microgram/l) for DBP. Multiple regression analyses revealed that, after correction for body mass index (BMI), age, heart rate, skinfold thickness, serum lipids, and glucose levels; blood lead was still a significant predictor of increased SBP and DBP.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7698070

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

    DTIC Science & Technology

    2014-01-01

    Architecture Adaptability - An NFR Approach”, Proceedings of the International Workshop on Principles of Software Evolution (IWPSE 2001), ACM...identify solutions neces- sary to make that system trustworthy for a specified time-scale. In this paper we apply the NFR Approach to a selected software ...Phoenix by using the NFR Approach and developed a process for applying this approach to other software systems. Our study identified an 89% shortfall

  3. Defining the nociceptive flexion reflex (NFR) threshold in human participants: A comparison of different scoring criteria

    PubMed Central

    Rhudy, Jamie L.; France, Christopher R.

    2007-01-01

    Despite the widespread use of the nociceptive flexion reflex (NFR) paradigm in clinical and experimental pain research, there is currently no consensus on how best to define NFR threshold. Accordingly, the present studies were designed to assess the accuracy and reliability of different NFR threshold scoring criteria. Study 1 compared 13 scoring criteria in their accuracy for identifying the presence of the NFR, then generated empirically derived cut-points for the best criteria, and examined the test-retest reliability of NFR thresholds derived from these cut-points. Study 2 evaluated the replicability of these findings in an independent sample. Results from the two studies suggested that standardized peak (NFR Interval Peak z score) and mean (NFR Interval z score) biceps femoris electromyogram (EMG) activity were accurate and reliable criteria for defining NFR threshold. Acknowledging that cut-points may need to be adjusted for different research designs, graphs depicting sensitivity and specificity across a range of cut-points have been provided to facilitate researcher’s decision-making. It is hoped that the results of these studies will promote a standard NFR threshold assessment methodology, and further encourage the application of the NFR paradigm in the investigation of mechanisms and characteristics of both painful and non-painful diseases. PMID:17070999

  4. Association between total serum cholesterol and suicide attempts in subjects with major depressive disorder: Exploring the role of clinical and biochemical confounding factors.

    PubMed

    Bartoli, Francesco; Crocamo, Cristina; Dakanalis, Antonios; Riboldi, Ilaria; Miotto, Alessio; Brosio, Enrico; Clerici, Massimo; Carrà, Giuseppe

    2017-04-01

    We tested whether serum total cholesterol levels might be associated with recent suicide attempts in subjects with major depressive disorder, after controlling for relevant individual characteristics. We conducted a comparative cross-sectional study including consecutive inpatients with major depressive disorder. We differentiated subjects admitted for a recent serious (violent or non-violent) suicide attempt and those without such recent history. Total cholesterol was measured from fasting blood tests. At univariate analyses, suicide attempters had levels of total cholesterol (174.0±45.7mg/dL) lower than non-attempters (193.9±42.6mg/dL) (p=0.004). This was confirmed among both violent (174.1±46.2mg/dL) and non-violent (173.8±46.1mg/dL) suicide attempters (p=0.035 and 0.016, respectively). However, logistic regression analyses, sequentially including demographic, clinical (comorbid alcohol and personality disorders), and biochemical factors, did not show any association between serum cholesterol and recent suicide attempts (p=0.172). Similar findings were observed in multinomial logistic regression analyses, for both violent (p=0.512) and non-violent (p=0.157) suicide attempts. Our findings do not support the hypothesis that serum cholesterol and suicide attempts are associated among subjects with major depressive disorder. The identification of valid and accessible biological markers of suicidal behaviors still represents a challenge for future research. Copyright © 2016 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

  5. 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.

  6. LysM domains mediate lipochitin–oligosaccharide recognition and Nfr genes extend the symbiotic host range

    PubMed Central

    Radutoiu, Simona; Madsen, Lene H; Madsen, Esben B; Jurkiewicz, Anna; Fukai, Eigo; Quistgaard, Esben M H; Albrektsen, Anita S; James, Euan K; Thirup, Søren; Stougaard, Jens

    2007-01-01

    Legume–Rhizobium symbiosis is an example of selective cell recognition controlled by host/non-host determinants. Individual bacterial strains have a distinct host range enabling nodulation of a limited set of legume species and vice versa. We show here that expression of Lotus japonicus Nfr1 and Nfr5 Nod-factor receptor genes in Medicago truncatula and L. filicaulis, extends their host range to include bacterial strains, Mesorhizobium loti or DZL, normally infecting L. japonicus. As a result, the symbiotic program is induced, nodules develop and infection threads are formed. Using L. japonicus mutants and domain swaps between L. japonicus and L. filicaulis NFR1 and NFR5, we further demonstrate that LysM domains of the NFR1 and NFR5 receptors mediate perception of the bacterial Nod-factor signal and that recognition depends on the structure of the lipochitin–oligosaccharide Nod-factor. We show that a single amino-acid variation in the LysM2 domain of NFR5 changes recognition of the Nod-factor synthesized by the DZL strain and suggests a possible binding site for bacterial lipochitin–oligosaccharide signal molecules. PMID:17690687

  7. LysM domains mediate lipochitin-oligosaccharide recognition and Nfr genes extend the symbiotic host range.

    PubMed

    Radutoiu, Simona; Madsen, Lene H; Madsen, Esben B; Jurkiewicz, Anna; Fukai, Eigo; Quistgaard, Esben M H; Albrektsen, Anita S; James, Euan K; Thirup, Søren; Stougaard, Jens

    2007-09-05

    Legume-Rhizobium symbiosis is an example of selective cell recognition controlled by host/non-host determinants. Individual bacterial strains have a distinct host range enabling nodulation of a limited set of legume species and vice versa. We show here that expression of Lotus japonicus Nfr1 and Nfr5 Nod-factor receptor genes in Medicago truncatula and L. filicaulis, extends their host range to include bacterial strains, Mesorhizobium loti or DZL, normally infecting L. japonicus. As a result, the symbiotic program is induced, nodules develop and infection threads are formed. Using L. japonicus mutants and domain swaps between L. japonicus and L. filicaulis NFR1 and NFR5, we further demonstrate that LysM domains of the NFR1 and NFR5 receptors mediate perception of the bacterial Nod-factor signal and that recognition depends on the structure of the lipochitin-oligosaccharide Nod-factor. We show that a single amino-acid variation in the LysM2 domain of NFR5 changes recognition of the Nod-factor synthesized by the DZL strain and suggests a possible binding site for bacterial lipochitin-oligosaccharide signal molecules.

  8. 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

  9. 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).

  10. [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.

  11. 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

  12. 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

  13. 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…

  14. 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…

  15. 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…

  16. 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…

  17. The product of the nitrogen fixation regulatory gene nfrX of Azotobacter vinelandii is functionally and structurally homologous to the uridylyltransferase encoded by glnD in enteric bacteria.

    PubMed Central

    Contreras, A; Drummond, M; Bali, A; Blanco, G; Garcia, E; Bush, G; Kennedy, C; Merrick, M

    1991-01-01

    We sequenced the nitrogen fixation regulatory gene nfrX from Azotobacter vinelandii, mutations in which cause a Nif- phenotype, and found that it encodes a 105-kDa protein (NfrX), the N terminus of which is highly homologous to that of the uridylyltransferase-uridylyl-removing enzyme encoded by glnD in Escherichia coli. In vivo complementation experiments demonstrate that the glnD and nfrX products are functionally interchangeable. A vinelandii nfrX thus appears to encode a uridylyltransferase-uridylyl-removing enzyme, and in this paper we report the first sequence of such a protein. The Nif- phenotype of nfrX mutants can be suppressed by a second mutation in a recently identified nifL-like gene immediately upstream of nifA in A. vinelandii. NifL mediates nif regulation in response to the N status in A. vinelandii, presumably by inhibiting NifA activator function as occurs in Klebsiella pneumoniae; thus, one role of NfrX is to modify, either directly or indirectly, the activity of the nifL product. PMID:1683868

  18. Corynoline Isolated from Corydalis bungeana Turcz. Exhibits Anti-Inflammatory Effects via Modulation of Nfr2 and MAPKs.

    PubMed

    Yang, Chunjuan; Zhang, Chengyue; Wang, Zhibin; Tang, Zhenqiu; Kuang, Haixue; Kong, Ah-Ng Tony

    2016-07-27

    Corydalis bungeana Turcz. is an anti-inflammatory medicinal herb used widely in traditional Chinese medicine for upper respiratory tract infections. It is demonstrated that corynoline is its active anti-inflammatory component. The nuclear factor-erythroid-2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway and the mitogen-activated protein kinase (MAPK) pathway play important roles in the regulation of inflammation. In this study, we investigated the potential anti-inflammatory mechanism of corynoline through modulation of Nfr2 and MAPKs. Lipopolysaccharide (LPS)-activated RAW264.7 cells were used to explore modulatory role of NO production and the activation of signaling proteins and transcription factors using nitrite assay, Western bloting and qPCR. Treatment with corynoline reduced production of nitric oxide (NO) and the protein and mRNA levels of inducible nitric oxide (iNOS) and cyclooxygenase-2 (COX-2) Treatment also significantly increased the expression of Nrf2, quinone oxidoreductase 1 (NQO1) and hemeoxygenase-1 (HO-1) at the mRNA and protein levels, which demonstrated that corynoline may protect cells from inflammation through the Nrf2/ARE pathway In addition, corynoline suppressed the expression of inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), at the mRNA and protein levels. Furthermore, molecular data revealed that corynoline inhibited lipopolysaccharide-stimulated phosphorylation of c-jun NH2-terminal kinase (JNK) and p38. Taken together, these results suggest that corynoline reduces the levels of pro-inflammatory mediators, such as iNOS, COX-2, TNF-α and IL-1β, by suppressing extracellular signal-regulated kinase 1/2 (ERK) and p38 phosphorylation in RAW264.7 cells, which is regulated by the Nrf2/ARE pathway. These findings reveal part of the molecular basis for the anti-inflammatory properties of corynoline.

  19. On the definition of a confounder

    PubMed Central

    VanderWeele, Tyler J.; Shpitser, Ilya

    2014-01-01

    Summary The causal inference literature has provided a clear formal definition of confounding expressed in terms of counterfactual independence. The causal inference literature has not, however, produced a clear formal definition of a confounder, as it has given priority to the concept of confounding over that of a confounder. We consider a number of candidate definitions arising from various more informal statements made in the literature. We consider the properties satisfied by each candidate definition, principally focusing on (i) whether under the candidate definition control for all “confounders” suffices to control for “confounding” and (ii) whether each confounder in some context helps eliminate or reduce confounding bias. Several of the candidate definitions do not have these two properties. Only one candidate definition of those considered satisfies both properties. We propose that a “confounder” be defined as a pre-exposure covariate C for which there exists a set of other covariates X such that effect of the exposure on the outcome is unconfounded conditional on (X, C) but such that for no proper subset of (X, C) is the effect of the exposure on the outcome unconfounded given the subset. A variable that helps reduce bias but not eliminate bias we propose referring to as a “surrogate confounder.” PMID:25544784

  20. 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.

  1. 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.

  2. On quantifying the magnitude of confounding

    PubMed Central

    Janes, Holly; Dominici, Francesca; Zeger, Scott

    2010-01-01

    When estimating the association between an exposure and outcome, a simple approach to quantifying the amount of confounding by a factor, Z, is to compare estimates of the exposure–outcome association with and without adjustment for Z. This approach is widely believed to be problematic due to the nonlinearity of some exposure-effect measures. When the expected value of the outcome is modeled as a nonlinear function of the exposure, the adjusted and unadjusted exposure effects can differ even in the absence of confounding (Greenland , Robins, and Pearl, 1999); we call this the nonlinearity effect. In this paper, we propose a corrected measure of confounding that does not include the nonlinearity effect. The performances of the simple and corrected estimates of confounding are assessed in simulations and illustrated using a study of risk factors for low birth–weight infants. We conclude that the simple estimate of confounding is adequate or even preferred in settings where the nonlinearity effect is very small. In settings with a sizable nonlinearity effect, the corrected estimate of confounding has improved performance. PMID:20203259

  3. 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.

  4. 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.

  5. Iron metabolism in children: Confounding factors

    PubMed Central

    Brittenham, Gary M.

    2011-01-01

    Characterization of iron metabolism in infants and children may be confounded by the diverse effects of developmental, genetic, and acquired influences on iron metabolism and laboratory measurements of iron status, especially in areas with intense perennial transmission of Plasmodium falciparum malaria. In the Pemba iron and folic acid supplementation trial, the coadministration of folic acid with iron is a further confounding factor. Because the design of the Pemba iron and folic acid supplementation study did not include a group that received iron supplementation without folic acid, the observed increase in serious adverse events cannot be ascribed unequivocally to iron alone, to folic acid alone, or to the combination of the two. In interpreting the results from the Pemba iron and folic acid supplementation trial, additional analyses of existing data from the trial and from earlier studies in the area could help clarify the roles of iron and folic acid. PMID:18297889

  6. 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

  7. 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.

  8. Resting-state FMRI confounds and cleanup

    PubMed Central

    Murphy, Kevin; Birn, Rasmus M.; Bandettini, Peter A.

    2013-01-01

    The goal of resting-state functional magnetic resonance imaging (FMRI) is to investigate the brain’s functional connections by using the temporal similarity between blood oxygenation level dependent (BOLD) signals in different regions of the brain “at rest” as an indicator of synchronous neural activity. Since this measure relies on the temporal correlation of FMRI signal changes between different parts of the brain, any non-neural activity-related process that affects the signals will influence the measure of functional connectivity, yielding spurious results. To understand the sources of these resting-state FMRI confounds, this article describes the origins of the BOLD signal in terms of MR physics and cerebral physiology. Potential confounds arising from motion, cardiac and respiratory cycles, arterial CO2 concentration, blood pressure/cerebral autoregulation, and vasomotion are discussed. Two classes of techniques to remove confounds from resting-state BOLD time series are reviewed: 1) those utilising external recordings of physiology and 2) data-based cleanup methods that only use the resting-state FMRI data itself. Further methods that remove noise from functional connectivity measures at a group level are also discussed. For successful interpretation of resting-state FMRI comparisons and results, noise cleanup is an often over-looked but essential step in the analysis pipeline. PMID:23571418

  9. 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.

  10. 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

  11. Brain death: assessment, controversy, and confounding factors.

    PubMed

    Arbour, Richard B

    2013-12-01

    When brain injury is refractory to aggressive management and is considered nonsurvivable, with loss of consciousness and brain stem reflexes, a brain death protocol may be initiated to determine death according to neurological criteria. Clinical evaluation typically entails 2 consecutive formal neurological examinations to document total loss of consciousness and absence of brain stem reflexes and then apnea testing to evaluate carbon dioxide unresponsiveness within the brain stem. Confounding factors such as use of therapeutic hypothermia, high-dose metabolic suppression, and movements associated with complex spinal reflexes, fasciculations, or cardiogenic ventilator autotriggering may delay initiation or completion of brain death protocols. Neurodiagnostic studies such as 4-vessel cerebral angiography can rapidly document absence of blood flow to the brain and decrease intervals between onset of terminal brain stem herniation and formal declaration of death by neurological criteria. Intracranial pathophysiology leading to brain death must be considered along with clinical assessment, patterns of vital signs, and relevant diagnostic studies.

  12. 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

  13. 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.

  14. 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.

  15. 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.

  16. 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

  17. Confounders of auscultatory blood pressure measurement.

    PubMed

    Baker, R H; Ende, J

    1995-04-01

    The appropriate use of any test requires the clinician to appreciate that test's limitations. By recognizing the potential confounders of the auscultatory assessment of blood pressure, the clinician minimizes the likelihood of enacting therapeutic decisions based on inaccurate data. When approaching the treatment of a hypertensive patient, several points should be kept in mind. First, the measurement of persistent and severe hypertension in a patient receiving treatment who describes symptoms of orthostatic hypotension with apparently adequate standing blood pressure or who lacks corroborating retinal, echocardiographic, or electrocardiographic signs of hypertension should raise the concern of pseudohypertension or a white-coat response. Similarly, when one finds a normal or near-normal systolic blood pressure in a patient with a clinical picture consistent with severe hypertension, one should make a directed effort to look for an unrecognized auscultatory gap. Second, marked discrepancies in measurements as obtained by different operators or in different settings should raise concern of the white-coat response or methodologic errors by one operator, such as undercuffing, excessive pressure on the head of the stethoscope, rapid deflation of the cuff, or use of different arms. In treating hypertension in even the minimally obese patient, a special point must be made that an adequate size cuff be used for all blood pressure determinations. Third, when blood pressure is determined with the patient in any but the satndardized back-and-arm-supported seated position described above, the clinician should acknowledge the possibility that the position may alter the patient's classification. Fourth, the diagnosis and management of hypertension requires multiple measurements of blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

  18. 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.

  19. 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.

  20. 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.

  1. Analysis of potential genomic confounding in genetic association studies and an online genomic confounding browser (GCB).

    PubMed

    Raistrick, Christopher A; Alharbi, Khalid K; Day, Ian N M; Gaunt, Tom R

    2011-11-01

    Genome-wide association studies have transformed genetic studies of disease susceptibility, identifying many variants that may tag functional polymorphism nearby. Variants are often ascribed to a physically close gene exhibiting plausible functionality for a causal pathway. However, more physically remote genes may be at a lesser linkage or linkage disequilibrium (LD) distance from the tested SNP and could therefore contain the functional variant tagged. This analysis aims to identify instances where research may be misled by misassociation of a variant with a gene and develop tools to analyse genomic confounding. A catalogue of reported associations was systematically analysed for unreported genes which may represent the true functionality ascribed to a reported variant, calculating physical and genetic distances for all genes within 1 cM of the tagging polymorphism. Results revealed 55 SNPs where recombination was lower between the identified SNP and a physically more remote gene than initially reported, and 374 where an alternative gene was genetically and physically closer than the reported gene. Analyses show potential for genomic confounding through false inferences of variant association to a gene. An online visualization tool (http://gcb.genes.org.uk/) was developed to plot genes by physical and genetic distance relative to a variant, along with LD data. © 2011 The Authors Annals of Human Genetics © 2011 Blackwell Publishing Ltd/University College London.

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

    PubMed

    Smith, Eric G

    2014-01-01

      Nonrandomized studies typically cannot account for confounding from unmeasured factors.    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.   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.   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).   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 straightforward.  The method's routine usefulness, however, has

  3. 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.

  4. Postglacial hillslope development in paraglacial tributary catchments (ESF-NFR SedyMONT-Norway Project, SedyMONT, Topo-Europe)

    NASA Astrophysics Data System (ADS)

    Laute, Katja; Beylich, Achim A.; Hansen, Louise; Vatne, Geir

    2010-05-01

    Topography and landforms of different spatial scales are generated by different operating processes and are characterized by different variables, evolved over different time periods. Changes in climate affect Earth surface systems and shapes Earth surface processes around the world and seem to have major impacts on sediment dynamics, especially in cold climate environments. Understanding climate and landform development from a Holocene to contemporary time perspective can contribute to document change of the Earth surface systems as well as to detect responsible processes for climatic and topographic change. Analyzing postglacial hillslope development and studying sediment transport within two small deglaciated, subarctic valley systems in Western Norway will improve the understanding of the complex response of mountain landscape formation. The innovative approach of this PhD research project is the combination of knowledge on Holocene process rates with data on subrecent to contemporary sedimentary fluxes, -budgets and process rates using different advanced methods and techniques. The PhD project is part of the NFR funded SedyMONT-Norway Project within the ESF EUROCORES TOPO-EUROPE SedyMONT (Timescales of sediment dynamics, climate and topographic change in mountain landscapes) Programme. Research is carried out within the Erdalen and Bødalen catchments of the Nordfjord valley-fjord system (inner Nordfjord, Western Norway). Both valleys can be described as steep U-shaped and glacier-fed tributary valleys. The runoff regime is complex with a high variability of discharge over the year. Instrumentation in both catchments includes an automatic weather station as well as five stationary stations for continuous and year-round monitoring of runoff, fluvial suspended sediment and solute transport. The main aims of the PhD project are to analyse (i) the spatial distribution of hillslopes, their contemporary structure, controls and current process rates, (ii) the

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. [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.

  10. 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

  11. Distinguishing selection bias and confounding bias in comparative effectiveness research

    PubMed Central

    Haneuse, Sebastien

    2014-01-01

    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. While inadequate control of confounding is the most-often cited source of potential bias, selection bias which arises when patients are differentially excluded from analyses is a distinct phenomenon with distinct consequences: confounding bias compromises internal validity while 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 on-going study of treatment choice for depression on weight change over time, we formally distinguish confounding and selection bias in CER. By formally distinguishing selection and confounding bias we clarify important scientific, design and analysis issues relevant to ensuring validity. First is that the two types of bias 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 statistical methods used to mitigate the two 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. PMID:24309675

  12. 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.

  13. 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.

  14. 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.

  15. 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

  16. 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.

  17. 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

  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. 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.

  20. Developing hazelnut tissue culture medium free of ion confounding

    USDA-ARS?s Scientific Manuscript database

    The general approach for tissue culture medium optimization is to use salts as factors in experimental design and analysis. However, using salts as factors leads to ion confounding, making it difficult to detect the effects of individual ions on particular growth responses. This study focused on tes...

  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. 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.

  5. Confounding factors affect the pathophysiology of eosinophilic esophagitis.

    PubMed

    Elitsur, Yoram

    2012-09-07

    Eosinophilic esophagitis is a newly diagnosed esophageal disease in adult and children. The clinical and pathological characteristics of this disease have been established and were recently summarized in the expert clinical guideline published in 2011. In spite of the wide knowledge accumulated on this disease, there are many areas where scientific data are missing, especially in regard to the disease's pathophysiology. Recent publications have suggested that other confounding factors modify the disease and may affect its clinical-phenotypic presentation. Those factors may include place of living, air pollution, race, genetic factors and other. In the present report we discussed and review those confounding factors, the new developments, and what direction we should go to further advance our knowledge of this disease.

  6. 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. Copyright © 2015 American College of Foot and Ankle Surgeons. Published by Elsevier Inc. All rights reserved.

  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. 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

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

    PubMed

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

    2015-06-10

    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

  10. Arsenic Cancer Risk Confounder in Southwest Taiwan Data Set

    PubMed Central

    Lamm, Steven H.; Engel, Arnold; Penn, Cecilia A.; Chen, Rusan; Feinleib, Manning

    2006-01-01

    Quantitative analysis for the risk of human cancer from the ingestion of inorganic arsenic has been based on the reported cancer mortality experience in the blackfoot disease (BFD)–endemic area of southwest Taiwan. Linear regression analysis shows that arsenic as the sole etiologic factor accounts for only 21% of the variance in the village standardized mortality ratios for bladder and lung cancer. A previous study had reported the influence of confounders (township, BFD prevalence, and artesian well dependency) qualitatively, but they have not been introduced into a quantitative assessment. In this six-township study, only three townships (2, 4, and 6) showed a significant positive dose–response relationship with arsenic exposure. The other three townships (0, 3, and 5) demonstrated significant bladder and lung cancer risks that were independent of arsenic exposure. The data for bladder and lung cancer mortality for townships 2, 4, and 6 fit an inverse linear regression model (p < 0.001) with an estimated threshold at 151 μg/L (95% confidence interval, 42 to 229 μg/L). Such a model is consistent with epidemiologic and toxicologic literature for bladder cancer. Exploration of the southwest Taiwan cancer mortality data set has clarified the dose–response relationship with arsenic exposure by separating out township as a confounding factor. PMID:16835062

  11. Confounding in association studies: month of birth and multiple sclerosis.

    PubMed

    Fiddes, Barnaby; Wason, James; Sawcer, Stephen

    2014-10-01

    Association studies form the backbone of biomedical research, with almost every effort in the field ultimately boiling down to a comparison between groups, coupled with some form of statistical test intended to determine whether or not any observed difference is more or less than would be expected by chance. Unfortunately, although the paradigm is powerful and frequently effective, it is often forgotten that false positive association can easily arise if there is any bias or systematic difference in the way in which study subjects are selected into the considered groups. To protect against such confounding, researchers generally try to match cases and controls for extraneous variables thought to correlate with the exposures of interest. However, if seemingly homogenously distributed exposures are actually more heterogeneous than appreciated, then matching may be inadequate and false positive results can still arise. In this review, we will illustrate these fundamental issues by considering the previously proposed relationship between month of birth and multiple sclerosis. This much discussed but false positive association serves as a reminder of just how heterogeneous even easily measured environmental risk factors can be, and how easily case control studies can be confounded by seemingly minor differences in ascertainment.

  12. Biological confounders for the values of cerebrospinal fluid proteins in Parkinson's disease and related disorders.

    PubMed

    Mollenhauer, Brit; Parnetti, Lucilla; Rektorova, Irena; Kramberger, Milica G; Pikkarainen, Maria; Schulz-Schaeffer, Walter J; Aarsland, Dag; Svenningsson, Per; Farotti, Lucia; Verbeek, Marcel M; Schlossmacher, Michael G

    2016-10-01

    Cerebrospinal fluid (CSF) has been extensively studied to explore biochemical alterations in subjects with neurodegenerative disorders. In Alzheimer's disease, levels of increased CSF tau protein and decreased levels of β-amyloid 1-42 (Aβ42) have been shown to correlate with brain plaque formation and tangle pathology. Intracellular Lewy inclusions containing aggregated α-synuclein (α-syn) represent a pathological hallmark of Parkinson's disease (PD). In most - but not all - studies published to date total CSF α-syn concentrations have been found to be decreased in disorders related to α-syn pathology, that is, PD, dementia with Lewy bodies and multiple system atrophy. However, these reports show extensive signal overlap among tested individuals, thereby diminishing its potential for routine use in clinical practice. To investigate potential biological (i.e., non-technical) confounders of reported CSF levels for α-syn, Aβ42, and tau in PD and related disorders, we carried out a methodical review of known factors that underlie signal variability and speculate on those that have not yet been tested. We discuss several biological factors, such as neuropathology, demographics, clinical phenotype, progression and duration of disease, concomitant illnesses and, last but not least, pharmacotherapy, which in isolation or combination can substantially alter values for CSF proteins of interest. Enhanced implementation of standardized clinical protocols, streamlined operating procedures, and further progress in the development of validated assays for CSF proteins have the potential to (i) inform us as to the pathogenesis of disease, (ii) support the laboratory-based diagnosis for symptomatic subjects in the future, and (iii) facilitate breakthrough therapies to alter the course of neurodegenerative disorders, such as PD and Alzheimer's disease. Cerebrospinal fluid (CSF) has been extensively studied to explore biochemical alterations in subjects with neurodegenerative

  13. 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.

  14. Processed Pseudogene Confounding Deletion/Duplication Assays for SMAD4.

    PubMed

    Millson, Alison; Lewis, Tracey; Pesaran, Tina; Salvador, David; Gillespie, Katrina; Gau, Chia-Ling; Pont-Kingdon, Genevieve; Lyon, Elaine; Bayrak-Toydemir, Pinar

    2015-09-01

    Mutations in SMAD4 have been associated with juvenile polyposis syndrome and combined juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome. SMAD4 is part of the SMAD gene family. To date, there has been no report in the literature of a SMAD4 pseudogene. An unusual SMAD4 duplication pattern was seen in multiple patient samples using two different duplication/deletion platforms: multiplex ligation-dependent probe amplification and chromosomal microarray. Follow-up confirmatory testing included real-time quantitative PCR and sequencing of an exon/exon junction, all results leading to the conclusion of the existence of a processed pseudogene. Examination of clinical results from two laboratories found a frequency of 0.26% (12 in 4672 cases) for this processed pseudogene. This is the first report of the presence of a processed pseudogene for SMAD4. We believe that knowledge of its existence is important for accurate interpretation of clinical diagnostic test results and for new assay designs. This study also indicates how a processed pseudogene may confound quantitative results, dependent on placement of probes and/or primers in a particular assay design, potentially leading to both false-positive and false-negative results. We also found that the SMAD4 processed pseudogene affects next-generation sequencing results by confounding the alignment of the sequences, resulting in erroneous variant calls. We recommend Sanger sequencing confirmation for SMAD4 variants. Copyright © 2015 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.

  15. 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

  16. Clinical breath analysis: discriminating between human endogenous compounds and exogenous (environmental) chemical confounders.

    PubMed

    Pleil, Joachim D; Stiegel, Matthew A; Risby, Terence H

    2013-03-01

    Volatile organic compounds (VOCs) in exhaled breath originate from current or previous environmental exposures (exogenous compounds) and internal metabolic (anabolic and catabolic) production (endogenous compounds). The origins of certain VOCs in breath presumed to be endogenous have been proposed to be useful as preclinical biomarkers of various undiagnosed diseases including lung cancer, breast cancer, and cardio-pulmonary disease. The usual approach is to develop difference algorithms comparing VOC profiles from nominally healthy controls to cohorts of patients presenting with a documented disease, and then to apply the resulting rules to breath profiles of subjects with unknown disease status. This approach to diagnosis has a progression of sophistication; at the most rudimentary level, all measurable VOCs are included in the model. The next level corrects exhaled VOC concentrations for current inspired air concentrations. At the highest level, VOCs exhibiting discriminatory value also require a plausible biochemical pathway for their production before inclusion. Although these approaches have all shown some level of success, there is concern that pattern recognition is prone to error from environmental contamination and between-subject variance. In this paper, we explore the underlying assumptions for the interpretation and assignment of endogenous compounds with probative value for assessing changes. Specifically, we investigate the influence of previous exposures, elimination mechanisms and partitioning of exogenous compounds as confounders of true endogenous compounds. We provide specific examples based on a simple classical pharmacokinetic approach to identify potential misinterpretations of breath data and propose some remedies.

  17. Determining Confounding Sensitivities In Eddy Current Thin Film Measurements

    SciTech Connect

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

    2016-07-01

    Determining Confounding Sensitivities In Eddy Current Thin Film Measurements Ethan Gros, Lalita Udpa, Electrical Engineering, Michigan State University, East Lansing MI 48824 James A. Smith, Experiment Analysis, Idaho National Laboratory, Idaho Falls ID 83415 Eddy current (EC) techniques are widely used in industry to measure the thickness of non-conductive films on a metal substrate. This is done 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 is 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 is 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 is 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

  18. 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.

  19. Smoking and Hormesis as Confounding Factors in Radiation Pulmonary Carcinogenesis

    PubMed Central

    Sanders, Charles L.; Scott, Bobby R.

    2008-01-01

    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 epi-demiological 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. PMID:18648572

  20. Biasogram: Visualization of Confounding Technical Bias in Gene Expression Data

    PubMed Central

    Krzystanek, Marcin; Szallasi, Zoltan; Eklund, Aron C.

    2013-01-01

    Gene expression profiles of clinical cohorts can be used to identify genes that are correlated with a clinical variable of interest such as patient outcome or response to a particular drug. However, expression measurements are susceptible to technical bias caused by variation in extraneous factors such as RNA quality and array hybridization conditions. If such technical bias is correlated with the clinical variable of interest, the likelihood of identifying false positive genes is increased. Here we describe a method to visualize an expression matrix as a projection of all genes onto a plane defined by a clinical variable and a technical nuisance variable. The resulting plot indicates the extent to which each gene is correlated with the clinical variable or the technical variable. We demonstrate this method by applying it to three clinical trial microarray data sets, one of which identified genes that may have been driven by a confounding technical variable. This approach can be used as a quality control step to identify data sets that are likely to yield false positive results. PMID:23613961

  1. 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

  2. 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.

  3. Biasogram: visualization of confounding technical bias in gene expression data.

    PubMed

    Krzystanek, Marcin; Szallasi, Zoltan; Eklund, Aron C

    2013-01-01

    Gene expression profiles of clinical cohorts can be used to identify genes that are correlated with a clinical variable of interest such as patient outcome or response to a particular drug. However, expression measurements are susceptible to technical bias caused by variation in extraneous factors such as RNA quality and array hybridization conditions. If such technical bias is correlated with the clinical variable of interest, the likelihood of identifying false positive genes is increased. Here we describe a method to visualize an expression matrix as a projection of all genes onto a plane defined by a clinical variable and a technical nuisance variable. The resulting plot indicates the extent to which each gene is correlated with the clinical variable or the technical variable. We demonstrate this method by applying it to three clinical trial microarray data sets, one of which identified genes that may have been driven by a confounding technical variable. This approach can be used as a quality control step to identify data sets that are likely to yield false positive results.

  4. 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.

  5. 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.

  6. 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

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. The confounding recent behaviour of the Quasi-Biennial Oscillation

    NASA Astrophysics Data System (ADS)

    Osprey, Scott; Butchart, Neal; Knight, Jeff; Scaife, Adam; Hamilton, Kevin; Anstey, James; Schenzinger, Verena; Zhang, Chunxi

    2017-04-01

    High above the equator winds slowly change from blowing eastward to westward and back again roughly every 28 months in a natural climate rhythm known as the quasibiennial oscillation (QBO). These regular winds have been recorded since the 1950s and emerge from natural processes within the tropics e.g. clouds, convection, rainfall and the wave disturbances arising from these. The latter break down high up in the stratosphere, analogous to waves on a beach. Although a little tricky to capture in climate models, our understanding of the basic processes underpinning this climate rhythm was thought to be relatively complete. However, early in 2016 the stratospheric heart skipped a beat, confounding our present understanding of it. The disruption was seen as a thin and rapidly growing westward wind jet at 25km within a deep background of eastward winds. The position of the thin jet could not be explained by waves percolating up through underlying winds from the turbulent lower atmosphere. Rather clues to the origin of the disruption pointed to agents outside the tropics - large scale waves usually found at mid-latitudes made their way to the tropics, causing the disruption. Clear links are found between the winds occurring in the tropical stratosphere and the sorts of seasonal weather experienced in the tropics (e.g. MJO) and Northern/Southern Europe. Because these tropical stratosphere winds are predictable out to years, weather centres are keen to exploit them for seasonal forecasting. The 2016 disruption was not anticipated by weather centres and this has clear implications for the limiting skill of future seasonal forecasts. The results from this study raise many questions. How will the disrupted QBO impact future seasonal forecasting? Will similar events recur more often in the future, and if so what role did anthropogenic climate change play in the 2016 event? Finally, what conditions ultimately resulted in the disruption? Osprey, S. M. et al. An unexpected

  12. Handling stress may confound murine gut microbiota studies.

    PubMed

    Allen-Blevins, Cary R; You, Xiaomeng; Hinde, Katie; Sela, David A

    2017-01-01

    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. 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. Our results demonstrate

  13. 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

  14. Influence of various confounding variables and storage conditions on metanephrine and normetanephrine levels in plasma.

    PubMed

    Deutschbein, Timo; Unger, Nicole; Jaeger, Andrea; Broecker-Preuss, Martina; Mann, Klaus; Petersenn, Stephan

    2010-08-01

    Measurements of plasma free metanephrines have been advocated as first-line tests for phaeochromocytoma. The aim of the study was to assess the impact of potential confounding variables. Comparative study between 2008 and 2009. Hundred and eighty healthy subjects. The effects of age, BMI, gender, menstrual cycle (sampling every 2 days), time of day (sampling every 2 h), venepunture (0, 15, 30, 60, 90 and 120 min), physical exercise (0, 15 and 30 min), coffee (0 and 60 min), breakfast (0 and 60 min) and various body positions (standing and supine rest, each 0 and 120 min) were evaluated. In addition, whole blood and plasma samples were stored at 4 degrees C or at 22 degrees C for 0, 1, 3, 24 and 72 h. Plasma free metanephrines were measured using radioimmunoassay (LDN). While metanephrine was significantly influenced by sex and age, BMI and sex were significant predictors of normetanephrine. Coffee (+20%) and food (+8%) elevated normetanephrine significantly (P < 0.05), while metanephrine remained stable. Physical exercise increased metanephrine (+82%) as well as normetanephrine (+84%) significantly (P < 0.005). Supine rest significantly decreased both metanephrine (-34%) and normetanephrine (-19%) when compared to standing rest (P < 0.01). Metanephrine and normetanephrine were not significantly influenced by time of day, menstrual cycle or venepuncture. When plasma samples were stored at 4 degrees C, metanephrine and normetanephrine were stable for 72 h. Physical exercise may lead to relevant changes in metanephrine and normetanephrine and should therefore be avoided prior to sampling. Although effects of age, sex and BMI were small, these variables should be considered when interpreting biochemical results. Blood should be taken in the supine position, and samples should be immediately centrifuged and stored at 4 degrees C to improve stability.

  15. 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

  16. Interpretation of epidemiological studies very often lacked adequate consideration of confounding.

    PubMed

    Hemkens, Lars G; Ewald, Hannah; Naudet, Florian; Ladanie, Aviv; Shaw, Jonathan G; Sajeev, Gautam; Ioannidis, John P A

    2017-09-21

    Confounding bias is a most pervasive threat to validity of observational epidemiological research. We assessed whether authors of observational epidemiological studies consider confounding bias when interpreting the findings. We randomly selected 120 cohort or case-control studies published in 2011 and 2012 by the general medical, epidemiological, and specialty journals with the highest impact factors. We used Web of Science to assess citation metrics through January 2017. 68 studies (56.7%, 95% confidence interval 47.8% to 65.5%) mentioned "confounding" in the Abstract or Discussion sections, another 20 (16.7%; 10.0% to 23.3%) alluded to it, and there was no mention or allusion at all in 32 studies (26.7%; 18.8% to 34.6%). Authors often acknowledged that for specific confounders there was no adjustment (34 studies; 28.3%) or deem it possible or likely that confounding affected their main findings (29 studies; 24.2%). However, only 2 studies (1.7%; 0% to 4.0%) specifically used the words "caution" or "cautious" for the interpretation due to confounding-related reasons and eventually only 4 studies (3.3%; 0.1% to 6.5%) had limitations related to confounding or any other bias in their Conclusions. Studies mentioning that the findings were possibly or likely affected by confounding were more frequently cited than studies with a statement that findings were unlikely affected (median 6.3 vs. 4.0 citations per year, p=0.04). Many observational studies lack satisfactory discussion of confounding bias. Even when confounding bias is mentioned, authors are typically confident that it is rather irrelevant to their findings and they rarely call for cautious interpretation. More careful acknowledgement of possible impact of confounding is not associated with lower citation impact. Copyright © 2017. Published by Elsevier Inc.

  17. Biochemical Engineering Fundamentals

    ERIC Educational Resources Information Center

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

    1976-01-01

    Discusses a biochemical engineering course that is offered as part of a chemical engineering curriculum and includes topics that influence the behavior of man-made or natural microbial or enzyme reactors. (MLH)

  18. 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...

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

    USDA-ARS?s Scientific Manuscript database

    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 ...

  20. 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.

  1. 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...

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

    USDA-ARS?s Scientific Manuscript database

    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 ...

  3. On the role of marginal confounder prevalence - implications for the high-dimensional propensity score algorithm.

    PubMed

    Schuster, Tibor; Pang, Menglan; Platt, Robert W

    2015-09-01

    The high-dimensional propensity score algorithm attempts to improve control of confounding in typical treatment effect studies in pharmacoepidemiology and is increasingly being used for the analysis of large administrative databases. Within this multi-step variable selection algorithm, the marginal prevalence of non-zero covariate values is considered to be an indicator for a count variable's potential confounding impact. We investigate the role of the marginal prevalence of confounder variables on potentially caused bias magnitudes when estimating risk ratios in point exposure studies with binary outcomes. We apply the law of total probability in conjunction with an established bias formula to derive and illustrate relative bias boundaries with respect to marginal confounder prevalence. We show that maximum possible bias magnitudes can occur at any marginal prevalence level of a binary confounder variable. In particular, we demonstrate that, in case of rare or very common exposures, low and high prevalent confounder variables can still have large confounding impact on estimated risk ratios. Covariate pre-selection by prevalence may lead to sub-optimal confounder sampling within the high-dimensional propensity score algorithm. While we believe that the high-dimensional propensity score has important benefits in large-scale pharmacoepidemiologic studies, we recommend omitting the prevalence-based empirical identification of candidate covariates. Copyright © 2015 John Wiley & Sons, Ltd.

  4. 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.

  5. The sign of the unmeasured confounding bias under various standard populations.

    PubMed

    Chiba, Yasutaka

    2009-08-01

    Unmeasured confounders are a common problem in drawing causal inferences in observational studies. VanderWeele (Biometrics 2008, 64, 702-706) presented a theorem that allows researchers to determine the sign of the unmeasured confounding bias when monotonic relationships hold between the unmeasured confounder and the treatment, and between the unmeasured confounder and the outcome. He showed that his theorem can be applied to causal effects with the total group as the standard population, but he did not mention the causal effects with treated and untreated groups as the standard population. Here, we extend his results to these causal effects, and apply our theorems to an observational study. When researchers have a sense of what the unmeasured confounder may be, conclusions can be drawn about the sign of the bias.

  6. 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.

  7. 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.

  8. 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…

  9. 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.

  10. 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.

  11. 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)

  12. 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

  13. 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)

  14. 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…

  15. 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

  16. Sibling comparison designs: bias from non-shared confounders and measurement error.

    PubMed

    Frisell, Thomas; Öberg, Sara; Kuja-Halkola, Ralf; Sjölander, Arvid

    2012-09-01

    Twins, full siblings, and half-siblings are increasingly used as comparison groups in matched cohort and matched case-control studies. The "within-pair" estimates acquired through these comparisons are free from confounding from all factors that are shared by the siblings. This has made sibling comparisons popular in studying associations thought likely to suffer confounding from socioeconomic or genetic factors. Despite the wide application of these designs in epidemiology, they have received little scrutiny from a statistical or methodological standpoint. In this paper we show, analytically and through a series of simulations, that the standard interpretation of the models is subject to several limitations that are rarely acknowledged.Although within-pair estimates will not be confounded by factors shared by the siblings, such estimates are more severely biased by non-shared confounders than the unpaired estimate. If siblings are less similar with regard to confounders than to the exposure under study, the within-pair estimate will always be more biased than the ordinary unpaired estimate. Attenuation of associations due to random measurement error in exposure will also be higher in the within-pair estimate, leading within-pair associations to be weaker than corresponding unpaired associations, even in the absence of confounding. Implications for the interpretation of sibling comparison results are discussed.

  17. 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.

  18. 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.

  19. 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.

  20. 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

  1. 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.

  2. 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.

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

    PubMed Central

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

    2014-01-01

    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. PMID:25530706

  4. Examining the Error of Mis-Specifying Nonlinear Confounding Effect with Application on Accelerometer-Measured Physical Activity

    ERIC Educational Resources Information Center

    Lee, Paul H.

    2017-01-01

    Purpose: Some confounders are nonlinearly associated with dependent variables, but they are often adjusted using a linear term. The purpose of this study was to examine the error of mis-specifying the nonlinear confounding effect. Methods: We carried out a simulation study to investigate the effect of adjusting for a nonlinear confounder in the…

  5. Bias, Confounding, and Interaction: Lions and Tigers, and Bears, Oh My!

    PubMed

    Vetter, Thomas R; Mascha, Edward J

    2017-09-01

    Epidemiologists seek to make a valid inference about the causal effect between an exposure and a disease in a specific population, using representative sample data from a specific population. Clinical researchers likewise seek to make a valid inference about the association between an intervention and outcome(s) in a specific population, based upon their randomly collected, representative sample data. Both do so by using the available data about the sample variable to make a valid estimate about its corresponding or underlying, but unknown population parameter. Random error in an experiment can be due to the natural, periodic fluctuation or variation in the accuracy or precision of virtually any data sampling technique or health measurement tool or scale. In a clinical research study, random error can be due to not only innate human variability but also purely chance. Systematic error in an experiment arises from an innate flaw in the data sampling technique or measurement instrument. In the clinical research setting, systematic error is more commonly referred to as systematic bias. The most commonly encountered types of bias in anesthesia, perioperative, critical care, and pain medicine research include recall bias, observational bias (Hawthorne effect), attrition bias, misclassification or informational bias, and selection bias. A confounding variable is a factor associated with both the exposure of interest and the outcome of interest. A confounding variable (confounding factor or confounder) is a variable that correlates (positively or negatively) with both the exposure and outcome. Confounding is typically not an issue in a randomized trial because the randomized groups are sufficiently balanced on all potential confounding variables, both observed and nonobserved. However, confounding can be a major problem with any observational (nonrandomized) study. Ignoring confounding in an observational study will often result in a "distorted" or incorrect estimate of

  6. 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).

  7. 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.

  8. 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.

  9. Confounding, causality, and confusion: the role of intermediate variables in interpreting observational studies in obstetrics.

    PubMed

    Ananth, Cande V; Schisterman, Enrique F

    2017-08-01

    Prospective and retrospective cohorts and case-control studies are some of the most important study designs in epidemiology because, under certain assumptions, they can mimic a randomized trial when done well. These assumptions include, but are not limited to, properly accounting for 2 important sources of bias: confounding and selection bias. While not adjusting the causal association for an intermediate variable will yield an unbiased estimate of the exposure-outcome's total causal effect, it is often that obstetricians will want to adjust for an intermediate variable to assess if the intermediate is the underlying driver of the association. Such a practice must be weighed in light of the underlying research question and whether such an adjustment is necessary should be carefully considered. Gestational age is, by far, the most commonly encountered variable in obstetrics that is often mislabeled as a confounder when, in fact, it may be an intermediate. If, indeed, gestational age is an intermediate but if mistakenly labeled as a confounding variable and consequently adjusted in an analysis, the conclusions can be unexpected. The implications of this overadjustment of an intermediate as though it were a confounder can render an otherwise persuasive study downright meaningless. This commentary provides an exposition of confounding bias, collider stratification, and selection biases, with applications in obstetrics and perinatal epidemiology. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. "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.

  11. 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

  12. 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.

  13. A Biochemical Double Slit

    NASA Astrophysics Data System (ADS)

    Kominis, Iannis

    2011-03-01

    Radical-ion-pair reactions, fundamental in photosynthesis and at the basis of the avian magnetic compass mechanism, have been recently shown to offer a rich playground for applying methods and concepts from quantum measurement/quantum information science. We will demonstrate that radical-ion-pair reactions are almost the exact analog of the optical double slit experiment, i.e. Nature has already engineered biochemical reactions performing the act of quantum interference. We will further elaborate on the non-trivial quantum effects pertaining in these reactions and the recent debate on their fundamental theoretical description that these effects have sparked.

  14. 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

  15. 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…

  16. 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…

  17. Effect of omitted confounders on the analysis of correlated binary data.

    PubMed

    Chao, W H; Palta, M; Young, T

    1997-06-01

    Marginal analysis using the generalized estimating equation approach is widely applied to correlated observations, as occur in studies with clusters and in longitudinal follow-up of individuals. In this article, we investigate the effect of confounding in such models. We assume that a risk factor x and a confounder z are related by a generalized linear model to the outcome y, which can be binary or ordinal. In order to investigate confounding arising from the omission of z, a joint structure for x and z must be specified. Modeling normally distributed (x,z) as sums of between- and within-individual (or cluster) components allows us to incorporate different degrees of between- and within-individual correlation. Such a structure includes, as special cases, cohort and period effects in longitudinal settings and random intercept models. The latter situation corresponds to allowing z to vary only on the between-individual (or cluster) level and to be uncorrelated with x, and leads to attenuation of the coefficient of x in marginal models with the logit and probit links. More complex situations occur when z is allowed to also vary on the within-individual (or cluster) level and when z is correlated with x. We examine the model specification and the expected bias when fitting a marginal model in the presence of the omitted confounder z. We derive general formulas and interpret the parameters and results in an ongoing cohort study. Testing for omitted covariates is also discussed.

  18. 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.

  19. 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.

  20. 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…

  1. 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.

  2. 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.

  3. 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…

  4. 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.

  5. 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

  6. 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

  7. Adjusting for unmeasured confounding in nonrandomized longitudinal studies: a methodological review.

    PubMed

    Streeter, Adam J; Lin, Nan Xuan; Crathorne, Louise; Haasova, Marcela; Hyde, Christopher; Melzer, David; Henley, William E

    2017-07-01

    Motivated by recent calls to use electronic health records for research, we reviewed the application and development of methods for addressing the bias from unmeasured confounding in longitudinal data. Methodological review of existing literature. We searched MEDLINE and EMBASE for articles addressing the threat to causal inference from unmeasured confounding in nonrandomized longitudinal health data through quasi-experimental analysis. Among the 121 studies included for review, 84 used instrumental variable analysis (IVA), of which 36 used lagged or historical instruments. Difference-in-differences (DiD) and fixed effects (FE) models were found in 29 studies. Five of these combined IVA with DiD or FE to try to mitigate for time-dependent confounding. Other less frequently used methods included prior event rate ratio adjustment, regression discontinuity nested within pre-post studies, propensity score calibration, perturbation analysis, and negative control outcomes. Well-established econometric methods such as DiD and IVA are commonly used to address unmeasured confounding in nonrandomized longitudinal studies, but researchers often fail to take full advantage of available longitudinal information. A range of promising new methods have been developed, but further studies are needed to understand their relative performance in different contexts before they can be recommended for widespread use. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  8. 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

  9. 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

  10. Confounding after risk-set sampling in the beryllium study of Sanderson et al.

    PubMed

    Rothman, Kenneth J; Mosquin, Paul L

    2011-10-01

    Beryllium is classified as carcinogenic on the basis largely of limited human data showing a modest increase in lung cancer from occupational exposure. With occupational exposure now curtailed, earlier results merit more scrutiny. We simulated data to understand the design implications of a landmark case-control study. We generated datasets from the original occupational cohort by randomly assigning lung cancer events to workers independently of their exposure. We analyzed the simulated data on the basis of different modes of risk-set sampling, with risk sets defined by calendar time, age, or both, to assess how much bias existed using several exposure metrics. We controlled for several time related variables to assess confounding. Finally, we re-analyzed the data from the original study, controlling for time-related covariates. No bias occurred using any type of risk-set sampling with unlagged exposures. When exposure was lagged 10 or 20 years, however, there was considerable confounding by year of birth and year of hire, which remained uncontrolled in the original study. Simulations and reanalysis show that much of the reported association with lagged exposure is attributable to confounding by year of birth and year of hire. Lagging changes the exposure variable and can thus lead to changes in the amount of confounding. Copyright © 2011 Elsevier Inc. All rights reserved.

  11. 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.

  12. 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.

  13. 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

  14. 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

    2017-05-01

    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. © The Author 2017. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  15. 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.

  16. 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. PMID:28405173

  17. Examining the Error of Mis-Specifying Nonlinear Confounding Effect With Application on Accelerometer-Measured Physical Activity.

    PubMed

    Lee, Paul H

    2017-06-01

    Some confounders are nonlinearly associated with dependent variables, but they are often adjusted using a linear term. The purpose of this study was to examine the error of mis-specifying the nonlinear confounding effect. We carried out a simulation study to investigate the effect of adjusting for a nonlinear confounder in the estimation of a causal relationship between the exposure and outcome in 3 ways: using a linear term, binning into 5 equal-size categories, or using a restricted cubic spline of the confounder. Continuous, binary, and survival outcomes were simulated. We examined the confounder across varying measurement error. In addition, we performed a real data analysis examining the 3 strategies to handle the nonlinear effects of accelerometer-measured physical activity in the National Health and Nutrition Examination Survey 2003-2006 data. The mis-specification of a nonlinear confounder had little impact on causal effect estimation for continuous outcomes. For binary and survival outcomes, this mis-specification introduced bias, which could be eliminated using spline adjustment only when there is small measurement error of the confounder. Real data analysis showed that the associations between high blood pressure, high cholesterol, and diabetes and mortality adjusted for physical activity with restricted cubic spline were about 3% to 11% larger than their counterparts adjusted with a linear term. For continuous outcomes, confounders with nonlinear effects can be adjusting with a linear term. Spline adjustment should be used for binary and survival outcomes on confounders with small measurement error.

  18. 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

  19. 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

  20. 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.

  1. 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

  2. Histopathological baseline levels and confounding factors in common sole (Solea solea) for marine environmental risk assessment.

    PubMed

    Cuevas, N; Zorita, I; Costa, P M; Larreta, J; Franco, J

    2015-09-01

    Liver and gonad histopathology, biometric parameters and hepatic metal bioaccumulation were assessed monthly over a one-year period in common soles from the Basque continental shelf, in order to determine baseline levels and confounding factors within biomonitoring studies. Biometric parameters and hepatic metal bioaccumulation varied according to season and gender. Accordingly, hepatic histopathological traits presented seasonal variations related to the reproductive cycle. However, the hepatic histopathological index showed that seasonality and gender were not significant confounding factors. Conversely, the gonad histopathological index was modulated by season and gender. As for organ comparison, the liver endured more severe histopathological damage than the gonad. In brief, the sampling period and gender may not affect the estimation of hepatic histopathological indices for biomonitoring purposes. Nonetheless, due to different sensitivities to environmental 'noise' variables, the sampling period and gender differentiation should be thoroughly considered for the assessment of gonad histopathology, biometrics and metal bioaccumulation. Copyright © 2015 Elsevier Ltd. All rights reserved.

  3. Overview of potential procedural and participant-related confounds for neuroimaging of the resting state

    PubMed Central

    Duncan, Niall W.; Northoff, Georg

    2013-01-01

    Studies of intrinsic brain activity in the resting state have become increasingly common. A productive discussion of what analysis methods are appropriate, of the importance of physiologic correction and of the potential interpretations of results has been ongoing. However, less attention has been paid to factors other than physiologic noise that may confound resting-state experiments. These range from straightforward factors, such as ensuring that participants are all instructed in the same manner, to more obscure participant-related factors, such as body weight. We provide an overview of such potentially confounding factors, along with some suggested approaches for minimizing their impact. A particular theme that emerges from the overview is the range of systematic differences between types of study groups (e.g., between patients and controls) that may influence resting-state study results. PMID:22964258

  4. Understanding Confounding Effects in Linguistic Coordination: An Information-Theoretic Approach

    PubMed Central

    Gao, Shuyang; Ver Steeg, Greg; Galstyan, Aram

    2015-01-01

    We suggest an information-theoretic approach for measuring stylistic coordination in dialogues. The proposed measure has a simple predictive interpretation and can account for various confounding factors through proper conditioning. We revisit some of the previous studies that reported strong signatures of stylistic accommodation, and find that a significant part of the observed coordination can be attributed to a simple confounding effect—length coordination. Specifically, longer utterances tend to be followed by longer responses, which gives rise to spurious correlations in the other stylistic features. We propose a test to distinguish correlations in length due to contextual factors (topic of conversation, user verbosity, etc.) and turn-by-turn coordination. We also suggest a test to identify whether stylistic coordination persists even after accounting for length coordination and contextual factors. PMID:26115446

  5. 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.

  6. 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.

  7. Correction of confounding bias in non-randomized studies by appropriate weighting.

    PubMed

    Schmoor, Claudia; Gall, Christine; Stampf, Susanne; Graf, Erika

    2011-03-01

    In non-randomized studies, the assessment of a causal effect of treatment or exposure on outcome is hampered by possible confounding. Applying multiple regression models including the effects of treatment and covariates on outcome is the well-known classical approach to adjust for confounding. In recent years other approaches have been promoted. One of them is based on the propensity score and considers the effect of possible confounders on treatment as a relevant criterion for adjustment. Another proposal is based on using an instrumental variable. Here inference relies on a factor, the instrument, which affects treatment but is thought to be otherwise unrelated to outcome, so that it mimics randomization. Each of these approaches can basically be interpreted as a simple reweighting scheme, designed to address confounding. The procedures will be compared with respect to their fundamental properties, namely, which bias they aim to eliminate, which effect they aim to estimate, and which parameter is modelled. We will expand our overview of methods for analysis of non-randomized studies to methods for analysis of randomized controlled trials and show that analyses of both study types may target different effects and different parameters. The considerations will be illustrated using a breast cancer study with a so-called Comprehensive Cohort Study design, including a randomized controlled trial and a non-randomized study in the same patient population as sub-cohorts. This design offers ideal opportunities to discuss and illustrate the properties of the different approaches. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  8. 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.

  9. 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.

  10. Confounder Summary Scores When Comparing the Effects of Multiple Drug Exposures

    PubMed Central

    Cadarette, Suzanne M.; Gagne, Joshua J.; Solomon, Daniel H.; Katz, Jeffrey N.; Stürmer, Til

    2009-01-01

    Purpose Little information is available comparing methods to adjust for confounding when considering multiple drug exposures. We compared three analytic strategies to control for confounding based on measured variables: conventional multivariable, exposure propensity score (EPS) and disease risk score (DRS). Methods Each method was applied to a dataset (2000–2006) recently used to examine the comparative effectiveness of four drugs. The relative effectiveness of risedronate, nasal calcitonin and raloxifene in preventing nonvertebral fracture, were each compared to alendronate. EPSs were derived both by using multinomial logistic regression (single model EPS) and by three separate logistic regression models (separate model EPS). DRSs were derived and event rates compared using Cox proportional hazard models. DRSs derived among the entire cohort (full cohort DRS) was compared to DRSs derived only among the referent alendronate (unexposed cohort DRS). Results Less than 5 percent deviation from the base estimate (conventional multivariable) was observed applying single model EPS, separate model EPS or full cohort DRS. Applying the unexposed cohort DRS when background risk for fracture differed between comparison drug exposure cohorts resulted in −7% to +13% deviation from our base estimate. Conclusions With sufficient numbers of exposed and outcomes, either conventional multivariable, EPS or full cohort DRS may be used to adjust for confounding to compare the effects of multiple drug exposures. However, our data also suggest that unexposed cohort DRS may be problematic when background risks differ between referent and exposed groups. Further empirical and simulation studies will help to clarify the generalizability of our findings. PMID:19757416

  11. The importance of scale for spatial-confounding bias and precision of spatial regression estimators

    PubMed Central

    Paciorek, Christopher J

    2010-01-01

    Residuals in regression models are often spatially correlated. Prominent examples include studies in environmental epidemiology to understand the chronic health effects of pollutants. I consider the effects of residual spatial structure on the bias and precision of regression coefficients, developing a simple framework in which to understand the key issues and derive informative analytic results. When unmeasured confounding introduces spatial structure into the residuals, regression models with spatial random effects and closely-related models such as kriging and penalized splines are biased, even when the residual variance components are known. Analytic and simulation results show how the bias depends on the spatial scales of the covariate and the residual: one can reduce bias by fitting a spatial model only when there is variation in the covariate at a scale smaller than the scale of the unmeasured confounding. I also discuss how the scales of the residual and the covariate affect efficiency and uncertainty estimation when the residuals are independent of the covariate. In an application on the association between black carbon particulate matter air pollution and birth weight, controlling for large-scale spatial variation appears to reduce bias from unmeasured confounders, while increasing uncertainty in the estimated pollution effect. PMID:21528104

  12. 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.

  13. 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.

  14. The impact of latent confounders in directed network analysis in neuroscience.

    PubMed

    Ramb, Rebecca; Eichler, Michael; Ing, Alex; Thiel, Marco; Weiller, Cornelius; Grebogi, Celso; Schwarzbauer, Christian; Timmer, Jens; Schelter, Björn

    2013-08-28

    In the analysis of neuroscience data, the identification of task-related causal relationships between various areas of the brain gives insights about the network of physiological pathways that are active during the task. One increasingly used approach to identify causal connectivity uses the concept of Granger causality that exploits predictability of activity in one region by past activity in other regions of the brain. Owing to the complexity of the data, selecting components for the analysis of causality as a preprocessing step has to be performed. This includes predetermined-and often arbitrary-exclusion of information. Therefore, the system is confounded by latent sources. In this paper, the effect of latent confounders is demonstrated, and paths of influence among three components are studied. While methods for analysing Granger causality are commonly based on linear vector autoregressive models, the effects of latent confounders are expected to be present also in nonlinear systems. Therefore, all analyses are also performed for a simulated nonlinear system and discussed with regard to applications in neuroscience.

  15. Joint Modelling of Confounding Factors and Prominent Genetic Regulators Provides Increased Accuracy in Genetical Genomics Studies

    PubMed Central

    Lawrence, Neil D.

    2012-01-01

    Expression quantitative trait loci (eQTL) studies are an integral tool to investigate the genetic component of gene expression variation. A major challenge in the analysis of such studies are hidden confounding factors, such as unobserved covariates or unknown subtle environmental perturbations. These factors can induce a pronounced artifactual correlation structure in the expression profiles, which may create spurious false associations or mask real genetic association signals. Here, we report PANAMA (Probabilistic ANAlysis of genoMic dAta), a novel probabilistic model to account for confounding factors within an eQTL analysis. In contrast to previous methods, PANAMA learns hidden factors jointly with the effect of prominent genetic regulators. As a result, this new model can more accurately distinguish true genetic association signals from confounding variation. We applied our model and compared it to existing methods on different datasets and biological systems. PANAMA consistently performs better than alternative methods, and finds in particular substantially more trans regulators. Importantly, our approach not only identifies a greater number of associations, but also yields hits that are biologically more plausible and can be better reproduced between independent studies. A software implementation of PANAMA is freely available online at http://ml.sheffield.ac.uk/qtl/. PMID:22241974

  16. 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

  17. 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.

  18. 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.

  19. 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

  20. 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

  1. Magnitude and direction of missing confounders had different consequences on treatment effect estimation in propensity score analysis.

    PubMed

    Nguyen, Tri-Long; Collins, Gary S; Spence, Jessica; Fontaine, Charles; Daurès, Jean-Pierre; Devereaux, Philip J; Landais, Paul; Le Manach, Yannick

    2017-07-01

    Propensity score (PS) analysis allows an unbiased estimate of treatment effects but assumes that all confounders are measured. We assessed the impact of omitting confounders from a PS analysis on clinical decision making. We conducted Monte Carlo simulations on hypothetical observational studies based on virtual populations and on the population from a large randomized trial (CRASH-2). In both series of simulations, PS analysis was conducted with all confounders and with omitted confounders, which were defined to have different strengths of association with the outcome and treatment exposure. After inverse probability of treatment weighting, we calculated the absolute risk differences and numbers needed to treat (NNT). In both series of simulations, omitting a confounder that was moderately associated with the outcome and exposure led to negligible bias on the NNT scale. The bias induced by omitting strongly positive confounding variables remained less than 15 patients to treat. Major bias and reversed effects were found only when omitting highly prevalent, strongly negative confounders that were similarly associated with the outcome and exposure with odds ratios greater than 4.00 (or <0.25). This omission was accompanied by a substantial decrease in analysis power. The omission of strongly negative confounding variables from a PS analysis can lead to incorrect clinical decision making. However, omitting these variables also decreases the analysis power, which may prevent the reporting of significant but misleading effects. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. 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

  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. 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)

  6. 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)

  7. Pre-Analytical Parameters Affecting Vascular Endothelial Growth Factor Measurement in Plasma: Identifying Confounders

    PubMed Central

    Walz, Johanna M.; Boehringer, Daniel; Deissler, Heidrun L.; Faerber, Lothar; Goepfert, Jens C.; Heiduschka, Peter; Kleeberger, Susannah M.; Klettner, Alexa; Krohne, Tim U.; Schneiderhan-Marra, Nicole; Ziemssen, Focke; Stahl, Andreas

    2016-01-01

    Background Vascular endothelial growth factor-A (VEGF-A) is intensively investigated in various medical fields. However, comparing VEGF-A measurements is difficult because sample acquisition and pre-analytic procedures differ between studies. We therefore investigated which variables act as confounders of VEGF-A measurements. Methods Following a standardized protocol, blood was taken at three clinical sites from six healthy participants (one male and one female participant at each center) twice one week apart. The following pre-analytical parameters were varied in order to analyze their impact on VEGF-A measurements: analyzing center, anticoagulant (EDTA vs. PECT / CTAD), cannula (butterfly vs. neonatal), type of centrifuge (swing-out vs. fixed-angle), time before and after centrifugation, filling level (completely filled vs. half-filled tubes) and analyzing method (ELISA vs. multiplex bead array). Additionally, intrapersonal variations over time and sex differences were explored. Statistical analysis was performed using a linear regression model. Results The following parameters were identified as statistically significant independent confounders of VEGF-A measurements: analyzing center, anticoagulant, centrifuge, analyzing method and sex of the proband. The following parameters were no significant confounders in our data set: intrapersonal variation over one week, cannula, time before and after centrifugation and filling level of collection tubes. Conclusion VEGF-A measurement results can be affected significantly by the identified pre-analytical parameters. We recommend the use of CTAD anticoagulant, a standardized type of centrifuge and one central laboratory using the same analyzing method for all samples. PMID:26730574

  8. 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

  9. Clinical and Evoked Pain, Personality Traits, and Emotional States: Can Familial Confounding Explain the Associations?

    PubMed Central

    Dansie, Elizabeth; Succop, Annemarie; Chopko, Laura; Afari, Niloofar

    2014-01-01

    Objectives Pain is a complex phenomenon influenced by context and person-specific factors. Affective dimensions of pain involve both enduring personality traits and fleeting emotional states. We examined how personality traits and emotional states are linked with clinical and evoked pain in a twin sample. Methods 99 female twin pairs were evaluated for clinical and evoked pain using the McGill Pain Questionnaire (MPQ) and dolorimetry, and completed the 120-item International Personality Item Pool (IPIP), the Positive and Negative Affect Scale (PANAS), and ratings of stress and mood. Using a co-twin control design we examined a) the relationship of personality traits and emotional states with clinical and evoked pain, and b) whether genetics and common environment (i.e. familial factors) may account for the associations. Results Neuroticism was associated with the sensory component of the MPQ; this relationship was not confounded by familial factors. None of the emotional state measures was associated with the MPQ. PANAS Negative Affect was associated with lower evoked pressure pain threshold and tolerance; these associations were confounded by familial factors. There were no associations between IPIP traits and evoked pain. Conclusions A relationship exists between neuroticism and clinical pain that is not confounded by familial factors. There is no similar relationship between negative emotional states and clinical pain. In contrast, the relationship between negative emotional states and evoked pain is strong while the relationship with enduring personality traits is weak. The relationship between negative emotional states and evoked pain appears to be non-causal and due to familial factors. PMID:25311873

  10. Clinical and evoked pain, personality traits, and emotional states: can familial confounding explain the associations?

    PubMed

    Strachan, Eric; Poeschla, Brian; Dansie, Elizabeth; Succop, Annemarie; Chopko, Laura; Afari, Niloofar

    2015-01-01

    Pain is a complex phenomenon influenced by context and person-specific factors. Affective dimensions of pain involve both enduring personality traits and fleeting emotional states. We examined how personality traits and emotional states are linked with clinical and evoked pain in a twin sample. 99 female twin pairs were evaluated for clinical and evoked pain using the McGill Pain Questionnaire (MPQ) and dolorimetry, and completed the 120-item International Personality Item Pool (IPIP), the Positive and Negative Affect Scale (PANAS), and ratings of stress and mood. Using a co-twin control design we examined a) the relationship of personality traits and emotional states with clinical and evoked pain and b) whether genetics and common environment (i.e. familial factors) may account for the associations. Neuroticism was associated with the sensory component of the MPQ; this relationship was not confounded by familial factors. None of the emotional state measures was associated with the MPQ. PANAS negative affect was associated with lower evoked pressure pain threshold and tolerance; these associations were confounded by familial factors. There were no associations between IPIP traits and evoked pain. A relationship exists between neuroticism and clinical pain that is not confounded by familial factors. There is no similar relationship between negative emotional states and clinical pain. In contrast, the relationship between negative emotional states and evoked pain is strong while the relationship with enduring personality traits is weak. The relationship between negative emotional states and evoked pain appears to be non-causal and due to familial factors. Copyright © 2014 Elsevier Inc. All rights reserved.

  11. A powerful and efficient set test for genetic markers that handles confounders

    PubMed Central

    Listgarten, Jennifer; Lippert, Christoph; Kang, Eun Yong; Xiang, Jing; Kadie, Carl M.; Heckerman, David

    2013-01-01

    Motivation: Approaches for testing sets of variants, such as a set of rare or common variants within a gene or pathway, for association with complex traits are important. In particular, set tests allow for aggregation of weak signal within a set, can capture interplay among variants and reduce the burden of multiple hypothesis testing. Until now, these approaches did not address confounding by family relatedness and population structure, a problem that is becoming more important as larger datasets are used to increase power. Results: We introduce a new approach for set tests that handles confounders. Our model is based on the linear mixed model and uses two random effects—one to capture the set association signal and one to capture confounders. We also introduce a computational speedup for two random-effects models that makes this approach feasible even for extremely large cohorts. Using this model with both the likelihood ratio test and score test, we find that the former yields more power while controlling type I error. Application of our approach to richly structured Genetic Analysis Workshop 14 data demonstrates that our method successfully corrects for population structure and family relatedness, whereas application of our method to a 15 000 individual Crohn’s disease case–control cohort demonstrates that it additionally recovers genes not recoverable by univariate analysis. Availability: A Python-based library implementing our approach is available at http://mscompbio.codeplex.com. Contact: jennl@microsoft.com or lippert@microsoft.com or heckerma@microsoft.com Supplementary information: Supplementary data are available at Bioinformatics online. PMID:23599503

  12. 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

  13. Pot binding as a variable confounding plant phenotype: theoretical derivation and experimental observations.

    PubMed

    Sinclair, Thomas R; Manandhar, Anju; Shekoofa, Avat; Rosas-Anderson, Pablo; Bagherzadi, Laleh; Schoppach, Remy; Sadok, Walid; Rufty, Thomas W

    2017-04-01

    Theoretical derivation predicted growth retardation due to pot water limitations, i.e., pot binding. Experimental observations were consistent with these limitations. Combined, these results indicate a need for caution in high-throughput screening and phenotyping. Pot experiments are a mainstay in many plant studies, including the current emphasis on developing high-throughput, phenotyping systems. Pot studies can be vulnerable to decreased physiological activity of the plants particularly when pot volume is small, i.e., "pot binding". It is necessary to understand the conditions under which pot binding may exist to avoid the confounding influence of pot binding in interpreting experimental results. In this paper, a derivation is offered that gives well-defined conditions for the occurrence of pot binding based on restricted water availability. These results showed that not only are pot volume and plant size important variables, but the potting media is critical. Artificial potting mixtures used in many studies, including many high-throughput phenotyping systems, are particularly susceptible to the confounding influences of pot binding. Experimental studies for several crop species are presented that clearly show the existence of thresholds of plant leaf area at which various pot sizes and potting media result in the induction of pot binding even though there may be no immediate, visual plant symptoms. The derivation and experimental results showed that pot binding can readily occur in plant experiments if care is not given to have sufficiently large pots, suitable potting media, and maintenance of pot water status. Clear guidelines are provided for avoiding the confounding effects of water-limited pot binding in studying plant phenotype.

  14. 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.

  15. 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.

  16. Heterogeneity in white blood cells has potential to confound DNA methylation measurements.

    PubMed

    Adalsteinsson, Bjorn T; Gudnason, Haukur; Aspelund, Thor; Harris, Tamara B; Launer, Lenore J; Eiriksdottir, Gudny; Smith, Albert V; Gudnason, Vilmundur

    2012-01-01

    Epigenetic studies are commonly conducted on DNA from tissue samples. However, tissues are ensembles of cells that may each have their own epigenetic profile, and therefore inter-individual cellular heterogeneity may compromise these studies. Here, we explore the potential for such confounding on DNA methylation measurement outcomes when using DNA from whole blood. DNA methylation was measured using pyrosequencing-based methodology in whole blood (n = 50-179) and in two white blood cell fractions (n = 20), isolated using density gradient centrifugation, in four CGIs (CpG Islands) located in genes HHEX (10 CpG sites assayed), KCNJ11 (8 CpGs), KCNQ1 (4 CpGs) and PM20D1 (7 CpGs). Cellular heterogeneity (variation in proportional white blood cell counts of neutrophils, lymphocytes, monocytes, eosinophils and basophils, counted by an automated cell counter) explained up to 40% (p<0.0001) of the inter-individual variation in whole blood DNA methylation levels in the HHEX CGI, but not a significant proportion of the variation in the other three CGIs tested. DNA methylation levels in the two cell fractions, polymorphonuclear and mononuclear cells, differed significantly in the HHEX CGI; specifically the average absolute difference ranged between 3.4-15.7 percentage points per CpG site. In the other three CGIs tested, methylation levels in the two fractions did not differ significantly, and/or the difference was more moderate. In the examined CGIs, methylation levels were highly correlated between cell fractions. In summary, our analysis detects region-specific differential DNA methylation between white blood cell subtypes, which can confound the outcome of whole blood DNA methylation measurements. Finally, by demonstrating the high correlation between methylation levels in cell fractions, our results suggest a possibility to use a proportional number of a single white blood cell type to correct for this confounding effect in analyses.

  17. Dynamic Causal Modelling and physiological confounds: a functional MRI study of vagus nerve stimulation.

    PubMed

    Reyt, Sébastien; Picq, Chloé; Sinniger, Valérie; Clarençon, Didier; Bonaz, Bruno; David, Olivier

    2010-10-01

    Dynamic Causal Modelling (DCM) has been proposed to estimate neuronal connectivity from functional magnetic resonance imaging (fMRI) using a biophysical model that links synaptic activity to hemodynamic processes. However, it is well known that fMRI is sensitive not only to neuronal activity, but also to many other psychophysiological responses which may be task-related, such as changes in cardio-respiratory activity. They are not explicitly taken into account in the generative models of DCM and their effects on estimated neuronal connectivity are not known. The main goal of this study was to report the face validity of DCM in the presence of strong physiological confounds that presumably cannot be corrected for, using an fMRI experiment of vagus nerve stimulation (VNS) performed in rats. First, a simple simulation was used to evaluate the principled ability of DCM to recover directed connectivity in the presence of a confounding factor. Second, we tested the experimental validity using measures of the BOLD correlates of left 5Hz VNS. Because VNS mostly activates the central autonomic regulation system, fMRI signals were likely to represent both direct and indirect vascular responses to such activation. In addition to the inference of standard statistical parametric maps, DCM was thus used to estimate directed neural connectivity in a small brain network including the nucleus tractus solitarius (NTS) known to receive vagal afferents. Though blood pressure changes may constitute a major physiological confound in this dataset, model comparison of DCMs still allowed the identification of the NTS as the input station of the VNS pathway to the brain. Our study indicates that current developments of DCM are robust to psychophysiological responses to some extent, but does not exclude the need to develop specific models of brain - body interactions within the DCM framework to better estimate neuronal connectivity from fMRI time series. Copyright 2010 Elsevier Inc. All

  18. 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

  19. 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

  20. 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.

  1. 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

  2. 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

  3. Confounding and Statistical Significance of Indirect Effects: Childhood Adversity, Education, Smoking, and Anxious and Depressive Symptomatology

    PubMed Central

    Sheikh, Mashhood Ahmed

    2017-01-01

    The life course perspective, the risky families model, and stress-and-coping models provide the rationale for assessing the role of smoking as a mediator in the association between childhood adversity and anxious and depressive symptomatology (ADS) in adulthood. However, no previous study has assessed the independent mediating role of smoking in the association between childhood adversity and ADS in adulthood. Moreover, the importance of mediator-response confounding variables has rarely been demonstrated empirically in social and psychiatric epidemiology. The aim of this paper was to (i) assess the mediating role of smoking in adulthood in the association between childhood adversity and ADS in adulthood, and (ii) assess the change in estimates due to different mediator-response confounding factors (education, alcohol intake, and social support). The present analysis used data collected from 1994 to 2008 within the framework of the Tromsø Study (N = 4,530), a representative prospective cohort study of men and women. Seven childhood adversities (low mother's education, low father's education, low financial conditions, exposure to passive smoke, psychological abuse, physical abuse, and substance abuse distress) were used to create a childhood adversity score. Smoking status was measured at a mean age of 54.7 years (Tromsø IV), and ADS in adulthood was measured at a mean age of 61.7 years (Tromsø V). Mediation analysis was used to assess the indirect effect and the proportion of mediated effect (%) of childhood adversity on ADS in adulthood via smoking in adulthood. The test-retest reliability of smoking was good (Kappa: 0.67, 95% CI: 0.63; 0.71) in this sample. Childhood adversity was associated with a 10% increased risk of smoking in adulthood (Relative risk: 1.10, 95% CI: 1.03; 1.18), and both childhood adversity and smoking in adulthood were associated with greater levels of ADS in adulthood (p < 0.001). Smoking in adulthood did not significantly mediate the

  4. 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.

  5. Confounding factors associated with oral mucositis assessment in patients receiving chemoradiotherapy for head and neck cancer.

    PubMed

    Chung, Yih-Lin; Pui, Newman N M

    2017-09-01

    The aim of this study was to identify patient-centered, mucositis-associated adverse impact factors and events that might confound physician-assessed oral mucositis (OM) in head and neck cancer (HNC) patients receiving chemoradiotherapy. This was a post hoc analysis of a previously conducted randomized trial to determine the efficacy of 5% phenylbutyrate mouthwash in preventing chemoradiotherapy-induced OM. This analysis identified patient-centered symptomatic, observable, and measurable factors that may confound physician scoring of the severity of OM during chemoradiotherapy. Confounding factors were then combined with physician-rated OM scores according to World Health Organization (WHO) and OM Assessment Scale (OMAS) criteria to investigate the therapeutic implications of OM treatment. The original analysis found no significant differences between experimental and placebo groups with respect to the cumulative incidence of physician-recorded severe OM (WHO ≥3 or OMAS ≥2), patient-reported adverse events, and opioid use. However, patients in the experimental arm had relatively lower rates of OM-associated adverse clinical issues including unplanned short radiation breaks, skipping of chemotherapy, nausea/vomiting, late loss of body weight, and early opioid use, all of which could potentially interfere with physician-assessed OM scoring. When WHO OM grade (functional impact and pain), OMAS ulceration size (organic impact), and prolonged radiation treatment time (cancer treatment impact) were combined, there were significantly fewer interruptions of chemoradiotherapy treatment in symptomatic OM patients in the experimental compared to the placebo group. The benefits conferred by reducing the amount of chemoradiotherapy-related, OM-associated adverse impacts in the experimental group were reflected by better 5-year locoregional recurrence-free survival. This exploratory study raises questions as to whether the severity reflected by physician-rated OM scores is

  6. LD Score regression distinguishes confounding from polygenicity in genome-wide association studies.

    PubMed

    Bulik-Sullivan, Brendan K; Loh, Po-Ru; Finucane, Hilary K; Ripke, Stephan; Yang, Jian; Patterson, Nick; Daly, Mark J; Price, Alkes L; Neale, Benjamin M

    2015-03-01

    Both polygenicity (many small genetic effects) and confounding biases, such as cryptic relatedness and population stratification, can yield an inflated distribution of test statistics in genome-wide association studies (GWAS). However, current methods cannot distinguish between inflation from a true polygenic signal and bias. We have developed an approach, LD Score regression, that quantifies the contribution of each by examining the relationship between test statistics and linkage disequilibrium (LD). The LD Score regression intercept can be used to estimate a more powerful and accurate correction factor than genomic control. We find strong evidence that polygenicity accounts for the majority of the inflation in test statistics in many GWAS of large sample size.

  7. 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.

  8. Abdominal obesity, hypertension, antihypertensive medication use and biochemical recurrence of prostate cancer after radical prostatectomy.

    PubMed

    Ohwaki, Kazuhiro; Endo, Fumiyasu; Hattori, Kazunori

    2015-03-01

    The aim of this study was to determine whether abdominal obesity, including visceral adipose tissue (VAT) measured by computed tomography and blood pressure (BP) were associated with biochemical recurrence of prostate cancer after prostatectomy. We investigated 283 patients who underwent radical prostatectomy for prostate cancer retrospectively. We obtained information on body mass index (BMI), waist circumference (WC), VAT, BP, antihypertensive drug use, pretreatment prostate-specific antigen levels, pathological Gleason scores and postoperative surgical margin status. Hypertension was defined as systolic BP (SBP)⩾130mmHg or diastolic BP⩾85mmHg. Among 283 patients, 41 (14%) developed biochemical recurrence subsequently. We performed a Cox proportional hazard regression analysis to assess the association of each obesity measurement and SBP with biochemical recurrence using clinical predictors as potential confounders. No association was observed between any obesity measurement assessed and biochemical recurrence. Adjusting for each of BMI, WC and VAT, a higher SBP was associated significantly with biochemical recurrence (hazard ratio [HR], adjusted for VAT=1.04; 95% confidence interval [CI]=1.02-1.07). Adjusting for obesity (BMI⩾25kg/m(2)), hypertension was also associated significantly with biochemical recurrence (HR=2.08; 95% CI=1.09-3.97). Compared with normotensive patients, those with untreated and uncontrolled hypertension had a significantly increased risk of biochemical recurrence (HR=2.45; 95% CI=1.06-5.66). A higher BP and untreated, uncontrolled hypertension were independent risk factors for biochemical recurrence after prostatectomy. Control of hypertension could be an important treatment strategy for preventing biochemical recurrence. Copyright © 2015 Elsevier Ltd. All rights reserved.

  9. Why Does Early Sexual Intercourse Predict Subsequent Maladjustment? Exploring Potential Familial Confounds

    PubMed Central

    Donahue, Kelly L.; Lichtenstein, Paul; Långström, Niklas; D’Onofrio, Brian M.

    2013-01-01

    Objective Previous studies have found an association between early age at first sexual intercourse and subsequent psychosocial maladjustment. Using a quasi-experimental approach, we examined the extent to which this observed association may be due to familial confounds not explored in prior research. Methods Using a population-based cohort of Swedish adult twins (ages 19–47; N = 12,126), we examined the nature of the association between early sexual intercourse (i.e., first intercourse occurring before age 16) and various outcomes reflecting psychosocial health, including substance use, depression, criminal convictions, and adolescent childbearing. We used two methods—discordant-twin analyses and bivariate twin modeling—to estimate the extent to which genetic and environmental confounds explained observed associations. Results Individuals who engaged in early intercourse were at greater risk for most of the adverse psychosocial health outcomes measured in this study. Twin pairs discordant for engaging in early intercourse, however, did not differ significantly in their risk for psychosocial maladjustment. Our results indicated that early age at first sexual intercourse and subsequent psychosocial maladjustment may be associated due to familial factors shared by twins. Conclusion Early intercourse may be associated with poor psychosocial health largely due to shared familial influences rather than through a direct causal connection. Effective and efficient interventions, therefore, should address other risk factors common to both early intercourse and poor psychosocial health. PMID:22708520

  10. 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.

  11. Assessing identity, redundancy and confounds in Gene Ontology annotations over time.

    PubMed

    Gillis, Jesse; Pavlidis, Paul

    2013-02-15

    The Gene Ontology (GO) is heavily used in systems biology, but the potential for redundancy, confounds with other data sources and problems with stability over time have been little explored. We report that GO annotations are stable over short periods, with 3% of genes not being most semantically similar to themselves between monthly GO editions. However, we find that genes can alter their 'functional identity' over time, with 20% of genes not matching to themselves (by semantic similarity) after 2 years. We further find that annotation bias in GO, in which some genes are more characterized than others, has declined in yeast, but generally increased in humans. Finally, we discovered that many entries in protein interaction databases are owing to the same published reports that are used for GO annotations, with 66% of assessed GO groups exhibiting this confound. We provide a case study to illustrate how this information can be used in analyses of gene sets and networks. Data available at http://chibi.ubc.ca/assessGO.

  12. On causal interpretation of race in regressions adjusting for confounding and mediating variables

    PubMed Central

    VanderWeele, Tyler J.; Robinson, Whitney R.

    2014-01-01

    We consider several possible interpretations of the “effect of race” when regressions are run with race as an exposure variable, controlling also for various confounding and mediating variables. When adjustment is made for socioeconomic status early in a person’s life, we discuss under what contexts the regression coefficients for race can be interpreted as corresponding to the extent to which a racial inequality would remain if various socioeconomic distributions early in life across racial groups could be equalized. When adjustment is also made for adult socioeconomic status, we note how the overall racial inequality can be decomposed into the portion that would be eliminated by equalizing adult socioeconomic status across racial groups and the portion of the inequality that would remain even if adult socioeconomic status across racial groups were equalized. We also discuss a stronger interpretation of the “effect of race” (stronger in terms of assumptions) involving the joint effects of race-associated physical phenotype (e.g. skin color), parental physical phenotype, genetic background and cultural context when such variables are thought to be hypothetically manipulable and if adequate control for confounding were possible. We discuss some of the challenges with such an interpretation. Further discussion is given as to how the use of selected populations in examining racial disparities can additionally complicate the interpretation of the effects. PMID:24887159

  13. The intermedius nerve as a confounding variable for monitoring of the free-running electromyogram.

    PubMed

    Prell, Julian; Strauss, Christian; Rachinger, Jens; Scheller, Christian; Alfieri, Alex; Herfurth, Kirsten; Rampp, Stefan

    2015-09-01

    A-trains, a facial nerve EMG-pattern, are correlated with postoperative functional impairment. However, an unknown confounder is suspected to cause false positive monitoring results. The intermedius nerve contains motor fibers targeting lower facial muscles; their significance for facial nerve monitoring is yet unknown. Intraoperative videotapes and free-running 9-channel facial nerve EMG assessed from 87 patients undergoing surgery for vestibular schwannoma were evaluated, and presence/absence of an identifiable intermedius nerve was determined. The prognostic value of train time, a quantitative measure for A-train activity, was evaluated for both the groups with and without an identifiable intermedius nerve. Correlation between traintime and outcome (Spearman's Rho) rose to 0.73 (p<0.001) when only patients without an identified intermedius nerve were considered, and fell to 0.43 (p<0.05) with the other patient group. This difference was statistically significant (p=0.036), was more prominent in the channels monitoring perioral facial muscles, and resulted from additional A-train activity in patients with an identifiable intermedius nerve. A separate intermedius nerve may be more prone to manipulation, leading to A-train activity without clinical correlate, thus causing false positive monitoring results. For interpretation of the free-running EMG, the intermedius nerve needs to be taken into account as a confounder. Copyright © 2015 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

  14. Confounders contributing to the reported associations of coffee or caffeine with disease.

    PubMed

    Schreiber, G B; Robins, M; Maffeo, C E; Masters, M N; Bond, A P; Morganstein, D

    1988-05-01

    The role of caffeine or coffee in causing or promoting the incidence of serious disease is equivocal. Two design factors may account for the discrepancies in reported findings on the effects of coffee drinking: (a) imprecision of measurement and (b) confounding variables. A study of 2,714 white U.S. adults disclosed that, of 32 risk factors analyzed by linear and logistic regression, only sex and cigarette smoking were found to be important potential confounders of caffeine and coffee intake. Partial R2 values of the other 30 risk factors were relatively small and were inconsistent for each sex. It is unlikely that any of these factors could explain any of the reported associations between caffeine or coffee consumption and certain diseases. However, certain weak associations with caffeine or coffee intake should be included in the study design when they are known to be risk factors of a disease under investigation. These factors for men are dietary fat intake, vitamin C intake, and body mass index; and for women are vitamin use, alcohol intake, stress, and perceived health status.

  15. On the Confounding Effect of Temperature on Chemical Shift-Encoded Fat Quantification

    PubMed Central

    Hernando, Diego; Sharma, Samir D.; Kramer, Harald; Reeder, Scott B.

    2014-01-01

    Purpose To characterize the confounding effect of temperature on chemical shift-encoded (CSE) fat quantification. Methods The proton resonance frequency of water, unlike triglycerides, depends on temperature. This leads to a temperature dependence of the spectral models of fat (relative to water) that are commonly used by CSE-MRI methods. Simulation analysis was performed for 1.5 Tesla CSE fat–water signals at various temperatures and echo time combinations. Oil–water phantoms were constructed and scanned at temperatures between 0 and 40°C using spectroscopy and CSE imaging at three echo time combinations. An explanted human liver, rejected for transplantation due to steatosis, was scanned using spectroscopy and CSE imaging. Fat–water reconstructions were performed using four different techniques: magnitude and complex fitting, with standard or temperature-corrected signal modeling. Results In all experiments, magnitude fitting with standard signal modeling resulted in large fat quantification errors. Errors were largest for echo time combinations near TEinit ≈ 1.3 ms, ΔTE ≈ 2.2 ms. Errors in fat quantification caused by temperature-related frequency shifts were smaller with complex fitting, and were avoided using a temperature-corrected signal model. Conclusion Temperature is a confounding factor for fat quantification. If not accounted for, it can result in large errors in fat quantifications in phantom and ex vivo acquisitions. PMID:24123362

  16. 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.

  17. 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.

  18. 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.

  19. A Geometric View of Global Signal Confounds in Resting-State Functional MRI

    PubMed Central

    He, Hongjian; Liu, Thomas T.

    2011-01-01

    Resting-state functional magnetic resonance imaging (fMRI) is proving to be an effective tool for mapping the long-range functional connections of the brain in both health and disease. One of the primary measures of connectivity is the correlation between the blood oxygenation level dependent (BOLD) time series observed in different brain regions. The computation of the correlation is often dominated by the presence of a strong global component that can introduce significant variability across functional connectivity maps acquired from different experimental scans or subjects. To address this issue, a variety of global signal correction methods have been proposed, but there is currently a lack of a clear consensus on the best approach to use. Furthermore, there has been concern that some global signal correction methods, such as global signal regression, may produce significant negative bias in the correlation values. In this paper we introduce a framework for visualizing the signal structure of resting-state fMRI data and characterizing the properties of the global signal. Using this framework, we demonstrate that a portion of the global signal can be viewed as an additive confound that increases with the mean BOLD amplitude. An approach for minimizing the contribution of this additive confound is presented, and an initial comparison with existing global signal correction methods is provided. PMID:21982929

  20. 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

  1. 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.

  2. BEST: Biochemical Engineering Simulation Technology

    SciTech Connect

    Not Available

    1996-01-01

    The idea of developing a process simulator that can describe biochemical engineering (a relatively new technology area) was formulated at the National Renewable Energy Laboratory (NREL) during the late 1980s. The initial plan was to build a consortium of industrial and U.S. Department of Energy (DOE) partners to enhance a commercial simulator with biochemical unit operations. DOE supported this effort; however, before the consortium was established, the process simulator industry changed considerably. Work on the first phase of implementing various fermentation reactors into the chemical process simulator, ASPEN/SP-BEST, is complete. This report will focus on those developments. Simulation Sciences, Inc. (SimSci) no longer supports ASPEN/SP, and Aspen Technology, Inc. (AspenTech) has developed an add-on to its ASPEN PLUS (also called BioProcess Simulator [BPS]). This report will also explain the similarities and differences between BEST and BPS. ASPEN, developed by the Massachusetts Institute of Technology for DOE in the late 1970s, is still the state-of-the-art chemical process simulator. It was selected as the only simulator with the potential to be easily expanded into the biochemical area. ASPEN/SP, commercially sold by SimSci, was selected for the BEST work. SimSci completed work on batch, fed-batch, and continuous fermentation reactors in 1993, just as it announced it would no longer commercially support the complete ASPEN/SP product. BEST was left without a basic support program. Luckily, during this same time frame, AspenTech was developing a biochemical simulator with its version of ASPEN (ASPEN PLUS), which incorporates most BEST concepts. The future of BEST will involve developing physical property data and models appropriate to biochemical systems that are necessary for good biochemical process design.

  3. Which Propensity Score Method Best Reduces Confounder Imbalance? An Example From a Retrospective Evaluation of a Childhood Obesity Intervention.

    PubMed

    Schroeder, Krista; Jia, Haomiao; Smaldone, Arlene

    Propensity score (PS) methods are increasingly being employed by researchers to reduce bias arising from confounder imbalance when using observational data to examine intervention effects. The purpose of this study was to examine PS theory and methodology and compare application of three PS methods (matching, stratification, weighting) to determine which best improves confounder balance. Baseline characteristics of a sample of 20,518 school-aged children with severe obesity (of whom 1,054 received an obesity intervention) were assessed prior to PS application. Three PS methods were then applied to the data to determine which showed the greatest improvement in confounder balance between the intervention and control group. The effect of each PS method on the outcome variable-body mass index percentile change at one year-was also examined. SAS 9.4 and Comprehensive Meta-analysis statistical software were used for analyses. Prior to PS adjustment, the intervention and control groups differed significantly on seven of 11 potential confounders. PS matching removed all differences. PS stratification and weighting both removed one difference but created two new differences. Sensitivity analyses did not change these results. Body mass index percentile at 1 year decreased in both groups. The size of the decrease was smaller in the intervention group, and the estimate of the decrease varied by PS method. Selection of a PS method should be guided by insight from statistical theory and simulation experiments, in addition to observed improvement in confounder balance. For this data set, PS matching worked best to correct confounder imbalance. Because each method varied in correcting confounder imbalance, we recommend that multiple PS methods be compared for ability to improve confounder balance before implementation in evaluating treatment effects in observational data.

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

    PubMed Central

    Haneuse, Sebastien; Schildcrout, Jonathan; Gillen, Daniel

    2012-01-01

    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. PMID:22130627

  5. 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.

  6. 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.

  7. Organochlorine compounds in the adipose tissue of deceased persons with and without cancer: a statistical survey of some potential confounders

    SciTech Connect

    Unger, M.; Olsen, J.; Clausen, J.

    1982-12-01

    A case-control study on the correlation between levels of polychlorinated biphenyls (PCB) and p,p'-DDE in adipose tissue of deceased cancer and noncancer patients is reported and related to potential confounders such as weight, height, occupation, and residence of deceased individuals, etc. Although taking into account the above-mentioned confounders, a significant association remained between the concentration of PCB and DDE in the subcutaneous adipose fat and cancer.

  8. Residual confounding explains the association between high parity and child mortality

    PubMed Central

    2013-01-01

    Background This study used data from recent Demographic and Health Surveys (DHS) to examine the impact of high parity on under-five and neonatal mortality. The analyses used various techniques to attempt eliminating selection issues, including stratification of analyses by mothers’ completed fertility. Methods We analyzed DHS datasets from 47 low- and middle-income countries. We only used data from women who were age 35 or older at the time of survey to have a measure of their completed fertility. We ran log-binominal regression by country to calculate relative risk between parity and both under-five and neonatal mortality, controlled for wealth quintile, maternal education, urban versus rural residence, maternal age at first birth, calendar year (to control for possible time trends), and birth interval. We then controlled for maternal background characteristics even further by using mothers’ completed fertility as a proxy measure. Results We found a statistically significant association between high parity and child mortality. However, this association is most likely not physiological, and can be largely attributed to the difference in background characteristics of mothers who complete reproduction with high fertility versus low fertility. Children of high completed fertility mothers have statistically significantly increased risk of death compared to children of low completed fertility mothers at every birth order, even after controlling for available confounders (i.e. among children of birth order 1, adjusted RR of under-five mortality 1.58, 95% CI: 1.42, 1.76). There appears to be residual confounders that put children of high completed fertility mothers at higher risk, regardless of birth order. When we examined the association between parity and under-five mortality among mothers with high completed fertility, it remained statistically significant, but negligible in magnitude (i.e. adjusted RR of under-five mortality 1.03, 95% CI: 1.02-1.05). Conclusions

  9. Potential confounding in the association between short birth intervals and increased neonatal, infant, and child mortality.

    PubMed

    Perin, Jamie; Walker, Neff

    2015-01-01

    Recent steep declines in child mortality have been attributed in part to increased use of contraceptives and the resulting change in fertility behaviour, including an increase in the time between births. Previous observational studies have documented strong associations between short birth spacing and an increase in the risk of neonatal, infant, and under-five mortality, compared to births with longer preceding birth intervals. In this analysis, we compare two methods to estimate the association between short birth intervals and mortality risk to better inform modelling efforts linking family planning and mortality in children. Our goal was to estimate the mortality risk for neonates, infants, and young children by preceding birth space using household survey data, controlling for mother-level factors and to compare the results to those from previous analyses with survey data. We assessed the potential for confounding when estimating the relative mortality risk by preceding birth interval and estimated mortality risk by birth interval in four categories: less than 18 months, 18-23 months, 24-35 months, and 36 months or longer. We estimated the relative risks among women who were 35 and older at the time of the survey with two methods: in a Cox proportional hazards regression adjusting for potential confounders and also by stratifying Cox regression by mother, to control for all factors that remain constant over a woman's childbearing years. We estimated the overall effects for birth spacing in a meta-analysis with random survey effects. We identified several factors known for their associations with neonatal, infant, and child mortality that are also associated with preceding birth interval. When estimating the effect of birth spacing on mortality, we found that regression adjustment for these factors does not substantially change the risk ratio for short birth intervals compared to an unadjusted mortality ratio. For birth intervals less than 18 months, standard

  10. 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

  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. Copyright 2008 John Wiley & Sons, Ltd.

  12. 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.

  13. 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.

  14. 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.

  15. Can Jurors Recognize Missing Control Groups, Confounds, and Experimenter Bias in Psychological Science?

    PubMed Central

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

    2010-01-01

    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. PMID:18587635

  16. 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. PMID:28392727

  17. 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.

  18. Multiorgan Involvement Confounding the Diagnosis of Bartonella henselae Infective Endocarditis in Children With Congenital Heart Disease.

    PubMed

    Ouellette, Christopher P; Joshi, Sarita; Texter, Karen; Jaggi, Preeti

    2017-05-01

    Two children with congenital heart disease status post surgical correction presented with prolonged constitutional symptoms, hepatosplenomegaly and pancytopenia. Concern for malignancy prompted bone marrow biopsies that were without evidence thereof. In case 1, echocardiography identified a multilobulated vegetation on the conduit valve. In case 2, transthoracic, transesophageal and intracardiac echocardiography were performed and were without evidence of cardiac vegetations; however, pulmonic emboli raised concern for infective endocarditis. Both patients underwent surgical resection of the infected material and had histopathologic evidence of infective endocarditis. Further diagnostics identified elevated cytoplasmic antineutrophil cytoplasmic antibodies and antiproteinase 3 antibodies in addition to acute kidney injury with crescentic glomerulonephritis on renal biopsy. Serologic evidence of infection with Bartonella henselae was observed in both patients. These 2 cases highlight the potential multiorgan involvement that may confound the diagnosis of culture-negative infective endocarditis caused by B. henselae.

  19. 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

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

    PubMed

    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.

  1. 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.

  2. 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.

  3. 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.

  4. 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

  5. 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.

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

    PubMed Central

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

    2015-01-01

    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. PMID:26759790

  7. 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.

  8. Adjusting for Confounding in Early Postlaunch Settings: Going Beyond Logistic Regression Models.

    PubMed

    Schmidt, Amand F; Klungel, Olaf H; Groenwold, Rolf H H

    2016-01-01

    Postlaunch data on medical treatments can be analyzed to explore adverse events or relative effectiveness in real-life settings. These analyses are often complicated by the number of potential confounders and the possibility of model misspecification. We conducted a simulation study to compare the performance of logistic regression, propensity score, disease risk score, and stabilized inverse probability weighting methods to adjust for confounding. Model misspecification was induced in the independent derivation dataset. We evaluated performance using relative bias confidence interval coverage of the true effect, among other metrics. At low events per coefficient (1.0 and 0.5), the logistic regression estimates had a large relative bias (greater than -100%). Bias of the disease risk score estimates was at most 13.48% and 18.83%. For the propensity score model, this was 8.74% and >100%, respectively. At events per coefficient of 1.0 and 0.5, inverse probability weighting frequently failed or reduced to a crude regression, resulting in biases of -8.49% and 24.55%. Coverage of logistic regression estimates became less than the nominal level at events per coefficient ≤5. For the disease risk score, inverse probability weighting, and propensity score, coverage became less than nominal at events per coefficient ≤2.5, ≤1.0, and ≤1.0, respectively. Bias of misspecified disease risk score models was 16.55%. In settings with low events/exposed subjects per coefficient, disease risk score methods can be useful alternatives to logistic regression models, especially when propensity score models cannot be used. Despite better performance of disease risk score methods than logistic regression and propensity score models in small events per coefficient settings, bias, and coverage still deviated from nominal.

  9. 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.

  10. 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

  11. Hypnotics and mortality--partial confounding by disease, substance abuse and socioeconomic factors?

    PubMed

    Kriegbaum, Margit; Hendriksen, Carsten; Vass, Mikkel; Mortensen, Erik Lykke; Osler, Merete

    2015-07-01

    The aim of this Cohort study of 10 527 Danish men was to investigate the extent to which the association between hypnotics and mortality is confounded by several markers of disease and living conditions. Exposure was purchases of hypnotics 1995-1999 ("low users" (150 or less defined daily dose (DDD)) or "high users" (151 or more DDD)). Follow-up for all-cause mortality was from 1 Jan 2000 to 19 June 2010. Cox proportional hazard models were used to study the association. Covariates were entered one at a time and simultaneously. Results were reported using hazard ratio (HR) and 95% confidence intervals (CI). When covariates were entered one at a time, the changes in HR estimates showed that psychiatric disease, socioeconomic position and substance abuse reduced the excess risk by 17-36% in the low user group and by 45-52% in the high user group. Somatic disease, intelligence score and cohabitation reduced the excess risk by 2-11% in the low user group and 8-24% in the high user group. When adjusting for all covariates, the HR was reduced to 1.22 95% CI (0.97-1.54) in the low user group and 1.43 95% CI (1.11-1.85) in the high user group. The results of this study point at psychiatric disease, substance abuse and socioeconomic position as potential confounding factors partly explaining the association between use of hypnotics and all-cause mortality. Copyright © 2015 John Wiley & Sons, Ltd.

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

    PubMed

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

    2014-08-01

    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. 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. 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%. 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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  13. A simulation study of confounding in generalized linear models for air pollution epidemiology.

    PubMed Central

    Chen, C; Chock, D P; Winkler, S L

    1999-01-01

    Confounding between the model covariates and causal variables (which may or may not be included as model covariates) is a well-known problem in regression models used in air pollution epidemiology. This problem is usually acknowledged but hardly ever investigated, especially in the context of generalized linear models. Using synthetic data sets, the present study shows how model overfit, underfit, and misfit in the presence of correlated causal variables in a Poisson regression model affect the estimated coefficients of the covariates and their confidence levels. The study also shows how this effect changes with the ranges of the covariates and the sample size. There is qualitative agreement between these study results and the corresponding expressions in the large-sample limit for the ordinary linear models. Confounding of covariates in an overfitted model (with covariates encompassing more than just the causal variables) does not bias the estimated coefficients but reduces their significance. The effect of model underfit (with some causal variables excluded as covariates) or misfit (with covariates encompassing only noncausal variables), on the other hand, leads to not only erroneous estimated coefficients, but a misguided confidence, represented by large t-values, that the estimated coefficients are significant. The results of this study indicate that models which use only one or two air quality variables, such as particulate matter [less than and equal to] 10 microm and sulfur dioxide, are probably unreliable, and that models containing several correlated and toxic or potentially toxic air quality variables should also be investigated in order to minimize the situation of model underfit or misfit. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 PMID:10064552

  14. Examining confounding by diet in the association between perfluoroalkyl acids and serum cholesterol in pregnancy.

    PubMed

    Skuladottir, Margret; Ramel, Alfons; Rytter, Dorte; Haug, Line Småstuen; Sabaredzovic, Azemira; Bech, Bodil Hammer; Henriksen, Tine Brink; Olsen, Sjurdur F; Halldorsson, Thorhallur I

    2015-11-01

    Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) have consistently been associated with higher cholesterol levels in cross sectional studies. Concerns have, however, been raised about potential confounding by diet and clinical relevance. To examine the association between concentrations of PFOS and PFOA and total cholesterol in serum during pregnancy taking into considerations confounding by diet. 854 Danish women who gave birth in 1988-89 and provided a blood sample and reported their diet in week 30 of gestation. Mean serum PFOS, PFOA and total cholesterol concentrations were 22.3 ng/mL, 4.1 ng/mL and 7.3 mmol/L, respectively. Maternal diet was a significant predictor of serum PFOS and PFOA concentrations. In particular intake of meat and meat products was positively associated while intake of vegetables was inversely associated (P for trend <0.01) with relative difference between the highest and lowest quartile in PFOS and PFOA concentrations ranging between 6% and 25% of mean values. After adjustment for dietary factors both PFOA and PFOS were positively and similarly associated with serum cholesterol (P for trend ≤0.01). For example, the mean increase in serum cholesterol was 0.39 mmol/L (95%CI: 0.09, 0.68) when comparing women in the highest to lowest quintile of PFOA concentrations. In comparison the mean increase in serum cholesterol was 0.61 mmol/L (95%CI: 0.17, 1.05) when comparing women in the highest to lowest quintile of saturated fat intake. In this study associations between PFOS and PFOA with serum cholesterol appeared unrelated to dietary intake and were similar in magnitude as the associations between saturated fat intake and serum cholesterol. Copyright © 2015 Elsevier Inc. All rights reserved.

  15. 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

  16. Breast-feeding and health consequences in early childhood: is there an impact of time-dependent confounding?

    PubMed

    Groenwold, R H H; Tilling, K; Moons, K G M; Hoes, A W; van der Ent, C K; Kramer, M S; Martin, R M; Sterne, J A C

    2014-01-01

    Estimated effects of breast-feeding on childhood health vary between studies, possibly due to confounding by baseline maternal and child characteristics. Possible time-dependent confounding has received little consideration. Our aim was to evaluate the impact of such confounding. We estimated the relationship between cumulative exclusive breast-feeding up to 6 months and wheezing, rash and body mass index (BMI) at 12 months [in the Whistler cohort (n = 494) and PROBIT (n = 11,463)], and wheezing, rash, asthma, hay fever, eczema, allergy and BMI at age 6.5 years (PROBIT). We adjusted for time-dependent confounding by weight, length, rash, respiratory illness and day care attendance using marginal structural models (MSMs). Weight and day care attendance appeared potential time-dependent confounders, since these predicted breast-feeding status and were influenced by previous breast-feeding. However, adjustment for time-dependent confounders did not markedly change the estimated associations. For example, in PROBIT the adjusted increase in BMI at 12 months per 1-month increase in exclusive breast-feeding was 0.04 (95% CI -0.09 to 0.01) using logistic regression and -0.06 (95% CI -0.11 to -0.01) using MSM. In Whistler, these estimates were each -0.05 (95% CI -0.10 to 0.00). In two cohort studies, there was little evidence of time-dependent confounding by weight, length, rash, respiratory illness or day care attendance of the effects of breast-feeding on early childhood health. © 2014 S. Karger AG, Basel.

  17. 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.

  18. 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

  19. 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.

  20. 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.

  1. With a careful look: still no low-level confound to face pop-out.

    PubMed

    Hershler, Orit; Hochstein, Shaul

    2006-09-01

    In this issue of Vision Research, VanRullen, R. (2006). On second glance: Still no high-level pop-out effect for faces. Vision Research, in press. challenges our earlier Vision Research paper, "At first sight: A high-level pop-out effect for faces" (Hershler, O., & Hochstein, S. (2005). At first sight: A high-level pop-out effect for faces. Vision Research, 45, 1707-1724). In that paper, we showed that faces pop-out from a great variety of heterogeneous distractors. This search must have been based on a holistic combination of facial features, since it could not have relied on any single low-level distinguishing feature-each of which was present in at least some of the distractors. VanRullen implies that the pop-out effect is not limited to faces, is not holistic, and is due to a low-level confound, namely that the "low-level" Fourier amplitude spectrum may differentiate between faces and other categories. We now show that he fails to substantiate all three claims. His first experiment replicates our own and shows once again that faces do indeed pop-out, while other objects, such as cars, do not. The claim regarding the non-holistic nature of face search is based on a failure to differentiate between holistic processing for face detection and for individual face identification. His central claim is that the Fourier amplitude spectrum is processed low-level and could be used for face pop-out. However, changing the amplitude spectrum may well affect high-level representations as well. For example, his demonstration uses hybrid images which are extremely fuzzy, rendering them difficult to identify. More importantly, this claim would lead to the conclusion that targets with a non-face phase spectrum and only a face amplitude spectrum would pop-out among distractors with different amplitude spectra. We demonstrate that this is, of course, not the case and that the Fourier amplitude is not the hoped for "low-level confound". Until another such "hidden" low level feature

  2. Is the Association between General Cognitive Ability and Violent Crime Caused by Family-Level Confounders?

    PubMed Central

    Frisell, Thomas; Pawitan, Yudi; Långström, Niklas

    2012-01-01

    Background Research has consistently found lower cognitive ability to be related to increased risk for violent and other antisocial behaviour. Since this association has remained when adjusting for childhood socioeconomic position, ethnicity, and parental characteristics, it is often assumed to be causal, potentially mediated through school adjustment problems and conduct disorder. Socioeconomic differences are notoriously difficult to quantify, however, and it is possible that the association between intelligence and delinquency suffer substantial residual confounding. Methods We linked longitudinal Swedish total population registers to study the association of general cognitive ability (intelligence) at age 18 (the Conscript Register, 1980–1993) with the incidence proportion of violent criminal convictions (the Crime Register, 1973–2009), among all men born in Sweden 1961–1975 (N = 700,514). Using probit regression, we controlled for measured childhood socioeconomic variables, and further employed sibling comparisons (family pedigree data from the Multi-Generation Register) to adjust for shared familial characteristics. Results Cognitive ability in early adulthood was inversely associated to having been convicted of a violent crime (β = −0.19, 95% CI: −0.19; −0.18), the association remained when adjusting for childhood socioeconomic factors (β = −0.18, 95% CI: −0.18; −0.17). The association was somewhat lower within half-brothers raised apart (β = −0.16, 95% CI: −0.18; −0.14), within half-brothers raised together (β = −0.13, 95% CI: (−0.15; −0.11), and lower still in full-brother pairs (β = −0.10, 95% CI: −0.11; −0.09). The attenuation among half-brothers raised together and full brothers was too strong to be attributed solely to attenuation from measurement error. Discussion Our results suggest that the association between general cognitive ability and violent criminality is confounded partly by

  3. Is the association between general cognitive ability and violent crime caused by family-level confounders?

    PubMed

    Frisell, Thomas; Pawitan, Yudi; Långström, Niklas

    2012-01-01

    Research has consistently found lower cognitive ability to be related to increased risk for violent and other antisocial behaviour. Since this association has remained when adjusting for childhood socioeconomic position, ethnicity, and parental characteristics, it is often assumed to be causal, potentially mediated through school adjustment problems and conduct disorder. Socioeconomic differences are notoriously difficult to quantify, however, and it is possible that the association between intelligence and delinquency suffer substantial residual confounding. We linked longitudinal Swedish total population registers to study the association of general cognitive ability (intelligence) at age 18 (the Conscript Register, 1980-1993) with the incidence proportion of violent criminal convictions (the Crime Register, 1973-2009), among all men born in Sweden 1961-1975 (N = 700,514). Using probit regression, we controlled for measured childhood socioeconomic variables, and further employed sibling comparisons (family pedigree data from the Multi-Generation Register) to adjust for shared familial characteristics. Cognitive ability in early adulthood was inversely associated to having been convicted of a violent crime (β = -0.19, 95% CI: -0.19; -0.18), the association remained when adjusting for childhood socioeconomic factors (β = -0.18, 95% CI: -0.18; -0.17). The association was somewhat lower within half-brothers raised apart (β = -0.16, 95% CI: -0.18; -0.14), within half-brothers raised together (β = -0.13, 95% CI: (-0.15; -0.11), and lower still in full-brother pairs (β = -0.10, 95% CI: -0.11; -0.09). The attenuation among half-brothers raised together and full brothers was too strong to be attributed solely to attenuation from measurement error. Our results suggest that the association between general cognitive ability and violent criminality is confounded partly by factors shared by brothers. However, most of the association remains even

  4. Association between obesity and glomerular hyperfiltration: the confounding effect of smoking and sodium and protein intakes.

    PubMed

    Ogna, Adam; Forni Ogna, Valentina; Bochud, Murielle; Guessous, Idris; Paccaud, Fred; Burnier, Michel; Wuerzner, Gregoire

    2016-04-01

    Glomerular hyperfiltration has been suggested as a possible mechanism linking obesity and chronic kidney disease (CKD), independently of classical risk factors. We explored the association of overweight and obesity with glomerular hyperfiltration in a large sample of the Swiss adult population, accounting for several confounders including dietary factors. Data from a 2010 to 2012 cross-sectional population-based survey in Switzerland were used. Creatinine clearance (CrCl) was determined from 24-h urine collection; CrCl > 140 ml/min was used to define glomerular hyperfiltration. Participants were categorized into lean (<25 kg/m(2)), overweight (25-29.9 kg/m(2)) and obese (≥30 kg/m(2)) according to body mass index (BMI). A total of 1339 participants were included in the analysis [median (IQR) age 49.4 (34.3-63.5) years, 48.9 % men]. The prevalences of overweight and obesity were 32.2 and 14.2 %, respectively. Median CrCl was 102[84-121] ml/min in lean, 110 [87-136] ml/min in overweight and 124 [97-150] ml/min in obese participants (p < 0.001). The prevalence of glomerular hyperfiltration increased across BMI categories (10.4, 20.8 and 34.7 %, respectively; p < 0.001). This positive association remained significant after adjusting for age, sex, hypertension, diabetes, smoking and dietary factors (sodium and protein intakes): odds ratio [95 %CI] 2.39 [1.52-3.76] (p < 0.001) for overweight versus lean and 4.10[2.31-7.27] (p < 0.001) for obesity versus lean. BMI categories and glomerular hyperfiltration are positively associated, independently of other known CKD risk factors and dietary confounders, suggesting that glomerular hyperfiltration may represent an early renal phenotype in obesity. Our observations confirm the significant association of glomerular hyperfiltration with sodium and protein intakes and identify sodium intake as an important modifying factor of the association between hyperfiltration and obesity.

  5. 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.

  6. Biochemical regulators in cardiac hypertrophy.

    PubMed

    Kölbel, F; Schreiber, V

    1983-01-01

    In recent years research has shown that muscle is capable of reacting to mechanical stimuli by altering biochemical processes. Myocardium is probably the source of a biochemical factor, or factors which activate myocardial protein synthesis. In experimentally induced cardiac hypertrophy adaptive alterations have been shown to occur not only in the adrenal medulla but also in the adrenal cortex. Finally, detection of cross reactivity between digitalis glycosides and a number of steroid hormones has succeeded. We assume that such cross reactivity indicates the existence of an endogenic factor of steroid character, which is produced in the adrenal gland and functions as an endogenic cardiotonic agent. During experimental cardiac hypertrophy its synthesis is possibly increased. We propose the term "endocardin" or "endocardiotonin" for this agent.

  7. 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.

  8. Compromised Motor Dexterity Confounds Processing Speed Task Outcomes in Stroke Patients.

    PubMed

    Low, Essie; Crewther, Sheila Gillard; Ong, Ben; Perre, Diana; Wijeratne, Tissa

    2017-01-01

    Most conventional measures of information processing speed require motor responses to facilitate performance. However, although not often addressed clinically, motor impairment, whether due to age or acquired brain injury, would be expected to confound the outcome measure of such tasks. The current study recruited 29 patients (20 stroke and 9 transient ischemic attack) with documented reduction in dexterity of the dominant hand, and 29 controls, to investigate the extent to which 3 commonly used processing speed measures with varying motor demands (a Visuo-Motor Reaction Time task, and the Wechsler Adult Intelligence Scale-IV Symbol Search and Coding subtests) may be measuring motor-related speed more so than cognitive speed. Analyses include correlations between indices of cognitive and motor speed obtained from two other tasks (Inspection Time and Pegboard task, respectively) with the three speed measures, followed by hierarchical regressions to determine the relative contribution of cognitive and motor speed indices toward task performance. Results revealed that speed outcomes on tasks with relatively high motor demands, such as Coding, were largely reflecting motor speed in individuals with reduced dominant hand dexterity. Thus, findings indicate the importance of employing measures with minimal motor requirements, especially when the assessment of speed is aimed at understanding cognitive rather than physical function.

  9. 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

  10. 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

  11. Task differences confound sex differences in receiver permissiveness in túngara frogs.

    PubMed

    Bernal, Ximena E; Rand, A Stanley; Ryan, Michael J

    2009-04-07

    In many mating systems, both sexes respond to the same sexual signal. In frogs, males typically call in response to advertisement calls, while females approach male calls in choosing a mate. The costs of signal detection errors are expected to differ between the sexes. Missed opportunities are costly for males because ignoring a signal results in failing to compete with rivals for mates, while their cost for misidentification is lower (time and energy displaying to the incorrect target). By contrast, for females, the cost of misidentification is high (mating with incorrect species or low-quality partner), while their cost for missed opportunity is lower because the operational sex ratio puts females at a premium. Consequently, females should be more selective in their response to signal variation than males. We report that presumed sexual differences in selectivity in túngara frogs (Physalaemus pustulosus) are task-specific rather than sex-specific. As predicted, male túngara frogs are less selective in their vocal responses than are females in their phonotactic responses. Males exhibiting phonotaxis to the same calls, however, are as selective as females, and are significantly more selective than when they respond vocally to the same calls. Our study shows that apparent differences between the sexes emerge from differences in the behaviours themselves and are not intrinsic to each sex. Analogous behavioural differences might confound sex differences in other systems; thus, we suggest consideration of the behavioural plasticity of sex as well as its stereotypy.

  12. 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.

  13. 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.

  14. 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.

  15. 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

  16. 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.

  17. Review of methods for handling confounding by cluster and informative cluster size in clustered data

    PubMed Central

    Seaman, Shaun; Pavlou, Menelaos; Copas, Andrew

    2014-01-01

    Clustered data are common in medical research. Typically, one is interested in a regression model for the association between an outcome and covariates. Two complications that can arise when analysing clustered data are informative cluster size (ICS) and confounding by cluster (CBC). ICS and CBC mean that the outcome of a member given its covariates is associated with, respectively, the number of members in the cluster and the covariate values of other members in the cluster. Standard generalised linear mixed models for cluster-specific inference and standard generalised estimating equations for population-average inference assume, in general, the absence of ICS and CBC. Modifications of these approaches have been proposed to account for CBC or ICS. This article is a review of these methods. We express their assumptions in a common format, thus providing greater clarity about the assumptions that methods proposed for handling CBC make about ICS and vice versa, and about when different methods can be used in practice. We report relative efficiencies of methods where available, describe how methods are related, identify a previously unreported equivalence between two key methods, and propose some simple additional methods. Unnecessarily using a method that allows for ICS/CBC has an efficiency cost when ICS and CBC are absent. We review tools for identifying ICS/CBC. A strategy for analysis when CBC and ICS are suspected is demonstrated by examining the association between socio-economic deprivation and preterm neonatal death in Scotland. PMID:25087978

  18. Confounding factors and genetic polymorphism in the evaluation of individual steroid profiling

    PubMed Central

    Kuuranne, Tiia; Saugy, Martial; Baume, Norbert

    2014-01-01

    In the fight against doping, steroid profiling is a powerful tool to detect drug misuse with endogenous anabolic androgenic steroids. To establish sensitive and reliable models, the factors influencing profiling should be recognised. We performed an extensive literature review of the multiple factors that could influence the quantitative levels and ratios of endogenous steroids in urine matrix. For a comprehensive and scientific evaluation of the urinary steroid profile, it is necessary to define the target analytes as well as testosterone metabolism. The two main confounding factors, that is, endogenous and exogenous factors, are detailed to show the complex process of quantifying the steroid profile within WADA-accredited laboratories. Technical aspects are also discussed as they could have a significant impact on the steroid profile, and thus the steroid module of the athlete biological passport (ABP). The different factors impacting the major components of the steroid profile must be understood to ensure scientifically sound interpretation through the Bayesian model of the ABP. Not only should the statistical data be considered but also the experts in the field must be consulted for successful implementation of the steroidal module. PMID:24764553

  19. 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.

  20. 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

  1. Overcoming confounds of stimulus blocking: an event-related fMRI design of semantic processing.

    PubMed

    Pilgrim, L K; Fadili, J; Fletcher, P; Tyler, L K

    2002-07-01

    The way in which meaning is represented and processed in the brain is a key issue in cognitive neuroscience, which can be usefully addressed by functional imaging techniques. In contrast to previous imaging studies of semantic knowledge, which have primarily used blocked designs, in this study we use an event-related fMRI (erfMRI) design, which has the advantage of enabling events to be presented pseudorandomly, thus reducing strategic processes and enabling more direct comparison with psychological behavioral studies. We used a semantic categorization task in which events were words representing either artifact or natural kinds concepts. Significant areas of activation for semantic processing included inferior frontal lobe bilaterally (BA 47) and left temporal regions, both inferior (BA 36 and 20) and middle (BA 21). These are areas that have been identified in previous neuroimaging studies of semantic knowledge. However, there were no significant differences between artifact and natural kinds concepts. These results are consistent with our previous imaging studies using blocked designs and suggest that conceptual knowledge is represented in a unitary, distributed neural system undifferentiated by domain of knowledge. These findings demonstrate that event-related designs can generate activations that are similar to those seen in blocked designs investigating semantics and, moreover, offer a greater capacity for interpretation free from the confounds of block effects.

  2. 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.

  3. 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.

  4. 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.

  5. 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

  6. 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.

  7. 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.

  8. 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.

  9. Mediation analysis for a survival outcome with time-varying exposures, mediators, and confounders.

    PubMed

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

    2017-08-15

    We propose an approach to conduct mediation analysis for survival data with time-varying exposures, mediators, and confounders. We identify certain interventional direct and indirect effects through a survival mediational g-formula and describe the required assumptions. We also provide a feasible parametric approach along with an algorithm and software to estimate these effects. We apply this method to analyze the Framingham Heart Study data to investigate the causal mechanism of smoking on mortality through coronary artery disease. The estimated overall 10-year all-cause mortality risk difference comparing "always smoke 30 cigarettes per day" versus "never smoke" was 4.3 (95% CI = (1.37, 6.30)). Of the overall effect, we estimated 7.91% (95% CI: = 1.36%, 19.32%) was mediated by the incidence and timing of coronary artery disease. The survival mediational g-formula constitutes a powerful tool for conducting mediation analysis with longitudinal data. Copyright © 2017 John Wiley & Sons, Ltd.

  10. 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).

  11. Splinting Strategies to Overcome Confounding Wound Contraction in Experimental Animal Models

    PubMed Central

    Davidson, Jeffrey M.; Yu, Fang; Opalenik, Susan R.

    2013-01-01

    Significance Clinical healing by secondary intention frequently occurs in skin that is firmly anchored to underlying (human) connective tissue. Small animals (rodents) are extensively utilized to model human cutaneous wound healing, but they heal by wound contraction, a process that is limited in the human and confounds quantitative and qualitative evaluation of experimental wound repair. Recent Advances To alleviate wound contraction in loose-skinned species, practical solutions include choosing anatomical sites with firmly attached dermis and subcutis (e.g., rabbit ear) or performing mechanical fixation of the skin by using one of a number of devices or splints. In each case, the wound volume remains relatively constant, allowing the histomorphometric or biomolecular quantification of the cellular response under well-controlled, experimental conditions. In addition, the defined aperture of the splinted wound allows the placement of a variety of materials, including scaffolds, cells, and biologically active formulations into the wound site in an effort to potentiate the healing response and abrogate scarring. In contrast, production of larger experimental wounds or the deliberate distraction of wound margins can be used to model a hypertrophic response. Critical Issues Device design parameters should consider ease of application, durability, and lack of interference with the normal influx of local and circulating cells to the wound site. Future Directions Improved methods of securing flexible splints would provide a more efficient experimental platform. These devices could also incorporate optical or electronic sensors that report both the mechanical and physiological status of the healing. PMID:24527337

  12. Traditional assessment of health outcome following total knee arthroplasty was confounded by response shift phenomenon.

    PubMed

    Razmjou, Helen; Schwartz, Carolyn E; Yee, Albert; Finkelstein, Joel A

    2009-01-01

    To examine the existence, direction, and effect of response shift as measured by the total score of Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and SF-36 physical and mental component score domains at 6 months and 1 year after primary total knee arthroplasty (TKA). Consecutive candidates participated in the study. In line with the Then-test design, two sets of questionnaires were completed at 6 months and 1 year postoperatively. Patients were divided into three groups on the basis of minimal clinically important differences (MCIDs). Parametric and nonparametric statistics and generalized mixed effects models were used. Two hundred and thirty-six patients completed the study. The magnitude of response shift increased over time for SF-36 physical and mental component scores. The traditional unadjusted presurgical and 1-year postsurgical assessment failed to reveal any mental health improvement, whereas the adjusted treatment effect demonstrated statistically significant changes. Response shift phenomenon increases with time in patients undergoing orthopedic interventions. The traditional pre- and post-assessment of joint replacement surgery may be confounded by a change in perspective and in internal standards of measurement in patients undergoing surgery. Response shift has substantial impact on measuring recovery in this population.

  13. 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

  14. Effect of water quality and confounding factors on digestive enzyme activities in Gammarus fossarum.

    PubMed

    Charron, L; Geffard, O; Chaumot, A; Coulaud, R; Queau, H; Geffard, A; Dedourge-Geffard, O

    2013-12-01

    The feeding activity and subsequent assimilation of the products resulting from food digestion allow organisms to obtain energy for growth, maintenance and reproduction. Among these biological parameters, we studied digestive enzymes (amylase, cellulase and trypsin) in Gammarus fossarum to assess the impact of contaminants on their access to energy resources. However, to enable objective assessment of a toxic effect of decreased water quality on an organisms' digestive capacity, it is necessary to establish reference values based on its natural variability as a function of changing biotic and abiotic factors. To limit the confounding influence of biotic factors, a caging approach with calibrated male organisms from the same population was used. This study applied an in situ deployment at 23 sites of the Rhone basin rivers, complemented by a laboratory experiment assessing the influence of two abiotic factors (temperature and conductivity). The results showed a small effect of conductivity on cellulase activity and a significant effect of temperature on digestive enzyme activity but only at the lowest temperature (7 °C). The experimental conditions allowed us to define an environmental reference value for digestive enzyme activities to select sites where the quality of the water impacted the digestive capacity of the organisms. In addition to the feeding rate, this study showed the relevance of digestive enzymes as biomarkers to be used as an early warning tool to reflect organisms' health and the chemical quality of aquatic ecosystems.

  15. 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.

  16. 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.

  17. 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

  18. Systematic review of biochemical biomarkers for neck and upper-extremity musculoskeletal disorders.

    PubMed

    Gold, Judith E; Hallman, David M; Hellström, Fredrik; Björklund, Martin; Crenshaw, Albert G; Djupsjobacka, Mats; Heiden, Marina; Mathiassen, Svend Erik; Piligian, George; Barbe, Mary F

    2016-03-01

    This study systematically summarizes biochemical biomarker research in non-traumatic musculoskeletal disorders (MSD). Two research questions guided the review: (i) Are there biochemical markers associated with neck and upper-extremity MSD? and (ii) Are there biochemical markers associated with the severity of neck and upper-extremity MSD? A literature search was conducted in PubMed and SCOPUS, and 87 studies met primary inclusion criteria. Following a quality screen, data were extracted from 44 articles of sufficient quality. Most of the 87 studies were cross-sectional and utilized convenience samples of patients as both cases and controls. A response rate was explicitly stated in only 11 (13%) studies. Less than half of the studies controlled for potential confounding through restriction or in the analysis. Most sufficient-quality studies were conducted in older populations (mean age in one or more analysis group >50 years). In sufficient-quality articles, 82% demonstrated at least one statistically significant association between the MSD and biomarker(s) studied. Evidence suggested that: (i) the collagen-repair marker TIMP-1 is decreased in fibro proliferative disorders, (ii) 5-HT (serotonin) is increased in trapezius myalgia, and (iii) triglycerides are increased in a variety of MSD. Only 5 studies showed an association between a biochemical marker and MSD severity. While some MSD biomarkers were identified, limitations in the articles examined included possible selection bias, confounding, spectrum effect (potentially heterogeneous biomarker associations in populations according to symptom severity or duration), and insufficient attention to comorbid conditions. A list of recommendations for future studies is provided.

  19. Translational Rodent Models for Research on Parasitic Protozoa—A Review of Confounders and Possibilities

    PubMed Central

    Ehret, Totta; Torelli, Francesca; Klotz, Christian; Pedersen, Amy B.; Seeber, Frank

    2017-01-01

    Rodents, in particular Mus musculus, have a long and invaluable history as models for human diseases in biomedical research, although their translational value has been challenged in a number of cases. We provide some examples in which rodents have been suboptimal as models for human biology and discuss confounders which influence experiments and may explain some of the misleading results. Infections of rodents with protozoan parasites are no exception in requiring close consideration upon model choice. We focus on the significant differences between inbred, outbred and wild animals, and the importance of factors such as microbiota, which are gaining attention as crucial variables in infection experiments. Frequently, mouse or rat models are chosen for convenience, e.g., availability in the institution rather than on an unbiased evaluation of whether they provide the answer to a given question. Apart from a general discussion on translational success or failure, we provide examples where infections with single-celled parasites in a chosen lab rodent gave contradictory or misleading results, and when possible discuss the reason for this. We present emerging alternatives to traditional rodent models, such as humanized mice and organoid primary cell cultures. So-called recombinant inbred strains such as the Collaborative Cross collection are also a potential solution for certain challenges. In addition, we emphasize the advantages of using wild rodents for certain immunological, ecological, and/or behavioral questions. The experimental challenges (e.g., availability of species-specific reagents) that come with the use of such non-model systems are also discussed. Our intention is to foster critical judgment of both traditional and newly available translational rodent models for research on parasitic protozoa that can complement the existing mouse and rat models. PMID:28638807

  20. 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

  1. 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

  2. Reverse causality and confounding and the associations of overweight and obesity with mortality.

    PubMed

    Lawlor, Debbie A; Hart, Carole L; Hole, David J; Davey Smith, George

    2006-12-01

    To examine the effect of reverse causality and confounding on the association of BMI with all-cause and cause-specific mortality. Data from two large prospective studies were used. One (a community-based cohort) included 8327 women and 7017 men who resided in two Scottish towns at the time of the baseline assessment in 1972-1976; the other (an occupational cohort) included 4016 men working in the central belt of Scotland at the time of the baseline assessment in 1970-1973. Participants in both cohorts were ages 45 to 64 years at baseline; the follow-up period was 28 to 34 years. In age-adjusted analyses that did not take account of reverse causality or smoking, there was no association between being overweight (BMI 25 to <30 kg/m(2)) and mortality, and weak to modest associations between obesity (BMI > or =30 kg/m(2)) and mortality. There was a strong association between smoking and lower BMI in women and men in both cohorts (all p < 0.0001). Among never-smokers and with the first 5 years of deaths removed, overweight was associated with an increase in all-cause mortality (relative risk ranging from 1.12 to 1.38), and obesity was associated with a doubling of risk in men in both cohorts (relative risk, 2.10 and 1.96, respectively) and a 60% increase in women (relative risk, 1.56). In both never-smokers and current smokers, being overweight or obese was associated with important increases in the risk of cardiovascular disease. These findings demonstrate that with appropriate control for smoking and reverse causality, both overweight and obesity are associated with important increases in all-cause and cause-specific mortality, and in particular with cardiovascular disease mortality.

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

    PubMed Central

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

    2016-01-01

    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. PMID:26667611

  4. Comorbidity of intellectual disability confounds ascertainment of autism: implications for genetic diagnosis.

    PubMed

    Polyak, Andrew; Kubina, Richard M; Girirajan, Santhosh

    2015-10-01

    While recent studies suggest a converging role for genetic factors towards risk for nosologically distinct disorders including autism, intellectual disability (ID), and epilepsy, current estimates of autism prevalence fail to take into account the impact of comorbidity of these disorders on autism diagnosis. We aimed to assess the effect of comorbidity on the diagnosis and prevalence of autism by analyzing 11 years (2000-2010) of special education enrollment data on approximately 6.2 million children per year. We found a 331% increase in the prevalence of autism from 2000 to 2010 within special education, potentially due to a diagnostic recategorization from frequently comorbid features such as ID. The decrease in ID prevalence equaled an average of 64.2% of the increase of autism prevalence for children aged 3-18 years. The proportion of ID cases potentially undergoing recategorization to autism was higher (P = 0.007) among older children (75%) than younger children (48%). Some US states showed significant negative correlations between the prevalence of autism compared to that of ID while others did not, suggesting state-specific health policy to be a major factor in categorizing autism. Further, a high frequency of autistic features was observed when individuals with classically defined genetic syndromes were evaluated for autism using standardized instruments. Our results suggest that current ascertainment practices are based on a single facet of autism-specific clinical features and do not consider associated comorbidities that may confound diagnosis. Longitudinal studies with detailed phenotyping and deep molecular genetic analyses are necessary to completely understand the cause of this complex disorder.

  5. 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.

  6. Geometry as a Confounder When Assessing Ventricular Systolic Function: Comparison Between Ejection Fraction and Strain.

    PubMed

    Stokke, Thomas M; Hasselberg, Nina E; Smedsrud, Marit K; Sarvari, Sebastian I; Haugaa, Kristina H; Smiseth, Otto A; Edvardsen, Thor; Remme, Espen W

    2017-08-22

    Preserved left ventricular (LV) ejection fraction (EF) and reduced myocardial strain are reported in patients with hypertrophic cardiomyopathy, ischemic heart disease, diabetes mellitus, and more. The authors performed a combined mathematical and echocardiographic study to understand the inconsistencies between EF and strains. An analytical equation showing the relationship between EF and the 4 parameters, global longitudinal strain (GLS), global circumferential strain (GCS), wall thickness, and short-axis diameter, was derived from an elliptical LV model. The equation was validated by measuring the 4 parameters by echocardiography in 100 subjects with EF ranging from 16% to 72% and comparing model-predicted EF with measured EF. The effect of the different parameters on EF was explored in the model and compared with findings in the patients. Calculated EF had very good agreement with measured EF (r = 0.95). The model showed that GCS contributes more than twice as much to EF than GLS. A significant reduction of GLS could be compensated by a small increase of GCS or wall thickness or reduced diameter. The model further demonstrated how EF can be maintained in ventricles with increased wall thickness or reduced diameter, despite reductions in both longitudinal and circumferential shortening. This was consistent with similar EF in 20 control subjects and 20 hypertrophic cardiomyopathy patients with increased wall thickness and reductions in both circumferential and longitudinal shortening (all p < 0.01). Reduced deformation despite preserved EF can be explained through geometric factors. Due to geometric confounders, strain better reflects systolic function in patients with preserved EF. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  7. Do respiratory epidemics confound the association between air pollution and daily deaths?

    PubMed

    Braga, A L; Zanobetti, A; Schwartz, J

    2000-10-01

    Daily deaths are associated with air pollution. This association might be con*hhy;founded by uncontrolled risk factors. In order to estimate the potential confounding caused by respiratory epidemics of the association between air pollution and health effects, a time series study of air pollution and daily deaths was carried out. Daily records of deaths for all ages were obtained from five US cities: Chicago, IL; Detroit, MI; Minneapolis, MN; Pittsburgh, PA; and Seattle, WA. Daily levels of particles with a 50% cut-off aerodynamic diameter of 10 microm (PM10) and weather measurements were obtained. City-specific analysis was carried out using Poisson regression, adjusting for time trend, ambient temperature, dew point, barometric pressure and day of the week. A cubic polynomial was used for each epidemic period (> or =10 days of excessive pneumonia hospital admissions), and a dummy variable was used to control for isolated epidemic days. A 10-microg x m(-3) increase in PM10 concentration (lag 0-1) was associated with increased daily deaths in Chicago (0.81%, 95% confidence internal (CI) 0.54-1.09); Detroit (0.87%, 95% CI 0.60-1.15), Minneapolis (1.34%, 95% CI 0.78-1.90), Pittsburgh (0.84%, 95% CI 0.51-1.18) and Seattle (0.52%, 95% CI 0.11-0.94). When controlling for respiratory epidemics, small decreases in the PMlo effect were observed (Chicago 9%, Detroit 11%, Minneapolis 3%, Pittsburgh 5%, and Seattle 15%). The overall effect of PM10 concentration was 0.85% (95% CI 0.60-1.10) per 10 microg x m(-3) before controlling for epidemics and 0.78% (95% CI 0.51-1.05) after. This study showed that the association between air pollution and daily deaths is not due to failure to control for influenza or pneumonia epidemics.

  8. The four diagnostic criteria for Restless Legs Syndrome are unable to exclude confounding conditions ("mimics").

    PubMed

    Hening, Wayne A; Allen, Richard P; Washburn, Mystinna; Lesage, Suzanne R; Earley, Christopher J

    2009-10-01

    Epidemiological survey studies have suggested that a large fraction of the adult population, from five to more than 10%, have symptoms of Restless Legs Syndrome (RLS). Recently, however, it has become clear that the positive predictive value of many questionnaire screens for RLS may be fairly low and that many individuals who are identified by these screens have other conditions that can "mimic" the features of RLS by satisfying the four diagnostic criteria. We noted the presence of such confounders in a case-control family study and sought to develop methods to differentiate them from true RLS. Family members from the case-control study were interviewed blindly by an RLS expert using the validated Hopkins telephone diagnostic interview (HTDI). Besides questions on the four key diagnostic features of RLS, the HTDI contains open-ended questions on symptom quality and relief strategies and other questions to probe the character of provocative situations and modes of relief. Based on the entire HDTI, a diagnosis of definite, probable or possible RLS or Not-RLS was made. Out of 1255 family members contacted, we diagnosed 1232: 402 (32.0%) had definite or probable RLS, 42 (3.3%) possible RLS, and 788 (62.8%) Not-RLS. Of the 788 family members who were determined not to have RLS, 126 could satisfy all four diagnostic criteria (16%). This finding indicates that the specificity of the four criteria was only 84%. Those with mimic conditions were found to have atypical presentations whose features could be used to assist in final diagnosis. A variety of conditions, including cramps, positional discomfort, and local leg pathology can satisfy all four diagnostic criteria for RLS and thereby "mimic" RLS by satisfying the four diagnostic criteria. Definitive diagnosis of RLS, therefore, requires exclusion of these other conditions, which may be more common in the population than true RLS. Short of an extended clinical interview and workup, certain features of presentation help

  9. Effects of heat waves on mortality: effect modification and confounding by air pollutants.

    PubMed

    Analitis, Antonis; Michelozzi, Paola; D'Ippoliti, Daniela; De'Donato, Francesca; Menne, Bettina; Matthies, Franziska; Atkinson, Richard W; Iñiguez, Carmen; Basagaña, Xavier; Schneider, Alexandra; Lefranc, Agnès; Paldy, Anna; Bisanti, Luigi; Katsouyanni, Klea

    2014-01-01

    Heat waves and air pollution are both associated with increased mortality. Their joint effects are less well understood. We explored the role of air pollution in modifying the effects of heat waves on mortality, within the EuroHEAT project. Daily mortality, meteorologic, and air pollution data from nine European cities for the years 1990-2004 were assembled. We defined heat waves by taking both intensity and duration into account. The city-specific effects of heat wave episodes were estimated using generalized estimating equation models, adjusting for potential confounders with and without inclusion of air pollutants (particles, ozone, nitrogen dioxide, sulphur dioxide, carbon monoxide). To investigate effect modification, we introduced an interaction term between heat waves and each single pollutant in the models. Random effects meta-analysis was used to summarize the city-specific results. The increase in the number of daily deaths during heat wave episodes was 54% higher on high ozone days compared with low, among people age 75-84 years. The heat wave effect on high PM10 days was increased by 36% and 106% in the 75-84 year and 85+ year age groups, respectively. A similar pattern was observed for effects on cardiovascular mortality. Effect modification was less evident for respiratory mortality, although the heat wave effect itself was greater for this cause of death. The heat wave effect was smaller (15-30%) after adjustment for ozone or PM10. The heat wave effect on mortality was larger during high ozone or high PM10 days. When assessing the effect of heat waves on mortality, lack of adjustment for ozone and especially PM10 overestimates effect parameters. This bias has implications for public health policy.

  10. 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

  11. 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. Copyright © 2016 Elsevier B.V. All rights reserved.

  12. Confounding Environmental Colour and Distribution Shape Leads to Underestimation of Population Extinction Risk

    PubMed Central

    Fowler, Mike S.; Ruokolainen, Lasse

    2013-01-01

    The colour of environmental variability influences the size of population fluctuations when filtered through density dependent dynamics, driving extinction risk through dynamical resonance. Slow fluctuations (low frequencies) dominate in red environments, rapid fluctuations (high frequencies) in blue environments and white environments are purely random (no frequencies dominate). Two methods are commonly employed to generate the coloured spatial and/or temporal stochastic (environmental) series used in combination with population (dynamical feedback) models: autoregressive [AR(1)] and sinusoidal (1/f) models. We show that changing environmental colour from white to red with 1/f models, and from white to red or blue with AR(1) models, generates coloured environmental series that are not normally distributed at finite time-scales, potentially confounding comparison with normally distributed white noise models. Increasing variability of sample Skewness and Kurtosis and decreasing mean Kurtosis of these series alter the frequency distribution shape of the realised values of the coloured stochastic processes. These changes in distribution shape alter patterns in the probability of single and series of extreme conditions. We show that the reduced extinction risk for undercompensating (slow growing) populations in red environments previously predicted with traditional 1/f methods is an artefact of changes in the distribution shapes of the environmental series. This is demonstrated by comparison with coloured series controlled to be normally distributed using spectral mimicry. Changes in the distribution shape that arise using traditional methods lead to underestimation of extinction risk in normally distributed, red 1/f environments. AR(1) methods also underestimate extinction risks in traditionally generated red environments. This work synthesises previous results and provides further insight into the processes driving extinction risk in model populations. We must let

  13. Confounding environmental colour and distribution shape leads to underestimation of population extinction risk.

    PubMed

    Fowler, Mike S; Ruokolainen, Lasse

    2013-01-01

    The colour of environmental variability influences the size of population fluctuations when filtered through density dependent dynamics, driving extinction risk through dynamical resonance. Slow fluctuations (low frequencies) dominate in red environments, rapid fluctuations (high frequencies) in blue environments and white environments are purely random (no frequencies dominate). Two methods are commonly employed to generate the coloured spatial and/or temporal stochastic (environmental) series used in combination with population (dynamical feedback) models: autoregressive [AR(1)] and sinusoidal (1/f) models. We show that changing environmental colour from white to red with 1/f models, and from white to red or blue with AR(1) models, generates coloured environmental series that are not normally distributed at finite time-scales, potentially confounding comparison with normally distributed white noise models. Increasing variability of sample Skewness and Kurtosis and decreasing mean Kurtosis of these series alter the frequency distribution shape of the realised values of the coloured stochastic processes. These changes in distribution shape alter patterns in the probability of single and series of extreme conditions. We show that the reduced extinction risk for undercompensating (slow growing) populations in red environments previously predicted with traditional 1/f methods is an artefact of changes in the distribution shapes of the environmental series. This is demonstrated by comparison with coloured series controlled to be normally distributed using spectral mimicry. Changes in the distribution shape that arise using traditional methods lead to underestimation of extinction risk in normally distributed, red 1/f environments. AR(1) methods also underestimate extinction risks in traditionally generated red environments. This work synthesises previous results and provides further insight into the processes driving extinction risk in model populations. We must let

  14. 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.

  15. Batch Effect Confounding Leads to Strong Bias in Performance Estimates Obtained by Cross-Validation

    PubMed Central

    Delorenzi, Mauro

    2014-01-01

    Background With the large amount of biological data that is currently publicly available, many investigators combine multiple data sets to increase the sample size and potentially also the power of their analyses. However, technical differences (“batch effects”) as well as differences in sample composition between the data sets may significantly affect the ability to draw generalizable conclusions from such studies. Focus The current study focuses on the construction of classifiers, and the use of cross-validation to estimate their performance. In particular, we investigate the impact of batch effects and differences in sample composition between batches on the accuracy of the classification performance estimate obtained via cross-validation. The focus on estimation bias is a main difference compared to previous studies, which have mostly focused on the predictive performance and how it relates to the presence of batch effects. Data We work on simulated data sets. To have realistic intensity distributions, we use real gene expression data as the basis for our simulation. Random samples from this expression matrix are selected and assigned to group 1 (e.g., ‘control’) or group 2 (e.g., ‘treated’). We introduce batch effects and select some features to be differentially expressed between the two groups. We consider several scenarios for our study, most importantly different levels of confounding between groups and batch effects. Methods We focus on well-known classifiers: logistic regression, Support Vector Machines (SVM), k-nearest neighbors (kNN) and Random Forests (RF). Feature selection is performed with the Wilcoxon test or the lasso. Parameter tuning and feature selection, as well as the estimation of the prediction performance of each classifier, is performed within a nested cross-validation scheme. The estimated classification performance is then compared to what is obtained when applying the classifier to independent data. PMID:24967636

  16. Batch effect confounding leads to strong bias in performance estimates obtained by cross-validation.

    PubMed

    Soneson, Charlotte; Gerster, Sarah; Delorenzi, Mauro

    2014-01-01

    With the large amount of biological data that is currently publicly available, many investigators combine multiple data sets to increase the sample size and potentially also the power of their analyses. However, technical differences ("batch effects") as well as differences in sample composition between the data sets may significantly affect the ability to draw generalizable conclusions from such studies. The current study focuses on the construction of classifiers, and the use of cross-validation to estimate their performance. In particular, we investigate the impact of batch effects and differences in sample composition between batches on the accuracy of the classification performance estimate obtained via cross-validation. The focus on estimation bias is a main difference compared to previous studies, which have mostly focused on the predictive performance and how it relates to the presence of batch effects. We work on simulated data sets. To have realistic intensity distributions, we use real gene expression data as the basis for our simulation. Random samples from this expression matrix are selected and assigned to group 1 (e.g., 'control') or group 2 (e.g., 'treated'). We introduce batch effects and select some features to be differentially expressed between the two groups. We consider several scenarios for our study, most importantly different levels of confounding between groups and batch effects. We focus on well-known classifiers: logistic regression, Support Vector Machines (SVM), k-nearest neighbors (kNN) and Random Forests (RF). Feature selection is performed with the Wilcoxon test or the lasso. Parameter tuning and feature selection, as well as the estimation of the prediction performance of each classifier, is performed within a nested cross-validation scheme. The estimated classification performance is then compared to what is obtained when applying the classifier to independent data.

  17. 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

  18. Climate change as a confounding factor in reversibility of acidification: RAIN and CLIMEX projects

    NASA Astrophysics Data System (ADS)

    Wright, R. F.; Jenkins, A.

    The RAIN and CLIMEX experiments at Risdalsheia, southernmost Norway, together cover 17 years (1984-2000) of whole-catchment manipulation of acid deposition and climate. A 1200 m2 roof placed over the forest canopy at KIM catchment excluded about 80% of ambient acid deposition; clean rain was sprinkled under the roof. A climate change treatment (3.7°C increase in air temperature and increase in air carbon dioxide concentrations to 560 ppmv) was superimposed on the clean rain treatment for four years (1995-1998). Sea-salt inputs and temperature are climate-related factors that influence water chemistry and can confound long-term trends caused by changes in deposition of sulphur and nitrogen. The RAIN and CLIMEX experiments at Risdalsheia provided direct experimental data that allow quantitative assessment of these factors. Run-off chemistry responded rapidly to the decreased acid deposition. Sulphate concentrations decreased by 50% within three years; nitrate and ammonium concentrations decreased to new steady-state levels within the first year. Acid neutralising capacity increased and hydrogen ion and inorganic aluminium decreased. Similar recovery from acidification was also observed at the reference catchment, ROLF, in response to the general 50% reduction in sulphate deposition over southern Norway in the late 1980s and 1990s. Variations in sea-salt deposition caused large variations in run-off chemistry at the reference catchment ROLF and the year-to-year noise in acid neutralising capacity was as large as the overall trend over the period. These variations were absent at KIM catchment because the sea-salt inputs were held constant over the entire 17 years of the clean rain treatment. The climate change experiment at KIM catchment resulted in increased leaching of inorganic nitrogen, probably due to increased mineralisation and nitrification rates in the soils.

  19. 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

  20. Biochemical testing of thyroid function.

    PubMed

    Klee, G G; Hay, I D

    1997-12-01

    Various published guidelines recommending serum thyrotropin (TSH)-first thyroid testing are outlined. The entities called "subclinical hypothyroidism" and "subclinical hyperthyroidism" are defined on the basis of abnormal TSH concentrations and normal values of other biochemical thyroid tests. The controversies about follow-up and treatment of these disorders are discussed. The laboratory experience of Mayo Clinic Rochester in using TSH-first thyroid testing and the subsequent implementation of a thyroid test ordering cascade are presented. Finally, recommendations are given for further optimizing laboratory testing for thyroid disorders.

  1. 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.

  2. 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).

  3. 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.

  4. 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.

  5. 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…

  6. 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.

  7. 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.

  8. 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.

  9. 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…

  10. Socioeconomic status and health in blacks and whites: the problem of residual confounding and the resiliency of race.

    PubMed

    Kaufman, J S; Cooper, R S; McGee, D L

    1997-11-01

    A large number of epidemiologic studies have focused on racial/ethnic differences, particularly between blacks and whites. Because health endpoints and racial categorizations are associated with socioeconomic status, investigators generally adjust for socioeconomic indicators. The intention is usually to control for confounding, thereby making groups comparable and excluding socioeconomic status as an alternative explanation to hypotheses of innate physiologic differences. A threat to the validity of these analyses is therefore the presence of residual confounding. We identify four potential sources of residual confounding in this analytical design: categorization of socioeconomic status variables, measurement error in socioeconomic indicators, use of aggregated socioeconomic status measures, and incommensurate socioeconomic indicators. Using simulations and examples from the literature, we demonstrate that the effect of residual confounding is to bias interpretation of data toward the conclusion of independent racial/ethnic group effects. Investigators often refer to possible "genetic" differences on the basis of models that control for socioeconomic status. We propose that such conclusions on the basis of this analytical strategy are generally unwarranted. Racial/ethnic differences in disease are a pressing public health concern, but the current approach does not often provide a basis for inference about putative biological factors in the etiology of this disparity.

  11. 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.

  12. Benchmarking of participant-level confound regression strategies for the control of motion artifact in studies of functional connectivity.

    PubMed

    Ciric, Rastko; Wolf, Daniel H; Power, Jonathan D; Roalf, David R; Baum, Graham L; Ruparel, Kosha; Shinohara, Russell T; Elliott, Mark A; Eickhoff, Simon B; Davatzikos, Christos; Gur, Ruben C; Gur, Raquel E; Bassett, Danielle S; Satterthwaite, Theodore D

    2017-07-01

    Since initial reports regarding the impact of motion artifact on measures of functional connectivity, there has been a proliferation of participant-level confound regression methods to limit its impact. However, many of the most commonly used techniques have not been systematically evaluated using a broad range of outcome measures. Here, we provide a systematic evaluation of 14 participant-level confound regression methods in 393 youths. Specifically, we compare methods according to four benchmarks, including the residual relationship between motion and connectivity, distance-dependent effects of motion on connectivity, network identifiability, and additional degrees of freedom lost in confound regression. Our results delineate two clear trade-offs among methods. First, methods that include global signal regression minimize the relationship between connectivity and motion, but result in distance-dependent artifact. In contrast, censoring methods mitigate both motion artifact and distance-dependence, but use additional degrees of freedom. Importantly, less effective de-noising methods are also unable to identify modular network structure in the connectome. Taken together, these results emphasize the heterogeneous efficacy of existing methods, and suggest that different confound regression strategies may be appropriate in the context of specific scientific goals. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  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. © The Author 2015. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  14. 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.

  15. Controlling confounding by frailty when estimating influenza vaccine effectiveness using predictors of dependency in activities of daily living.

    PubMed

    Zhang, Henry T; McGrath, Leah J; Wyss, Richard; Ellis, Alan R; Stürmer, Til

    2017-08-24

    To improve control of confounding by frailty when estimating the effect of influenza vaccination on all-cause mortality by controlling for a published set of claims-based predictors of dependency in activities of daily living (ADL). Using Medicare claims data, a cohort of beneficiaries >65 years of age was followed from September 1, 2007, to April 12, 2008, with covariates assessed in the 6 months before follow-up. We estimated Cox proportional hazards models of all-cause mortality, with influenza vaccination as a time-varying exposure. We controlled for common demographics, comorbidities, and health care utilization variables and then added 20 ADL dependency predictors. To gauge residual confounding, we estimated pre-influenza season hazard ratios (HRs) between September 1, 2007 and January 5, 2008, which should be 1.0 in the absence of bias. A cohort of 2 235 140 beneficiaries was created, with a median follow-up of 224 days. Overall, 52% were vaccinated and 4% died during follow-up. During the pre-influenza season period, controlling for demographics, comorbidities, and health care use resulted in a HR of 0.66 (0.64, 0.67). Adding the ADL dependency predictors moved the HR to 0.68 (0.67, 0.70). Controlling for demographics and ADL dependency predictors alone resulted in a HR of 0.68 (0.66, 0.70). Results were consistent with those in the literature, with significant uncontrolled confounding after adjustment for demographics, comorbidities, and health care use. Adding ADL dependency predictors moved HRs slightly closer to the null. Of the comorbidities, health care use variables, and ADL dependency predictors, the last set reduced confounding most. However, substantial uncontrolled confounding remained. Copyright © 2017 John Wiley & Sons, Ltd.

  16. 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.

  17. Bistability in biochemical signaling models.

    PubMed

    Sobie, Eric A

    2011-09-20

    This Teaching Resource provides lecture notes, slides, and a student assignment for a two-part lecture on the principles underlying bistability in biochemical signaling networks, which are illustrated with examples from the literature. The lectures cover analog, or graded, versus digital, all-or-none, responses in cells, with examples from different types of biological processes requiring each. Rate-balance plots are introduced as a method for determining whether generic one-variable systems exhibit one or several stable steady states. Bifurcation diagrams are presented as a more general method for detecting the presence of bistability in biochemical signaling networks. The examples include an artificial toggle switch, the lac operon in bacteria, and the mitogen-activated protein kinase cascade in both Xenopus oocytes and mammalian cells. The second part of the lecture links the concepts of bistability more closely to the mathematical tools provided by dynamical systems analysis. The examples from the first part of the lecture are analyzed with phase-plane techniques and bifurcation analysis, using the scientific programming language MATLAB. Using these programs as a template, the assignment requires the students to implement a model from the literature and analyze the stability of this model's steady states.

  18. 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.

  19. Vector Encoding in Biochemical Networks

    NASA Astrophysics Data System (ADS)

    Potter, Garrett; Sun, Bo

    Encoding of environmental cues via biochemical signaling pathways is of vital importance in the transmission of information for cells in a network. The current literature assumes a single cell state is used to encode information, however, recent research suggests the optimal strategy utilizes a vector of cell states sampled at various time points. To elucidate the optimal sampling strategy for vector encoding, we take an information theoretic approach and determine the mutual information of the calcium signaling dynamics obtained from fibroblast cells perturbed with different concentrations of ATP. Specifically, we analyze the sampling strategies under the cases of fixed and non-fixed vector dimension as well as the efficiency of these strategies. Our results show that sampling with greater frequency is optimal in the case of non-fixed vector dimension but that, in general, a lower sampling frequency is best from both a fixed vector dimension and efficiency standpoint. Further, we find the use of a simple modified Ornstein-Uhlenbeck process as a model qualitatively captures many of our experimental results suggesting that sampling in biochemical networks is based on a few basic components.

  20. 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

  1. 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

  2. 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.

  3. 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.

  4. Associations between lifestyle and air pollution exposure: Potential for confounding in large administrative data cohorts.

    PubMed

    Strak, Maciej; Janssen, Nicole; Beelen, Rob; Schmitz, Oliver; Karssenberg, Derek; Houthuijs, Danny; van den Brink, Carolien; Dijst, Martin; Brunekreef, Bert; Hoek, Gerard

    2017-07-01

    Cohorts based on administrative data have size advantages over individual cohorts in investigating air pollution risks, but often lack in-depth information on individual risk factors related to lifestyle. If there is a correlation between lifestyle and air pollution, omitted lifestyle variables may result in biased air pollution risk estimates. Correlations between lifestyle and air pollution can be induced by socio-economic status affecting both lifestyle and air pollution exposure. Our overall aim was to assess potential confounding by missing lifestyle factors on air pollution mortality risk estimates. The first aim was to assess associations between long-term exposure to several air pollutants and lifestyle factors. The second aim was to assess whether these associations were sensitive to adjustment for individual and area-level socioeconomic status (SES), and whether they differed between subgroups of the population. Using the obtained air pollution-lifestyle associations and indirect adjustment methods, our third aim was to investigate the potential bias due to missing lifestyle information on air pollution mortality risk estimates in administrative cohorts. We used a recent Dutch national health survey of 387,195 adults to investigate the associations of PM10, PM2.5, PM2.5-10, PM2.5 absorbance, OP(DTT,) OP(ESR) and NO2 annual average concentrations at the residential address from land use regression models with individual smoking habits, alcohol consumption, physical activity and body mass index. We assessed the associations with and without adjustment for neighborhood and individual SES characteristics typically available in administrative data cohorts. We illustrated the effect of including lifestyle information on the air pollution mortality risk estimates in administrative cohort studies using a published indirect adjustment method. Current smoking and alcohol consumption were generally positively associated with air pollution. Physical activity and

  5. Association of Acetaminophen Use During Pregnancy With Behavioral Problems in Childhood: Evidence Against Confounding.

    PubMed

    Stergiakouli, Evie; Thapar, Anita; Davey Smith, George

    2016-10-01

    Acetaminophen (paracetamol) is used by a large proportion of pregnant women. Research suggests that acetaminophen use in pregnancy is associated with abnormal fetal neurodevelopment. However, it is possible that this association might be confounded by unmeasured behavioral factors linked to acetaminophen use. To examine associations between offspring behavioral problems and (1) maternal prenatal acetaminophen use, (2) maternal postnatal acetaminophen use, and (3) partner's acetaminophen use. From February 2015 to March 2016, we collected and analyzed data from the Avon Longitudinal Study of Parents and Children (ALSPAC), a prospective birth cohort. We studied 7796 mothers enrolled in ALSPAC between 1991 and 1992 along with their children and partners. Acetaminophen use was assessed by questionnaire completion at 18 and 32 weeks of pregnancy and when the child was 61 months old. Maternal reports of behavioral problems using the Strengths and Difficulties Questionnaire (SDQ) when the children were 7 years old. We estimated risk ratios for behavioral problems in children after prenatal, postnatal, and partner's exposure to acetaminophen and mutually adjusted each association. Maternal prenatal acetaminophen use at 18 (n = 4415; 53%) and 32 weeks of pregnancy (n = 3381; 42%) was associated with higher odds of having conduct problems (risk ratio [RR], 1.42; 95% CI, 1.25-1.62) and hyperactivity symptoms (RR, 1.31; 95% CI, 1.16-1.49), while maternal acetaminophen use at 32 weeks was also associated with higher odds of having emotional symptoms (RR, 1.29; 95% CI, 1.09-1.53) and total difficulties (RR, 1.46; 95% CI, 1.21-1.77). This was not the case for maternal postnatal (n = 6916; 89%) or partner's (n = 3454; 84%) acetaminophen use. We found the associations between maternal prenatal acetaminophen use and all the SDQ domains unchanged even after adjusting for maternal postnatal or partner's acetaminophen use. Children exposed to acetaminophen prenatally

  6. Systemic confounders affecting serum measurements of omega-3 and -6 polyunsaturated fatty acids in patients with retinal disease.

    PubMed

    Bühler, Anima D; Bucher, Felicitas; Augustynik, Michael; Wöhrl, Jan; Martin, Gottfried; Schlunck, Günther; Agostini, Hansjürgen; Böhringer, Daniel; Pütz, Gerhard; Stahl, Andreas

    2016-09-05

    Omega-3 polyunsaturated fatty acids (PUFAs) have a highly anti-angiogenic effect in animal models. However, the clinical relevance of omega-3PUFAs in human retinal pathologies remains unclear. The ARED 2 study found no effect of omega-3 PUFA supplementation on progression of age related macular degeneration (AMD). The aim of this study was to compare serum levels of omega-3- and omega-6 PUFAs between patients with diabetic retinopathy (DR), AMD and retinal vein occlusion (RVO), and to identify potential confounders of serum level measurements. Venous blood samples were collected from 44 patients with DR, 25 with AMD, 12 with RVO and 27 controls. The lipid phase was extracted and analyzed using mass spectrometry. Retinal disease staging was done by indirect funduscopy and FAG where appropriate. Patient demographics and medical history including current medication and fasting state were acquired. Tukey contrasts for multiple comparisons of the mean and linear regression analysis were used for statistical analysis. Our data revealed no significant differences in omega-6 PUFA serum levels between patients with AMD, DR, RVO and controls (p > 0.858). Uncorrected omega-3 PUFA levels were significantly higher in patients with AMD compared to DR but not compared to controls (p = 0.004). However, after correcting for possible confounders such as body mass index (BMI), age, sex, fasting and use of statins, no statistically significant difference remained for serum omega-3 PUFA levels. Fasting was identified as an independent confounder of total omega-6 PUFAs, three individual omega-6 PUFAs and one omega-3 PUFA(p < 0.0427). Statin use was identified as an independent confounder of α-linolenic acid (an omega-3PUFA; p = 0.0210). In this pilot study with relatively low patient numbers, we report significant differences in serum levels of omega-3PUFAs among patients with different types of retinal diseases. However, these differences were not robust for disease

  7. 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.

  8. 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

  9. 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.

  10. Distinguishing benign confounding treatment changes from residual prostate cancer on MRI following laser ablation

    NASA Astrophysics Data System (ADS)

    Litjens, G.; Huisman, H.; Elliott, R.; Shih, N.; Feldman, M.; Viswanath, S.; Fütterer, J.; Bomers, J.; Madabhushi, A.

    2014-03-01

    Laser interstitial thermotherapy (LITT) is a relatively new focal therapy technique for the ablation of localized prostate cancer. However, very little is known about the specific effects of LITT within the ablation zone and the surrounding normal tissue regions. For instance, it is important to be able to assess the extent of residual cancer within the prostate following LITT, which may be masked by thermally induced benign necrotic changes. Fortunately LITT is MRI compatible and hence this allows for quantitatively assessing LITT induced changes via multi-parametric MRI. Of course definite validation of any LITT induced changes on MRI requires confirmation via histopathology. The aim of this study was to quantitatively assess and distinguish the imaging characteristics of prostate cancer and benign confounding treatment changes following LITTon 3 Tesla multi-parametric MRI by carefully mapping the treatment related changes from the ex vivo surgically resected histopathologic specimens onto the pre-operative in vivo imaging. A better understanding of the imaging characteristics of residual disease and successfully ablated tissue might lead to improved treatment monitoring and as such patient prognosis. A unique clinical trial at the Radboud University Medical Center, in which 3 patients underwent a prostatectomy after LITT treatment, yielded ex-vivo histopathologic specimens along with pre- and post-LITT MRI. Using this data we (1) identified the computer extracted MRI signatures associated with treatment effects including benign necrotic changes and residual disease and (2) subsequently evaluated the computer extracted MRI features previously identified in distinguishing LITT induced changes in the ablated area relative to the residual disease. Towards this end first a pathologist annotated the ablated area and the residual disease on the ex-vivo histology and then we transferred the annotations to the post-LITT MRI using semi-automatic elastic registration. The

  11. 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.

  12. 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. Copyright © 2014 Elsevier Ltd. All rights reserved.

  13. County-level hurricane exposure and birth rates: application of difference-in-differences analysis for confounding control.

    PubMed

    Grabich, Shannon C; Robinson, Whitney R; Engel, Stephanie M; Konrad, Charles E; Richardson, David B; Horney, Jennifer A

    2015-01-01

    Epidemiological analyses of aggregated data are often used to evaluate theoretical health effects of natural disasters. Such analyses are susceptible to confounding by unmeasured differences between the exposed and unexposed populations. To demonstrate the difference-in-difference method our population included all recorded Florida live births that reached 20 weeks gestation and conceived after the first hurricane of 2004 or in 2003 (when no hurricanes made landfall). Hurricane exposure was categorized using ≥74 mile per hour hurricane wind speed as well as a 60 km spatial buffer based on weather data from the National Oceanic and Atmospheric Administration. The effect of exposure was quantified as live birth rate differences and 95 % confidence intervals [RD (95 % CI)]. To illustrate sensitivity of the results, the difference-in-differences estimates were compared to general linear models adjusted for census-level covariates. This analysis demonstrates difference-in-differences as a method to control for time-invariant confounders investigating hurricane exposure on live birth rates. Difference-in-differences analysis yielded consistently null associations across exposure metrics and hurricanes for the post hurricane rate difference between exposed and unexposed areas (e.g., Hurricane Ivan for 60 km spatial buffer [-0.02 births/1000 individuals (-0.51, 0.47)]. In contrast, general linear models suggested a positive association between hurricane exposure and birth rate [Hurricane Ivan for 60 km spatial buffer (2.80 births/1000 individuals (1.94, 3.67)] but not all models. Ecological studies of associations between environmental exposures and health are susceptible to confounding due to unmeasured population attributes. Here we demonstrate an accessible method of control for time-invariant confounders for future research.

  14. Biomechanical and psychosocial exposures are independent risk factors for carpal tunnel syndrome: assessment of confounding using causal diagrams.

    PubMed

    Harris-Adamson, Carisa; Eisen, Ellen A; Neophytou, Andreas; Kapellusch, Jay; Garg, Arun; Hegmann, Kurt T; Thiese, Matthew S; Dale, Ann Marie; Evanoff, Bradley; Bao, Stephen; Silverstein, Barbara; Gerr, Fred; Burt, Susan; Rempel, David

    2016-11-01

    Between 2001 and 2010, six research groups conducted coordinated prospective studies of carpal tunnel syndrome (CTS) incidence among US workers from various industries to estimate exposure-response relationships. This analysis examined the presence and magnitude of confounding between biomechanical and workplace psychosocial factors and incidence of dominant-hand CTS. 1605 participants, without CTS at enrolment, were followed for up to 3.5 years (2471 person-years). Demographic information, medical history and workplace psychosocial stress measures were collected at baseline. Individual workplace biomechanical exposures were collected for each task and combined across the workweek using time-weighted averaging (TWA). CTS case criteria were based on symptoms and results of electrophysiological testing. HRs were estimated with Cox proportional hazard models. Confounding was assessed using causal diagrams and an empirical criterion of 10% or greater change in effect estimate magnitude. There were 109 incident CTS cases (IR=4.41/100 person-years; 6.7% cumulative incidence). The relationships between CTS and forceful repetition rate, % time forceful hand exertion and the Threshold Limit Value for Hand Activity Level (TLV-HAL) were slightly confounded by decision latitude with effect estimates being attenuated towards the null (10-14% change) after adjustment. The risk of CTS among participants reporting high job strain was attenuated towards the null by 14% after adjusting for the HAL Scale or the % time forceful hand exertions. Although attenuation of the relationships between CTS and some biomechanical and work psychosocial exposures was observed after adjusting for confounding, the magnitudes were small and confirmed biomechanical and work psychosocial exposures as independent risk factors for incident CTS. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  15. 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

  16. Childhood adversity and psychosis: examining whether the association is due to genetic confounding using a monozygotic twin differences approach.

    PubMed

    Alemany, S; Goldberg, X; van Winkel, R; Gastó, C; Peralta, V; Fañanás, L

    2013-05-01

    To test whether the association between childhood adversity and positive and negative psychotic experiences is due to genetic confounding. Childhood adversity and psychotic experiences were assessed in an ongoing sample of 226 twins from the general population. A monozygotic (MZ) twin differences approach was used to assess possible genetic confounding. In the whole sample, childhood adversity was significantly associated with positive (β=45; SE=0.16; P=0.008) and negative psychotic experiences (β=0.77; SE=0.18; P<0.01). Within-pair MZ twin differences in exposure to childhood adversity were significantly associated with differences in positive (β=71; SE=0.29; P=0.016) and negative psychotic experiences (β=98; SE=0.38; P=0.014) in a subsample of 85 MZ twin pairs. Individuals exposed to childhood adversity are more likely to report psychotic experiences. Furthermore, our findings indicate that this association is not due to genetic confounding. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

  17. Is the Association of Subjective SES and Self-Rated Health Confounded by Negative Mood? An Experimental Approach

    PubMed Central

    Kraus, Michael W.; Adler, Nancy; David Chen, Teh-Way

    2012-01-01

    Objective Lower subjective socioeconomic status (SSS) consistently shows associations with poorer health with the strongest relationships emerging with global self-rated health. Though often interpreted as reflecting the impact of low SSS on health, the association could also arise from confounding SSS with negative affect. In this research we sought to determine if negative affect confounds, or alternatively, is on the causal pathway linking SSS to self-rated health. Methods 300 adult participants—recruited from throughout the United States—were randomized to experience sadness, shame, or a neutral mood induction wherein they wrote about and visualized a particularly emotionally evocative event. Participants subsequently completed measures of SSS, self-rated health, depression, and negative mood. Results Consistent with predictions, neither SSS scores nor the association of SSS with self-rated health, depression, and chronic negative affect differed by mood induction condition, controlling for demographic factors that covary with SSS (e.g., age, gender, education, income). Moreover, chronic negative affect partially explained the relationship between SSS and self-rated health, independent of manipulated mood. Conclusions These findings support the utility of the measurement of SSS, and provide evidence suggesting that chronic negative affect is a likely mediator of the SSS association with global health rather than a confounder. PMID:22329426

  18. 'Mechanical restraint-confounders, risk, alliance score': testing the clinical validity of a new risk assessment instrument.

    PubMed

    Deichmann Nielsen, Lea; Bech, Per; Hounsgaard, Lise; Alkier Gildberg, Frederik

    2017-08-01

    Unstructured risk assessment, as well as confounders (underlying reasons for the patient's risk behaviour and alliance), risk behaviour, and parameters of alliance, have been identified as factors that prolong the duration of mechanical restraint among forensic mental health inpatients. To clinically validate a new, structured short-term risk assessment instrument called the Mechanical Restraint-Confounders, Risk, Alliance Score (MR-CRAS), with the intended purpose of supporting the clinicians' observation and assessment of the patient's readiness to be released from mechanical restraint. The content and layout of MR-CRAS and its user manual were evaluated using face validation by forensic mental health clinicians, content validation by an expert panel, and pilot testing within two, closed forensic mental health inpatient units. The three sub-scales (Confounders, Risk, and a parameter of Alliance) showed excellent content validity. The clinical validations also showed that MR-CRAS was perceived and experienced as a comprehensible, relevant, comprehensive, and useable risk assessment instrument. MR-CRAS contains 18 clinically valid items, and the instrument can be used to support the clinical decision-making regarding the possibility of releasing the patient from mechanical restraint. The present three studies have clinically validated a short MR-CRAS scale that is currently being psychometrically tested in a larger study.

  19. 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.

  20. 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

  1. 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.

  2. 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.

  3. 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

  4. 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.

  5. 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

  6. 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

  7. 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.

  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. [Biochemical aspects of chronic rheumatic inflammation].

    PubMed

    Delbrück, A

    1975-01-01

    Morphological phenomena in rheumatoid arthritis are closely correlated to the biochemical aberrations of connective tissue metabolism. Both, morphological and biochemical analysis of the altered tissue portions demonstrate evidence for uncontrolled proliferation resp. metabolism similar to human and experimental malignoma. The present state of biochemical knowledge in this field permits to describe the metabolic state of the afflicted tissue by means of enzyme activity and substrate pattern and to draw some conclusions in respect to the pathogenesis of inflammatory processes involved in chronic rheumatic diseases.

  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. 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.

  12. Metabolomic analysis for the study of maturation in pediatrics: Effect of confounding factors in a pilot study.

    PubMed

    Blanco, María Encarnación; González, Oskar; Albóniga, Oihane Elena; Alonso, María Luz; Alonso, Rosa María

    2017-09-01

    A pilot study for the investigation of the maturation grade of children has been carried out using plasma samples already analyzed in a previous pharmacokinetic study. By using a meticulous data treatment, possible confounding factors that may hinder the obtained results were identified. By doing so, it was possible to obtain enough evidence to support the feasibility of performing a larger study eluding some unwanted variability and minimizing not only the number of subjects involved but also the time and money spent on the study. In the pilot study the metabolic profiles obtained using UHPLC-TOF-MS technique of plasma samples from 14 newborn piglets (<5 days) were compared with the plasma profiles of 16 infant piglets (8 weeks). The type of anaesthesia administered, gender, vein or artery of blood extraction and time of sampling were studied as possible confounding factors. Unsupervised analysis by principal component analysis (PCA) clearly differentiated between neonates and children. During the data treatment and the statistical analysis, the effect of confounding factors such as the anaesthetic regimen was identified and removed, while the effect of the rest of studied factors was not considered relevant, and the discrimination between the two groups based on the age was maintained. This allowed extracting relevant conclusions for a future study design while avoiding the unnecessary sacrifice of animals. Furthermore, the results obtained demonstrate the utility of metabolomics in the discovery of novel putative plasma biomarkers such as carnitines that can be correlated with the maturation state of paediatric patients. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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

    PubMed

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

    2015-01-01

    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. 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. 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). 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.

  14. Brief Communication: Latent toxoplasmosis and salivary testosterone concentration--important confounding factors in second to fourth digit ratio studies.

    PubMed

    Flegr, Jaroslav; Lindová, Jitka; Pivoñková, Vera; Havlícek, Jan

    2008-12-01

    A sexually dimorphic characteristic, the second to fourth digit ratio (2D:4D ratio), has been shown to reflect the prenatal concentration of sex steroid hormones and to correlate with many personality, physiological, and life history traits. The correlations are usually stronger for the right than the left hand. Most studies have shown that the 2D:4D ratio does not vary with age or postnatal concentration of sex steroid hormones. Recently, a strong association between left hand 2D:4D ratio and infection with a common human parasite Toxoplasma has been reported. We hypothesized that the confounding effect of Toxoplasma infection on left hand 2D:4D ratio could be responsible for the stronger association between different traits and right hand rather than left hand 2D:4D ratio. This confounding effect of toxoplasmosis could also be responsible for the difficulty in finding an association between 2D:4D ratio and age or postnatal steroid hormone concentration. To test this hypothesis, we analyzed the association between sex and age and 2D:4D ratio in a population of 194 female and 106 male students with and without controlling for the confounding variables of Toxoplasma infection and testosterone concentration. Our results showed that the relationship between age and sex and 2D:4D ratio increased sharply when Toxoplasma infection and testosterone concentration were controlled. These results suggest that left hand 2D:4D ratio is more susceptible to postnatal influences and that the confounding factors of Toxoplasma infection, testosterone concentration and possibly also age, should be controlled in future 2D:4D ratio studies. Because of a stronger 2D:4D dimorphism in Toxoplasma-infected than Toxoplasma-free subjects, we predict that 2D:4D ratio dimorphism as well as right hand/left hand 2D:4D ratio dimorphism will be higher in countries with a high prevalence of Toxoplasma infection than in those with a low prevalence. (c) 2008 Wiley-Liss, Inc.

  15. 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.

  16. 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

    2016-01-01

    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 CT scans performed in children. We identify CSS predisposing to leukemia and brain tumors through a systematic literature search and summarize prevalence and risk estimates. Because there is virtually no empirical evidence 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 the current and previous patterns of CT scans among CSS patients. We estimate that radiation-related RRs for leukemia are not meaningfully confounded by Down syndrome, Noonan syndrome, or other CSS. In contrast, RRs for brain tumors may be overestimated due to confounding by tuberous sclerosis complex (TSC) while von Hippel-Lindau disease, neurofibromatosis type 1, or other CSS do not meaningfully confound. Empirical data on the use of CT scans among CSS patients are urgently needed. Our assessment indicates that associations with leukemia reported in previous studies are unlikely to be substantially confounded by unmeasured CSS, whereas brain tumor risks might have been overestimated due to confounding by TSC. Future studies should identify TSC patients in order to avoid overestimation of brain tumor risks due to radiation exposure from CT scans. ©2015 American Association for Cancer Research.

  17. [Biochemical aspects of fetal hypoxia].

    PubMed

    Biringer, K; Danko, J; Dókus, K; Mat'asová, K; Zibolen, M; Pullmann, R

    2011-09-01

    To evaluate validity of biochemical diagnostic methods of fetal hypoxia. A case-control study. Department of Gynecology and Obstetrics, Jessenius Faculty of Medicine, Comenius University, Martin, Slovak Republic. We included 67 patients, and they were retrospectively divided into group of controls (n=36), and studied group (n=31) according to pH in umbilical artery (UA) <7.15. Acid-base parameters were assessed with Rapidlab 248, Bayer Healthcare LLC, East Walpole, USA. We determined criterion for metabolic acidosis (MAC) as pH UA <7.15, resp. base deficit (BD) UA >12 mmol/l. Postpartal lactate concentration in umbilical vein (UV) and UA was determined with lactatemeter Accutrend Lactate, Roche Diagnostics, Switzerland. Quantitative assessment of fetal human protein S100B was provided with ELISA (Sangtec 100 ELISA, DiaSorin Inc., Stillwater, Minnesota, USA). Fetal erythropoietin concentration in UV was examined with immunoenzymatic assessment Access EPO (Beckman Coulter, Inc., Fullerton, CA, USA). histograms, Kolmogorov-Smirnov test, Mann-Whitney test, Spearman's rho; statistical significance: p<0.05, Receiver Operating Characteristic curves, Area Under the Curve. The best correlation was between fetal acid-base parameters and lactate in UA (p<0.0005). Significant correlation was between EPO in UV, and protein S100B in UV (p<0.05). EPO in UV significantly correlated with lactate in UA (p<0.05). Correlation between EPO in UV and protein S100B was not significant. According to ROC curves in prediction of fetal hypoxia, we found an excellent accuracy (AUC>0.9) for lactate in UA, good accuracy (AUC>0.7) had EPO in UV. Results for protein S100B were not significant. The highest sensitivity had EPO in UV, while the highest specificity has had lactate in UA. An indisputable evidence of labor management quality is the fetal metabolic status. On the basis of our results, the suitable clinical markers are lactate and EPO, in addition to acid-base parameters.

  18. Biochemical thermodynamics: applications of Mathematica.

    PubMed

    Alberty, Robert A

    2006-01-01

    reactants. Thus loading this package makes available 774 mathematical functions for these properties. These functions can be added and subtracted to obtain changes in these properties in biochemical reactions and apparent equilibrium constants.

  19. 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)

  20. 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)

  1. 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.

  2. 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)

  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. 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

  5. [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.

  6. Association of C-reactive protein with blood pressure and hypertension: life course confounding and mendelian randomization tests of causality.

    PubMed

    Davey Smith, George; Lawlor, Debbie A; Harbord, Roger; Timpson, Nic; Rumley, Ann; Lowe, Gordon D O; Day, Ian N M; Ebrahim, Shah

    2005-05-01

    C-reactive protein (CRP) has repeatedly been associated with blood pressure and prevalent and incident hypertension, but whether a causal link exists is uncertain. We assessed the cross-sectional relations of CRP to systolic blood pressure, pulse pressure, and prevalent hypertension in a representative sample of >3500 British women aged 60 to 79 years. For both outcomes, substantial associations were observed. However, these associations were greatly attenuated by adjustment for a wide range of confounding factors acting over the life course. We further investigated causality using a Mendelian randomization approach by examining the association of the 1059G/C polymorphism in the human CRP gene with CRP and with blood pressure, pulse pressure, and hypertension. The polymorphism was associated with a robust difference in CRP, and the expectation would be for higher blood pressure and pulse pressure and greater prevalence of hypertension among those carrying the genetic variant associated with higher CRP levels. This was not observed, and the predicted causal effects of CRP on blood pressure, pulse pressure, and hypertension using instrumental variables methods were close to 0, although with wide CIs. CRP levels are associated with blood pressure, pulse pressure, and hypertension, but adjustment for life course confounding and a Mendelian randomization approach suggest the elevated CRP levels do not lead to elevated blood pressure.

  7. 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.

  8. 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.

  9. 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.

  10. The obesity paradox in stable chronic heart failure does not persist after matching for indicators of disease severity and confounders.

    PubMed

    Frankenstein, Lutz; Zugck, Christian; Nelles, Manfred; Schellberg, Dieter; Katus, Hugo A; Remppis, B Andrew

    2009-12-01

    To verify whether controlling for indicators of disease severity and confounders represents a solution to the obesity paradox in chronic heart failure (CHF). From a cohort of 1790 patients, we formed 230 nested matched triplets by individually matching patients with body mass index (BMI) > 30 kg/m(2) (Group 3), BMI 20-24.9 k/m(2) (Group 1) and BMI 25-29.9 kg/m(2) (Group 2), according to NT-proBNP, age, sex, and NYHA class (triplet = one matched patient from each group). Although in the pre-matching cohort, BMI group was a significant univariable prognostic indicator, it did not retain significance [heart rate (HR): 0.91, 95% CI: 0.78-1.05, chi(2): 1.67] when controlled for group propensities as covariates. Furthermore, in the matched cohort, 1-year mortality and 3-year mortality did not differ significantly. Here, BMI again failed to reach statistical significance for prognosis, either as a continuous or categorical variable, whether crude or adjusted. This result was confirmed in the patients not selected for matching. NT-proBNP, however, remained statistically significant (log(NT-proBNP): HR: 1.49, 95% CI: 1.13-1.97, chi(2): 7.82) after multivariable adjustment. The obesity paradox does not appear to persist in a matched setting with respect to indicators of disease severity and other confounders. NT-proBNP remains an independent prognostic indicator of adverse outcome irrespective of obesity status.

  11. 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.

  12. 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.

  13. 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

  14. Age and preoperative pain are major confounders for sex differences in postoperative pain outcome: A prospective database analysis

    PubMed Central

    Yahiaoui-Doktor, Maryam; Meissner, Winfried; Van Aken, Hugo; Zahn, Peter

    2017-01-01

    Objectives Current literature is in disagreement regarding female sex as a risk factor for pain after surgery. We hypothesized, that sex differences exist but that they are influenced by certain factors. Here, we investigated the influence of sex for different clinically relevant postoperative pain (POP) outcome parameters and evaluated the role of assumed confounders for sex differences. Methods From 1372 screened patients undergoing orthopedic surgery at the university hospital of Muenster between March 2010 and June 2011, 890 patients were included. The validated International Pain Outcomes questionnaire was used to assess the role of sex for several aspects of POP including pain severity, physical and emotional functional interference as well as the patient’s perceptions of the care they received on the first day after surgery. Assessed confounders were age, preoperative chronic pain, anesthetic technique employed and surgical procedure. All statistical analyses were performed with SPSS Statistics Software 22. Results Linear regression analysis demonstrated that sex was a statistically significant risk factor for “worst pain since surgery”. Additionally, significant sex differences in “time spent in severe pain”, “feeling anxious due to pain”, “feeling helpless due to pain” and “opioid consumption since surgery” could be identified. An univariate general linear model showed that “age” and “preoperative pain” were significant confounders for sex differences. Further descriptive subgroup analysis revealed consistent sex differences for several POP outcome variables especially in patients older than 50 years or patients with preoperative chronic pain. However, sex differences disappeared in younger patients and in patients without preoperative pain. Discussion Our data confirmed that sex differences exist in pain intensity and frequency, pain interference with feelings and opioid consumption during the first 24 hours postoperatively

  15. 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

  16. 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.

  17. 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.

  18. 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.

  19. 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

  20. 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 (a...

  1. 40 CFR 158.2010 - Biochemical pesticides 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 data...) PESTICIDE PROGRAMS DATA REQUIREMENTS FOR PESTICIDES Biochemical Pesticides § 158.2010 Biochemical pesticides... required to support registration of biochemical pesticides. Sections 158.2080 through 158.2084 identify the...

  2. 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 (a...

  3. 40 CFR 158.2010 - Biochemical pesticides 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 data...) PESTICIDE PROGRAMS DATA REQUIREMENTS FOR PESTICIDES Biochemical Pesticides § 158.2010 Biochemical pesticides... required to support registration of biochemical pesticides. Sections 158.2080 through 158.2084 identify the...

  4. 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 (a...

  5. 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 (a...

  6. 40 CFR 158.2010 - Biochemical pesticides 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 data...) PESTICIDE PROGRAMS DATA REQUIREMENTS FOR PESTICIDES Biochemical Pesticides § 158.2010 Biochemical pesticides... required to support registration of biochemical pesticides. Sections 158.2080 through 158.2084 identify the...

  7. 40 CFR 158.2010 - Biochemical pesticides 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 data...) PESTICIDE PROGRAMS DATA REQUIREMENTS FOR PESTICIDES Biochemical Pesticides § 158.2010 Biochemical pesticides... required to support registration of biochemical pesticides. Sections 158.2080 through 158.2084 identify the...

  8. 40 CFR 158.2010 - Biochemical pesticides 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 data...) PESTICIDE PROGRAMS DATA REQUIREMENTS FOR PESTICIDES Biochemical Pesticides § 158.2010 Biochemical pesticides... required to support registration of biochemical pesticides. Sections 158.2080 through 158.2084 identify the...

  9. 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 (a...

  10. Risk of bias and confounding of observational studies of Zika virus infection: A scoping review of research protocols

    PubMed Central

    Haby, Michelle M.; Martínez-Vega, Ruth; Pinzón-Flores, Carlos E.; Smith, Emma; Pinart, Mariona; Broutet, Nathalie; Becerra-Posada, Francisco; Aldighieri, Sylvain; Van Kerkhove, Maria D.

    2017-01-01

    Introduction Given the severity and impact of the current Zika virus (ZIKV) outbreak in the Americas, numerous countries have rushed to develop research studies to assess ZIKV and its potential health consequences. In an effort to ensure that studies are comprehensive, both internally and externally valid, and with reliable results, the World Health Organization, the Pan American Health Organization, Institut Pasteur, the networks of Fiocruz, the Consortia for the Standardization of Influenza Seroepidemiology (CONSISE) and the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) have generated six standardized clinical and epidemiological research protocols and questionnaires to address key public health questions on ZIKV. Methods We conducted a systematic search of ongoing study protocols related to ZIKV research. We analyzed the content of protocols of 32 cohort studies and 13 case control studies for systematic bias that could produce erroneous results. Additionally we aimed to characterize the risks of bias and confounding in observational studies related to ZIKV and to propose ways to minimize them, including the use of six newly standardized research protocols. Results Observational studies of ZIKV face an array of challenges, including measurement of exposure and outcomes (microcephaly and Guillain-Barré Syndrome). Potential confounders need to be measured where known and controlled for in the analysis. Selection bias due to non-random selection is a significant issue, particularly in the case-control design, and losses to follow-up is equally important for the cohort design. Conclusion Observational research seeking to answer key questions on the ZIKV should consider these restrictions and take precautions to minimize bias in an effort to provide reliable and valid results. Utilization of the standardized research protocols developed by the WHO, PAHO, Institut Pasteur, and CONSISE will harmonize the key methodological aspects

  11. Confounding factors for early death in incident end-stage renal disease patients: Role of emergency dialysis start.

    PubMed

    Descamps, Chrystèle; Labeeuw, Michel; Trolliet, Pierre; Cahen, Rémi; Ecochard, René; Pouteil-Noble, Claire; Villar, Emmanuel

    2011-01-01

    Hemodialysis (HD) has been associated with higher 1-year mortality than peritoneal dialysis (PD) after dialysis start. Confounding effects of late referral, emergency dialysis start, or start with central venous catheter on this association have never been studied concomitantly. Survival was studied among the 495 incident dialysed patients in our department from 1995 to 2006 and followed at least 1 year until December 31, 2007. Nested Cox models adjusted on patient characteristics explored factors associated with 1-year and ≥1-year mortality. Hemodialysis patients were 332 (67.1%), 104 (21.0%) were late referred (<6 months), 167 (33.7%) started dialysis in emergency, and 144 (29.1%) started with central venous catheter. When adjusted only on age, sex, and comorbidities, HD was associated with poor 1-year outcome: adjusted hazard ratio (aHR) for death in HD vs. PD was 1.77, P=0.02. In fully adjusted model, among first dialysis feature variables, only emergency dialysis start was significantly associated with 1-year mortality: aHR 1.53, P=0.02. Dialysis modality was not associated with 1-year mortality rates in this fully adjusted model: aHR in HD vs. PD became 1.03, P=0.91. In ≥1-year period, HD was associated with lower mortality than PD (aHR 0.61, P=0.004), whereas other first dialysis features were not associated with death. Other factors associated with death were age, type 2 diabetes, peripheral vascular disease, heart failure, and hepatic failure. Negative association between HD and 1-year survival on dialysis was explained by confounders. Emergency dialysis start was strongly associated with early mortality on dialysis. Its prevention may improve patient survival. © 2011 The Authors. Hemodialysis International © 2011 International Society for Hemodialysis.

  12. 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.

  13. 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.

  14. Risk of bias and confounding of observational studies of Zika virus infection: A scoping review of research protocols.

    PubMed

    Reveiz, Ludovic; Haby, Michelle M; Martínez-Vega, Ruth; Pinzón-Flores, Carlos E; Elias, Vanessa; Smith, Emma; Pinart, Mariona; Broutet, Nathalie; Becerra-Posada, Francisco; Aldighieri, Sylvain; Van Kerkhove, Maria D

    2017-01-01

    Given the severity and impact of the current Zika virus (ZIKV) outbreak in the Americas, numerous countries have rushed to develop research studies to assess ZIKV and its potential health consequences. In an effort to ensure that studies are comprehensive, both internally and externally valid, and with reliable results, the World Health Organization, the Pan American Health Organization, Institut Pasteur, the networks of Fiocruz, the Consortia for the Standardization of Influenza Seroepidemiology (CONSISE) and the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) have generated six standardized clinical and epidemiological research protocols and questionnaires to address key public health questions on ZIKV. We conducted a systematic search of ongoing study protocols related to ZIKV research. We analyzed the content of protocols of 32 cohort studies and 13 case control studies for systematic bias that could produce erroneous results. Additionally we aimed to characterize the risks of bias and confounding in observational studies related to ZIKV and to propose ways to minimize them, including the use of six newly standardized research protocols. Observational studies of ZIKV face an array of challenges, including measurement of exposure and outcomes (microcephaly and Guillain-Barré Syndrome). Potential confounders need to be measured where known and controlled for in the analysis. Selection bias due to non-random selection is a significant issue, particularly in the case-control design, and losses to follow-up is equally important for the cohort design. Observational research seeking to answer key questions on the ZIKV should consider these restrictions and take precautions to minimize bias in an effort to provide reliable and valid results. Utilization of the standardized research protocols developed by the WHO, PAHO, Institut Pasteur, and CONSISE will harmonize the key methodological aspects of each study design to minimize bias at

  15. Neuroticism explains unwanted variance in Implicit Association Tests of personality: possible evidence for an affective valence confound

    PubMed Central

    Fleischhauer, Monika; Enge, Sören; Miller, Robert; Strobel, Alexander; Strobel, Anja

    2013-01-01

    Meta-analytic data highlight the value of the Implicit Association Test (IAT) as an indirect measure of personality. Based on evidence suggesting that confounding factors such as cognitive abilities contribute to the IAT effect, this study provides a first investigation of whether basic personality traits explain unwanted variance in the IAT. In a gender-balanced sample of 204 volunteers, the Big-Five dimensions were assessed via self-report, peer-report, and IAT. By means of structural equation modeling (SEM), latent Big-Five personality factors (based on self- and peer-report) were estimated and their predictive value for unwanted variance in the IAT was examined. In a first analysis, unwanted variance was defined in the sense of method-specific variance which may result from differences in task demands between the two IAT block conditions and which can be mirrored by the absolute size of the IAT effects. In a second analysis, unwanted variance was examined in a broader sense defined as those systematic variance components in the raw IAT scores that are not explained by the latent implicit personality factors. In contrast to the absolute IAT scores, this also considers biases associated with the direction of IAT effects (i.e., whether they are positive or negative in sign), biases that might result, for example, from the IAT's stimulus or category features. None of the explicit Big-Five factors was predictive for method-specific variance in the IATs (first analysis). However, when considering unwanted variance that goes beyond pure method-specific variance (second analysis), a substantial effect of neuroticism occurred that may have been driven by the affective valence of IAT attribute categories and the facilitated processing of negative stimuli, typically associated with neuroticism. The findings thus point to the necessity of using attribute category labels and stimuli of similar affective valence in personality IATs to avoid confounding due to recoding. PMID

  16. Accounting for the Confound of Meninges in Segmenting Entorhinal and Perirhinal Cortices in T1-Weighted MRI

    PubMed Central

    Wisse, Laura E.M.; Das, Sandhitsu R.; Wang, Hongzhi; Wolk, David A.; Manjón, Jose V.; Yushkevich, Paul A.

    2017-01-01

    Quantification of medial temporal lobe (MTL) cortices, including entorhinal cortex (ERC) and perirhinal cortex (PRC), from in vivo MRI is desirable for studying the human memory system as well as in early diagnosis and monitoring of Alzheimer’s disease. However, ERC and PRC are commonly over-segmented in T1-weighted (T1w) MRI because of the adjacent meninges that have similar intensity to gray matter in T1 contrast. This introduces errors in the quantification and could potentially confound imaging studies of ERC/PRC. In this paper, we propose to segment MTL cortices along with the adjacent meninges in T1w MRI using an established multi-atlas segmentation framework together with super-resolution technique. Experimental results comparing the proposed pipeline with existing pipelines support the notion that a large portion of meninges is segmented as gray matter by existing algorithms but not by our algorithm. Cross-validation experiments demonstrate promising segmentation accuracy. Further, agreement between the volume and thickness measures from the proposed pipeline and those from the manual segmentations increase dramatically as a result of accounting for the confound of meninges. Evaluated in the context of group discrimination between patients with amnestic mild cognitive impairment and normal controls, the proposed pipeline generates more biologically plausible results and improves the statistical power in discriminating groups in absolute terms comparing to other techniques using T1w MRI. Although the performance of the proposed pipeline is inferior to that using T2-weighted MRI, which is optimized to image MTL sub-structures, the proposed pipeline could still provide important utilities in analyzing many existing large datasets that only have T1w MRI available. PMID:28752156

  17. 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.

  18. 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. © 2016 John Wiley & Sons Ltd.

  19. Accounting for the Confound of Meninges in Segmenting Entorhinal and Perirhinal Cortices in T1-Weighted MRI.

    PubMed

    Xie, Long; Wisse, Laura E M; Das, Sandhitsu R; Wang, Hongzhi; Wolk, David A; Manjón, Jose V; Yushkevich, Paul A

    2016-10-01

    Quantification of medial temporal lobe (MTL) cortices, including entorhinal cortex (ERC) and perirhinal cortex (PRC), from in vivo MRI is desirable for studying the human memory system as well as in early diagnosis and monitoring of Alzheimer's disease. However, ERC and PRC are commonly over-segmented in T1-weighted (T1w) MRI because of the adjacent meninges that have similar intensity to gray matter in T1 contrast. This introduces errors in the quantification and could potentially confound imaging studies of ERC/PRC. In this paper, we propose to segment MTL cortices along with the adjacent meninges in T1w MRI using an established multi-atlas segmentation framework together with super-resolution technique. Experimental results comparing the proposed pipeline with existing pipelines support the notion that a large portion of meninges is segmented as gray matter by existing algorithms but not by our algorithm. Cross-validation experiments demonstrate promising segmentation accuracy. Further, agreement between the volume and thickness measures from the proposed pipeline and those from the manual segmentations increase dramatically as a result of accounting for the confound of meninges. Evaluated in the context of group discrimination between patients with amnestic mild cognitive impairment and normal controls, the proposed pipeline generates more biologically plausible results and improves the statistical power in discriminating groups in absolute terms comparing to other techniques using T1w MRI. Although the performance of the proposed pipeline is inferior to that using T2-weighted MRI, which is optimized to image MTL sub-structures, the proposed pipeline could still provide important utilities in analyzing many existing large datasets that only have T1w MRI available.

  20. Reanalysis of mortality from lung cancer among diatomaceous earth industry workers, with consideration of potential confounding by asbestos exposure.

    PubMed Central

    Checkoway, H; Heyer, N J; Demers, P A; Gibbs, G W

    1996-01-01

    OBJECTIVE: To evaluate the potential for confounding from asbestos exposure, primarily chrysotile, on the relation between crystalline silica and mortality from lung cancer among diatomaceous earth (diatomite) workers. METHODS: A reanalysis of a cohort mortality study of diatomite workers was performed to take into account quantitative estimates of asbestos exposure. The reanalysis was limited to a subset of the original cohort, comprising 2266 white men for whom asbestos exposure could be reconstructed with greatest confidence. Comparisons between mortality from lung cancer (standardised mortality ratios (SMR)) were made between rates for 1942-87 for United States white men, and workers cross classified according to cumulative exposures to crystalline silica and asbestos. Comparisons of internal rates, involving Poisson regression modeling, were conducted for exposure to crystalline silica, with and without adjustment for asbestos exposure. Exposures were lagged by 15 years to take into account disease latency. RESULTS: There was an overall excess of lung cancer (SMR 1.41; 52 observed). The SMRs for four categories of increasing crystalline silica among the workers not exposed to asbestos were 1.13, 0.87, 2.14, 2.00. An SMR of 8.31 (three observed) was found for workers with the highest cumulative exposure to both dusts. Internal analysis, after adjustment for asbestos exposure, yielded rate ratios for categories of exposure to crystalline silica: 1.00 (reference), 1.37, 1.80, and 1.79. CONCLUSIONS: Asbestos exposure was not an important confounder of the association between crystalline silica and mortality from lung cancer in this cohort. Although based on a small number of deaths from lung cancer, the data suggest possible synergy between these exposures. An extended follow up of this cohort is in progress and should enable better assessments of independent and combined effects on risk of lung cancer. PMID:8882123

  1. 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.

  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. Simulation of cellular biochemical system kinetics.

    PubMed

    Beard, Daniel A

    2011-01-01

    The goal of realistically and reliably simulating the biochemical processes underlying cellular function is achievable through a systematic approach that makes use of the broadest possible amount of in vitro and in vivo data, and is consistent with all applicable physical chemical theories. Progress will be facilitated by establishing: (1) a concrete self-consistent theoretical foundation for systems simulation; (2) extensive and accurate databases of thermodynamic properties of biochemical reactions; (3) parameterized and validated models of enzyme and transporter catalytic mechanisms that are consistent with physical chemical theoretical foundation; and (4) software tools for integrating all these concepts, data, and models into a cohesive representation of cellular biochemical systems. Ongoing initiatives are laying the groundwork for the broad-based community cooperation that will be necessary to pursue these elements of a strategic infrastructure for systems simulation on a large scale. Copyright © 2010 John Wiley & Sons, Inc.

  4. eQuilibrator—the biochemical thermodynamics calculator

    PubMed Central

    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. PMID:22064852

  5. Biochemical characteristics among Mycobacterium bovis BCG substrains.

    PubMed

    Hayashi, Daisuke; Takii, Takemasa; Mukai, Tetsu; Makino, Masahiko; Yasuda, Emi; Horita, Yasuhiro; Yamamoto, Ryuji; Fujiwara, Akiko; Kanai, Keita; Kondo, Maki; Kawarazaki, Aya; Yano, Ikuya; Yamamoto, Saburo; Onozaki, Kikuo

    2010-05-01

    In order to evaluate the biochemical characteristics of 14 substrains of Mycobacterium bovis bacillus Calmette Guérin (BCG) - Russia, Moreau, Japan, Sweden, Birkhaug, Danish, Glaxo, Mexico, Tice, Connaught, Montreal, Phipps, Australia and Pasteur - we performed eight different biochemical tests, including those for nitrate reduction, catalase, niacin accumulation, urease, Tween 80 hydrolysis, pyrazinamidase, p-amino salicylate degradation and resistance to thiophene 2-carboxylic acid hydrazide. Catalase activities of the substrains were all low. Data for nitrate reduction, niacin accumulation, Tween 80 hydrolysis, susceptibility to hydrogen peroxide and nitrate, and optimal pH for growth were all variable among these substrains. These findings suggest that the heterogeneities of biochemical characteristics are relevant to the differences in resistance of BCG substrains to environmental stress. The study also contributes to the re-evaluation of BCG substrains for use as vaccines.

  6. Biochemical Screening for in utero Drug Exposure.

    PubMed

    Wright, Tricia E

    2015-01-01

    Licit and illicit drug use is a common complication of pregnancy. Accurate information on drug use is difficult to obtain for many reasons as women fear self-disclosure or consenting for drug testing due to stigma, guilt, and fear of social and legal harm. As information about drug use is clinically very important, biochemical testing is an important adjunct to careful maternal history. In addition, research studies depend on accurate measures of exposure when reporting risks of a substance. This paper delineates available matrices for and methods of biochemical drug testing in pregnant women and neonates.

  7. [Experimental testing of micro biochemical analytical system].

    PubMed

    Chen, Gang; Wen, Zhi-yu; Wen, Zhong-quan; Xu, Yi; Li, Xia; Jiang, Zi-ping

    2005-03-01

    A micro biochemical analytical system based on a micro fiber spectrometer is introduced. Experiment was carried out to calibrate and test the analysis system. In the experiment, the absorption spectra of Fe2+ -ferroin solution bodies with different concentrations were obtained. The working curve shows a fine linearity of the analysis system. The authors also compared the experimental results obtained from 722-spectrometer and those from our analysis system. It was shown that their system can meet the requirement of practical use. This system also has many advantages, such as real-time whole spectrum analyzing and small volume, and is an ideal instrument for biochemical analysis.

  8. 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…

  9. 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…

  10. 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.

  11. 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)

  12. 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…

  13. Metabonomics and medicine: the Biochemical Oracle.

    PubMed

    Mitchell, Steve; Holmes, Elaine; Carmichael, Paul

    2002-10-01

    Occasionally, a new idea emerges that has the potential to revolutionize an entire field of scientific endeavour. It is now within our grasp to be able to detect subtle perturbations within the phenomenally complex biochemical matrix of living organisms. The discipline of metabonomics promises an all-encompassing approach to understanding total, yet fundamental, changes occurring in disease processes, drug toxicity and cell function.

  14. Biochemical Approaches to Improved Nitrogen Fixation

    USDA-ARS?s Scientific Manuscript database

    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...

  15. 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…

  16. 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)

  17. 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…

  18. 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

  19. 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…

  20. 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.

  1. Biochemical reactions of ozone in plants

    Treesearch

    J. Brian Mudd

    1998-01-01

    Plants react biochemically to ozone in three phases: with constitutive chemicals in the apoplastic fluid and cell membranes; by forming messenger molecules by the affected constitutive materials (ethylene); and by responding to the messenger molecules with pathogenic RNAs and proteins. For instance, plant reactions with ozone result in constitutive molecules such as...

  2. 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.

  3. PHOSPHATE BINDER USE AND MORTALITY AMONG HEMODIALYSIS PATIENTS IN THE DOPPS: EVALUATION OF POSSIBLE CONFOUNDING BY NUTRITIONAL STATUS

    PubMed Central

    Lopes, Antonio Alberto; Tong, Lin; Thumma, Jyothi; Li, Yun; Fuller, Douglas S.; Morgenstern, Hal; Bommer, Jürgen; Kerr, Peter G; Tentori, Francesca; Akiba, Takashi; Gillespie, Brenda; Robinson, Bruce M.; Port, Friedrich K; Pisoni, Ronald L.

    2014-01-01

    residual confounding. Conclusions Longer survival and better nutritional status were observed for MHD patients prescribed PBs and in facilities with greater percentage PB prescription. Understanding the mechanisms for explaining this effect and ruling out possible residual confounding require additional research. PMID:22385781

  4. Effect of confounding variables on hemodynamic response function estimation using averaging and deconvolution analysis: An event-related NIRS study.

    PubMed

    Aarabi, Ardalan; Osharina, Victoria; Wallois, Fabrice

    2017-07-15

    Slow and rapid event-related designs are used in fMRI and functional near-infrared spectroscopy (fNIRS) experiments to temporally characterize the brain hemodynamic response to discrete events. Conventional averaging (CA) and the deconvolution method (DM) are the two techniques commonly used to estimate the Hemodynamic Response Function (HRF) profile in event-related designs. In this study, we conducted a series of simulations using synthetic and real NIRS data to examine the effect of the main confounding factors, including event sequence timing parameters, different types of noise, signal-to-noise ratio (SNR), temporal autocorrelation and temporal filtering on the performance of these techniques in slow and rapid event-related designs. We also compared systematic errors in the estimates of the fitted HRF amplitude, latency and duration for both techniques. We further compared the performance of deconvolution methods based on Finite Impulse Response (FIR) basis functions and gamma basis sets. Our results demonstrate that DM was much less sensitive to confounding factors than CA. Event timing was the main parameter largely affecting the accuracy of CA. In slow event-related designs, deconvolution methods provided similar results to those obtained by CA. In rapid event-related designs, our results showed that DM outperformed CA for all SNR, especially above -5 dB regardless of the event sequence timing and the dynamics of background NIRS activity. Our results also show that periodic low-frequency systemic hemodynamic fluctuations as well as phase-locked noise can markedly obscure hemodynamic evoked responses. Temporal autocorrelation also affected the performance of both techniques by inducing distortions in the time profile of the estimated hemodynamic response with inflated t-statistics, especially at low SNRs. We also found that high-pass temporal filtering could substantially affect the performance of both techniques by removing the low-frequency components of

  5. 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. Copyright © 2016 Elsevier Inc. All rights reserved.

  6. 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.

  7. 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.

  8. Pattern classification of brain activation during emotional processing in subclinical depression: psychosis proneness as potential confounding factor.

    PubMed

    Modinos, Gemma; Mechelli, Andrea; Pettersson-Yeo, William; Allen, Paul; McGuire, Philip; Aleman, Andre

    2013-01-01

    We used Support Vector Machine (SVM) to perform multivariate pattern classification based on brain activation during emotional processing in healthy participants with subclinical depressive symptoms. Six-hundred undergraduate students completed the Beck Depression Inventory II (BDI-II). Two groups were subsequently formed: (i) subclinical (mild) mood disturbance (n = 17) and (ii) no mood disturbance (n = 17). Participants also completed a self-report questionnaire on subclinical psychotic symptoms, the Community Assessment of Psychic Experiences Questionnaire (CAPE) positive subscale. The functional magnetic resonance imaging (fMRI) paradigm entailed passive viewing of negative emotional and neutral scenes. The pattern of brain activity during emotional processing allowed correct group classification with an overall accuracy of 77% (p = 0.002), within a network of regions including the amygdala, insula, anterior cingulate cortex and medial prefrontal cortex. However, further analysis suggested that the classification accuracy could also be explained by subclinical psychotic symptom scores (correlation with SVM weights r = 0.459, p = 0.006). Psychosis proneness may thus be a confounding factor for neuroimaging studies in subclinical depression.

  9. 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.

  10. 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.

  11. 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.

  12. Octopus visual system: a functional MRI model for detecting neuronal electric currents without a blood-oxygen-level-dependent confound.

    PubMed

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

    2014-11-01

    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 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. 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. 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. 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. Copyright © 2013 Wiley Periodicals, Inc.

  13. 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.

  14. Ecstasy use and higher-level cognitive functions: weak effects of ecstasy after control for potential confounds.

    PubMed

    Bedi, G; Redman, J

    2008-09-01

    Although there have been several reports linking ecstasy use with lowered cognitive function, much previous research suffers from substantial methodological limitations. The present study aimed to examine associations between ecstasy use and higher-level cognitive functions, using a larger sample size than most previous research and better controlling for a range of potential confounds. A cross-sectional cohort design assessed 45 currently abstinent ecstasy polydrug users (EP), 48 cannabis polydrug users (CP) and 40 legal drug users (LD). Standardized neuropsychological tests were used to measure attention, verbal, visual and working memory and executive function. Prospective memory function was also assessed. It was not possible to discriminate between groups on the basis of the cognitive functions assessed. Regression analyses showed an inverse association between lifetime dose of ecstasy and verbal memory performance. A combination of drug-use variables, including measures of ecstasy use, contributed to prediction of attention/working memory. However, individual associations were small, explaining 1-6% of variance in cognitive scores. Although the results suggest that heavy use of ecstasy is associated with some lowering of higher-level cognitive functions, they do not indicate a clinical picture of substantial cognitive dysfunction.

  15. Rectal versus non-rectal primary signet ring cell carcinoma of the colorectum: a retrospective survival analysis controlled for confounders.

    PubMed

    Ciarrocchi, Andrea

    2014-09-01

    Our objective was to compare the outcomes of rectal and non-rectal primary signet ring cell adenocarcinoma of the colorectum. A retrospective survival analysis was performed using the Surveillance, Epidemiology, and End Results Program database between 2004 and 2009 on subjects who were diagnosed as having a primary signet ring cell carcinoma of the colorectum. Cox proportional hazard regression analysis controlled for confounders was used to assess overall survival comparing rectal and non-rectal cancers. Our population was composed of 1,484 patients: 200 affected by rectal cancer and 1,284 by non-rectal cancer. Unadjusted survival curves resulted to be almost superimposable (P = 0.916). After controlling for age, gender, race, tumor stage, grade, and size, tumor location demonstrated a statistically significant impact on overall survival (P = 0.032; 95% confidence interval 0.640-0.980; hazard ratio 0.792). On the basis of analysis of information from the SEER database, the signet ring cell carcinoma of the rectum was associated to a worse prognosis as compared to non-rectal cancer.

  16. 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

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

    PubMed

    He, Tao; Ding, Yun; Wang, Zhiguo

    2015-11-13

    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.

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

    PubMed

    Blocker, Tomica D; Ophir, Alexander G

    2013-06-01

    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.

  19. 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

  20. Identifying confounds to increase specificity during a "no task condition". Evidence for hippocampal connectivity using fMRI.

    PubMed

    Rombouts, S A R B; Stam, C J; Kuijer, J P A; Scheltens, Ph; Barkhof, F

    2003-10-01

    Functional MRI can be applied to study connectivity in the brain during a "no task condition." This study focuses on applying a multiple linear regression analysis to identify spurious connectivity caused by confounding factors such as physiologic noise and to separate these from hippocampal connectivity caused by the blood oxygen level dependent (BOLD) signal during a no-task condition. Regressors of interest (hippocampal time courses) as well as regressors of no interest (respiratory signal and cerebrospinal fluid), were included in the analysis, and each yielded a connectivity map. This method was applied at high sampling rate (limited volume, proper physiologic noise sampling), low sampling rate (whole brain scans possible), and at high and low spatial resolution in five healthy control subjects. Regressors of no interest showed specific connectivity patterns, different from hippocampal regressors. The latter showed connectivity between left and right hippocampus. The current study shows successful application of a multiple regression analysis to study connectivity between left and right hippocampus. Both maps of hippocampal connectivity caused by BOLD signal and connectivity caused by spurious signals could be identified.

  1. A detailed guide for quantification of myocardial scar with the Selvester QRS score in the presence of electrocardiogram confounders.

    PubMed

    Loring, Zak; Chelliah, Sreetharan; Selvester, Ronald H; Wagner, Galen; Strauss, David G

    2011-01-01

    The Selvester QRS score translates subtle changes in ventricular depolarization measured by the electrocardiogram into information about myocardial scar location and size. This estimated scar has been shown to have a high degree of correlation with autopsy-measured myocardial infarct size. In addition, multiple studies have demonstrated the value of the QRS score in post-myocardial infarct patients to provide prognostic information. Recent studies have demonstrated that increasing QRS score is predictive of increased implantable defibrillator shocks for ventricular tachycardia and fibrillation as well as decreased response to cardiac resynchronization therapy. Although QRS scoring has never achieved widespread clinical use, increased interest in patient selection and risk-stratification techniques for implantable defibrillators and cardiac resynchronization therapy has led to renewed interest in QRS scoring and its potential to identify which patients will benefit from device therapy. The QRS score criteria were updated in 2009 to expand their use to a broader population by accounting for the different ventricular depolarization sequences in patients with bundle-branch/fascicular blocks or ventricular hypertrophy. However, these changes also introduced additional complexity and nuance to the scoring procedure. This article provides detailed instructions and examples on how to apply the QRS score criteria in the presence of confounding conduction types to facilitate understanding and enable development and application of automated QRS scoring. Published by Elsevier Inc.

  2. 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

  3. 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

  4. Biochemical and immunohistochemical characterization of Mimosa annexin.

    PubMed

    Hoshino, Daisuke; Hayashi, Asami; Temmei, Yusuke; Kanzawa, Nobuyuki; Tsuchiya, Takahide

    2004-09-01

    To characterize the biochemical properties of plant annexin, we isolated annexin from Mimosa pudica L. and analyzed the biochemical properties conserved between Mimosa annexin and animal annexins, e.g. the ability to bind phospholipid and F-actin in the presence of calcium. We show that Mimosa annexin is distributed in a wide variety of tissues. Immunoblot analysis also revealed that the amount of annexin is developmentally regulated. To identify novel functions of Mimosa annexin, we examined the pattern of distribution and the regulation of its expression in the pulvinus. The amount of annexin in the pulvinus increased at night and was sensitive to abscisic acid; however, there was no detectable induction of annexin by cold or mechanical stimulus. Annexin distribution in the cell periphery during the daytime was changed to a cytoplasmic distribution at night, indicating that Mimosa annexin may contribute to the nyctinastic movement in the pulvinus.

  5. Thermodynamics of biochemical networks and duality theorems.

    PubMed

    De Martino, Daniele

    2013-05-01

    One interesting yet difficult computational issue has recently been posed in biophysics in regard to the implementation of thermodynamic constraints to complex networks. Biochemical networks of enzymes inside cells are among the most efficient, robust, differentiated, and flexible free-energy transducers in nature. How is the second law of thermodynamics encoded for these complex networks? In this article it is demonstrated that for chemical reaction networks in the steady state the exclusion (presence) of closed reaction cycles makes possible (impossible) the definition of a chemical potential vector. Interestingly, this statement is encoded in one of the key results in combinatorial optimization, i.e., the Gordan theorem of the alternatives. From a computational viewpoint, the theorem reveals that calculating a reaction's free energy and identifying infeasible loops in flux states are dual problems whose solutions are mutually exclusive, and this opens the way for efficient and scalable methods to perform the energy balance analysis of large-scale biochemical networks.

  6. 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.

  7. Molecular and biochemical mechanisms of preterm labour.

    PubMed

    Mohan, Aarthi R; Loudon, Jenifer A; Bennett, Phillip R

    2004-12-01

    Parturition involves the synchronization of myometrial activity and structural changes of the cervix, leading to regular co-ordinated uterine contractions and cervical dilatation and effacement. The biochemical events involved in parturition resemble an inflammatory reaction, with growing evidence pointing to a crucial role for pro-inflammatory cytokines and prostaglandins in labour. There is accumulating evidence that there are common mediators involved in the regulation of 'labour-associated proteins', and that, in each case, an increase or decrease in gene expression mediates changes in their concentration. It is possible, therefore, that targeting these common mediators may represent newer strategies for the prevention of preterm labour. Our aim is to review the mechanical and biochemical mechanisms that may be involved in the processes of term and preterm labour. Specifically, we will consider the regulation of some of the 'labour-associated proteins', chemotactic cytokines, prostaglandins and enzymes of the prostaglandin biosynthetic pathway and the oxytocin receptor.

  8. Thermodynamics of Computational Copying in Biochemical Systems

    NASA Astrophysics Data System (ADS)

    Ouldridge, Thomas E.; Govern, Christopher C.; ten Wolde, Pieter Rein

    2017-04-01

    Living cells use readout molecules to record the state of receptor proteins, similar to measurements or copies in typical computational devices. But is this analogy rigorous? Can cells be optimally efficient, and if not, why? We show that, as in computation, a canonical biochemical readout network generates correlations; extracting no work from these correlations sets a lower bound on dissipation. For general input, the biochemical network cannot reach this bound, even with arbitrarily slow reactions or weak thermodynamic driving. It faces an accuracy-dissipation trade-off that is qualitatively distinct from and worse than implied by the bound, and more complex steady-state copy processes cannot perform better. Nonetheless, the cost remains close to the thermodynamic bound unless accuracy is extremely high. Additionally, we show that biomolecular reactions could be used in thermodynamically optimal devices under exogenous manipulation of chemical fuels, suggesting an experimental system for testing computational thermodynamics.

  9. Advances in Biochemical Indices of Zooplankton Production.

    PubMed

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

    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. © 2017 Elsevier Ltd. All rights reserved.

  10. Structural and biochemical characterization of DSL ribozyme.

    PubMed

    Horie, Souta; Ikawa, Yoshiya; Inoue, Tan

    2006-01-06

    We recently reported on the molecular design and synthesis of a new RNA ligase ribozyme (DSL), whose active site was selected from a sequence library consisting of 30 random nucleotides set on a defined 3D structure of a designed RNA scaffold. In this study, we report on the structural and biochemical analyses of DSL. Structural analysis indicates that the active site, which consists of the selected sequence, attaches to the folded scaffold as designed. To see whether DSL resembles known ribozymes, a biochemical assay was performed. Metal-dependent kinetic studies suggest that the ligase requires Mg2+ ions. The replacement of Mg2+ with Co(NH3)6(3+) prohibits the reaction, indicating that DSL requires innersphere coordination of Mg2+ for a ligation reaction. The results show that DSL has requirements similar to those of previously reported catalytic RNAs.

  11. 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

  12. 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.

  13. 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.

  14. Biochemical and pharmacologic comparison of thrombolytic agents.

    PubMed

    Stringer, K A

    1996-01-01

    The number of thrombolytic drugs for the management of acute myocardial infarction is rapidly expanding. New agents, some of which are biochemically modified versions of currently available thrombolytics, will soon arrive in the marketplace. The pharmacologic differences of the new drugs are the basis for clinical differences such as enhanced clot lysis and prolonged elimination half-life. Ultimately, these features may result in improved infarct artery patency and patient survival.

  15. 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.

  16. Inkjet printed (bio)chemical sensing devices.

    PubMed

    Komuro, Nobutoshi; Takaki, Shunsuke; Suzuki, Koji; Citterio, Daniel

    2013-07-01

    Inkjet printing has evolved from an office printing application to become an important tool in industrial mass fabrication. In parallel, this technology is increasingly used in research laboratories around the world for the fabrication of entire (bio)chemical sensing devices or single functional elements of such devices. Regularly stated characteristics of inkjet printing making it attractive to replace an alternative material deposition method are low cost, simplicity, high resolution, speed, reproducibility, flexibility, non-contact, and low amount of waste generated. With this review, we give an overview over areas of (bio)chemical sensing device development profiting from inkjet printing applications. A variety of printable functional sensor elements are introduced by examples, and the advantages and challenges of the inkjet method are pointed out. It is demonstrated that inkjet printing is already a routine tool for the fabrication of some (bio)chemical sensing devices, but also that novel applications are being continuously developed. Finally, some inherent limitations of the method and challenges for the further exploitation of this technology are pointed out.

  17. 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

  18. 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.

  19. 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.

  20. [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.

  1. 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.

  2. 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

  3. 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.

  4. 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.

  5. 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

  6. 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 grandparen