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Background In observational studies, moderate drinking is associated with a reduced risk of more than twenty different diseases and health problems. However, it would be premature to conclude that there is a causal relationship. Method This paper critically reviews the evidence for such associations. Findings It was found that reasons for questioning the causal association of moderate drinking and a reduced health risk are: the lack of dose-response relationships; the characteristics and lifestyles of today's abstainers and moderate drinkers; the lack of plausible biological mechanisms; the problems in the classification of drinking groups, and; the general limitations of observational studies. Conclusions The evidence for the harmful effects of alcohol is undoubtedly stronger than the evidence for beneficial effects. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed at exploring the relationship between intelligence quotient (IQ) and alcohol consumption in a large sample of young males. This study explored whether IQ influences alcohol drinking and which pathways might be involved. We further hypothesized that IQ differences between lifetime abstainers and former drinkers exist, and that they primarily result from different group characteristics. Method: Within a psychiatric-epidemiological survey using a cross-sectional design IQ-tests were administered to approximately 50,000 Swiss conscripts at age of about 20 years. The sample was divided into four alcohol consumption categories (rare, occasional, moderate and daily drinking) and two non-drinker categories (former drinking and lifetime abstinence). Probabilities for different levels of consumption or former drinking against lifetime abstention in relation to IQ were estimated using multinomial logistic regression. Models were adjusted for education, disability pension, tobacco/cannabis use, migration, parental alcohol disorders, and mental health. Results: After adjusting for confounders full-scale IQ displayed positive associations with being a rare (OR 1.13; CI 95 % 1.07–1.19), occasional (OR 1.41; CI 95 % 1.33–1.48), and moderate drinker (OR 1.53; CI 95 % 1.45–1.62), and negative associations with being a former drinker (OR 0.85; CI 95 % 0.79–0.93). Daily drinking was positively associated only with the performance subscale IQ (OR 1.12; CI 95 % 1.02–1.22). Confounders contributed significantly to the IQ–alcohol association and, therefore, highlight the distinction of non-drinkers into lifetime abstainers and former drinkers. Conclusions: Our data confirmed the positive link between IQ and moderate drinking. Lower IQ in non-drinkers, however, seems to be related to earlier consumption and the presence of other risk factors. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that has major implications for health-related quality of life (HRQoL). Improvements in the monitoring and management of SLE improves survival; however, improvement of HRQoL remains of paramount importance among these patients. Measurement of HRQoL has been recommended in clinical practice and research including drug development and testing in clinical trials. Both generic and disease specific instruments have been developed to ascertain HRQoL. In an increasingly global collaborative environment, the importance of assessing HRQoL across nations, acknowledgment of their confounders, and limitations of used instruments are critical. Here, we review selected major developments in the past 5 years highlighting: the importance of measuring HRQoL in SLE patients, the benefits and limitations of instruments that exist, and their application in research settings. [ABSTRACT FROM AUTHOR]

High-dimensional mediation analysis has been developed to study whether epigenetic phenotype in a high-dimensional data form would mediate the causal pathway of exposure to disease. However, most existing models are designed based on the assumption that there are no confounders between the exposure, the mediators, and the outcome. In practice, this assumption may not be feasible since high-dimensional mediation analysis (HIMA) tends to be observational where a randomized controlled trial (RCT) cannot be conducted for some economic or ethical reasons. Thus, to deal with the confounders in HIMA cases, we proposed three propensity score-related approaches named PSR (propensity score regression), PSW (propensity score weighting), and PSU (propensity score union) to adjust for the confounder bias in HIMA, and compared them with the traditional covariate regression method. The procedures mainly include four parts: calculating the propensity score, sure independence screening, MCP (minimax concave penalty) variable selection, and joint-significance testing. Simulation results show that the PSU model is the most recommended. Applying our models to the TCGA lung cancer dataset, we find that smoking may lead to lung disease through the mediation effect of some specific DNA-methylation sites, including site Cg24480765 in gene RP11-347H15.2 and site Cg22051776 in gene KLF3., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Luo, Yan, Cui, Yuan and Yu.)

Purpose: To examine whether changes in maternal overweight and obesity from pre-pregnancy to two decades postpartum predict the body mass index (BMI) of adult offspring. Methods: We used a subsample of 1997 mother-offspring pairs from the 7,223 original cohorts of women who gave birth in Brisbane, Australia, between 1981 and 1984. Multiple linear regression and multinomial logistic regression were used to examine the relationship between change in maternal BMI from pre-pregnancy to 21-year postpartum, and offspring BMI at 21-year, adjusting for potential confounding factors. Results: At 21-year postpartum, 31.15 % mothers were overweight and a further 30.80 % were obese. Mothers gained a mean weight of 16.07 kg over the 21 year. We found that the offspring of mothers who became overweight or remained overweight at 21-year postpartum were at greater risk of being overweight and obese at 21 years. In the adjusted model, offspring of mothers who had normal BMI before pregnancy but became overweight by 21-year postpartum were (odds ratio) 1.72 (95 % CI = 1.20, 2.47) times more likely to be overweight. Compared to offspring of mothers who maintained normal weight over two decades, offspring of mothers who remained persistently overweight were (odds ratio) 5.39 (95 % CI = 3.50, 8.30) times more likely to be obese by age 21 year. Conclusions: The findings of this study suggest that long-term changes in maternal BMI from pre-pregnancy to 21-year postpartum are independently associated with BMI in their young adult offspring. [ABSTRACT FROM AUTHOR]

Background Over several decades, many cohort studies from the medical epidemiology literature have observed that compared with abstainers, moderate drinkers experience lower risk for a range of diseases. It was very difficult to separate the hypothesised physiological protective effect of moderate drinking from its well-correlated confounders in observational study settings. Aims To investigate the association between current alcohol consumption levels of randomly selected family members and the current self-reported health status of other members living within the same family, using a large-scale representative general population survey. Method Poisson regression models of the association between randomly selected key respondent alcohol consumption and health status of cohabiting family members using data from the 2008, 2009 and 2010 National Health Interview Surveys. Self-reported alcohol consumption of randomly selected key participants and self-reported health status of adult and child (parent reported) family members living in the same household were measured and compared. Results After controlling for a large range of commonly reported confounders, inverse associations were evident between light and moderate alcohol consumption of key participants and the prevalence of adverse health status among their family members, including children. Conclusions The superior health status attributed to family members of light and moderate drinkers is highly likely to be spurious and due to residual confounding rather than physiologically protective effects of alcohol. Unaccounted for confounding is likely to underpin apparent 'protective effects' due to moderate drinking commonly reported from observational studies of all-cause mortality, heart disease, stroke and other chronic diseases. [ABSTRACT FROM AUTHOR]

Rationale Despite their inherently pervasive limitations, data from observational studies are increasingly relied upon by health care decision makers to fill critical information gaps created by lack of evidence from randomized controlled trials. Aim and objective The aim and objective of this article was to revisit the major issues associated with observational studies from secondary data sources. Method The method of this article was canvass of the literature. Results Sources of bias are highlighted and steps intended to minimize bias are summarized. Conclusion Efforts should be made to improve causal inference of treatment effects from observational studies found in secondary data sources. Extra care and caution should be exercised in the interpretation and reporting of results from these studies. [ABSTRACT FROM AUTHOR]

Objectives: To identify potential confounders and co-interventions systematically to optimise control of confounding for three non-randomized studies of interventions (NRSI) designed to quantify bleeding in populations exposed to different dual antiplatelet therapy (DAPT)., Study Design and Setting: Systematic review, interviews, and surveys with clinicians. We searched Ovid Medline, Ovid Embase, and the Cochrane Library to identify randomized-controlled trials and cohort studies of DAPT interventions. Two researchers independently screened citations, identified eligible studies and extracted data. We conducted individual semi-structured interviews with six cardiologists and six cardiac surgeons to elicit factors clinicians consider when they prescribe DAPT. We administered two online surveys for members of professional cardiology and cardiac surgery organisations., Results: We screened 2,544 records, identified 322 eligible studies, and extracted data from 47. We identified 10 co-interventions and 70 potential confounders: review 31 (91%); interviews 19 (56%); surveys 31 (91%). 16/34 (47%) were identified by all three methods while, 3/34 (9%) were picked up by one method only., Conclusion: The review identified the majority of factors, but the interviews identified hard-to-measure factors such as perceived patient adherence and local prescribing culture. The methods could, in principle, be widely applied when designing or reviewing non-randomized studies of interventions (NRSI)., (Copyright © 2022. Published by Elsevier Inc.)

High-throughput studies have been extensively conducted in the research of complex human diseases. As a representative example, consider gene-expression studies where thousands of genes are profiled at the same time. An important objective of such studies is to rank the diagnostic accuracy of biomarkers (e.g. gene expressions) for predicting outcome variables while properly adjusting for confounding effects from low-dimensional clinical risk factors and environmental exposures. Existing approaches are often fully based on parametric or semi-parametric models and target evaluating estimation significance as opposed to diagnostic accuracy. Receiver operating characteristic (ROC) approaches can be employed to tackle this problem. However, existing ROC ranking methods focus on biomarkers only and ignore effects of confounders. In this article, we propose a model-based approach which ranks the diagnostic accuracy of biomarkers using ROC measures with a proper adjustment of confounding effects. To this end, three different methods for constructing the underlying regression models are investigated. Simulation study shows that the proposed methods can accurately identify biomarkers with additional diagnostic power beyond confounders. Analysis of two cancer gene-expression studies demonstrates that adjusting for confounders can lead to substantially different rankings of genes. [ABSTRACT FROM PUBLISHER]

In this article, I discuss many of the points raised in the thoughtful comments by Hinduja and Patchin (2012, this issue), Menesini (2012, this issue), and Smith (2012, this issue) on my original article “Cyberbullying: An overrated phenomenon” (Olweus, 2012, this issue). After having seriously considered the arguments of my commentators, I still think there is strong empirical evidence for my original position—supported by one or more but not all of my commentators—that cyberbullying is a basically low-frequent phenomenon and that there has not occurred a marked increase in the prevalence rates of cyberbullying over the past five or six years. With regard to the possible negative effects of cyberbullying, over and above the effects of traditional bullying, I note with appreciation that this issue has received some attention in the recent research literature but I also make a call for more systematic consideration of potential confounders in such studies. A good deal of the discussion in the comments and the current article concerned the issue of whether cyberbullying should be regarded as a form of bullying on a par with traditional forms of bullying or if it is distinct enough to be considered a partly separate phenomenon or dimension. I conclude by arguing that in order for research on cyberbullying to proceed in a systematic and fruitful way, it is necessary to place it in proper context (along with traditional bullying) and to communicate a somewhat more realistic picture of its prevalence and nature. [ABSTRACT FROM AUTHOR]

Abstract: Total body (TB) dual-energy X-ray absorptiometry (DXA) can assess regional body composition, which may necessitate greater attention to patient positioning and analysis than required for whole body assessment. This report describes technical challenges experienced in performing TB DXA, explores the frequency with which autoanalysis inaccuracies occur, assesses their effect on regional body composition results, and describes a uniform clinical approach for TB DXA positioning and analysis. Patient positioning followed manufacturer recommendations with additional facility-imposed procedures. On visual inspection, it was apparent that automated analysis often did not meet manufacturer guidelines, thus requiring manual alteration. To explore the frequency with which manual adjustments were needed, and the impact on results, TB scans were obtained in 20 men and 20 women aged 18–93yr. The head line was altered in 98%, one or both shoulder lines in 93%, and the lateral hip boundary in 40%. Manual and automated TB analyses were highly correlated (r 2 =0.98–1.00). However, regional result correlation was less robust, that is, automated and manual appendicular lean mass differed by more than our least significant change in 33%. In conclusion, manual correction of automated TB DXA scan analysis is often needed. Such alterations do not affect TB measures but may affect regional body composition results. [Copyright &y& Elsevier]

A Confounder is a variable whose presence affects the variables being studied so that the results do not reflect the actual relationship. There are various ways to exclude or control confounding variables including Randomization, Restriction and Matching. But all these methods are applicable at the time of study design. When experimental designs are premature, impractical, or impossible, researchers must rely on statistical methods to adjust for potentially confounding effects. These Statistical models (especially regression models) are flexible to eliminate the effects of confounders. [ABSTRACT FROM AUTHOR]

The article reports on research conducted to investigate the outcome of specific implants in total ankle arthroplasty in clinical studies and national registries reported in literature. Researchers conducted a structured literature review. They found that the average revision rate published in peer-reviewed scientific articles was significantly lower than the outcome achieved according to national arthroplasty registry data.

Objectives To determine whether exposure to prenatal ultrasound increases non-right-handedness in boys. Methods The association between exposure to prenatal ultrasound and handedness was tested, using logistic regression analysis, in the Helsinki Ultrasound Trial data. We applied an intention-to-treat approach in this analysis of a subset of 4150 subjects whose parents answered a follow-up questionnaire on handedness when the children were aged 13-15 years. Results The odds ratio for non-right-handedness of children who had been exposed to prenatal ultrasound was 1.16 (0.98-1.37) for all subjects, 1.12 (0.89-1.41) for boys and 1.24 (0.97-1.58) for girls. Conclusions We could not confirm the hypothesis that prenatal ultrasound exposure and handedness are associated. Our findings were independent of the particular definition of handedness used, whether it was considered according to the writing hand alone or defined using a laterality quotient. [ABSTRACT FROM AUTHOR]

The paper reviews approaches expected to be helpful for researchers involved in tobacco control studies. Classifications of studies are discussed starting from most general ones and related to any studies in the field of health sciences and ending with more specific for tobacco control. Part of the paper is devoted to structuring study data and building its design, including outcome measures, determinants, confounders, effect measure modifiers and mediators. Significant place is devoted to evaluative studies. Examples mostly come from the papers of Kazan authors presented at the first and second conferences 'Health of Kazan-city dwellers and tobacco' and other sources the author relies on. [ABSTRACT FROM AUTHOR]

In a partially randomized preference trial (PRPT) patients with no treatment preference are allocated to groups at random, but those who express a preference receive the treatment of their choice. It has been suggested that the design can improve the external and internal validity of trials. We used computer simulation to illustrate the impact that an unmeasured confounder could have on the results and conclusions drawn from a PRPT. We generated 4000 observations ('patients') that reflected the distribution of the Beck Depression Index (DBI) in trials of depression. Half were randomly assigned to a randomized controlled trial (RCT) design and half were assigned to a PRPT design. In the RCT, 'patients' were evenly split between treatment and control groups; whereas in the preference arm, to reflect patient choice, 87.5% of patients were allocated to the experimental treatment and 12.5% to the control. Unadjusted analyses of the PRPT data consistently overestimated the treatment effect and its standard error. This lead to Type I errors when the true treatment effect was small and Type II errors when the confounder effect was large. The PRPT design is not recommended as a method of establishing an unbiased estimate of treatment effect due to the potential influence of unmeasured confounders. Copyright © 2011 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Pre-eclampsia (P-EC) is a major cause of maternal and fetal morbidity and mortality. Inherited thrombophilia has been suggested to increase the risk of P-EC or may accelerate the pathophysiological process. In the past 20 years, numerous studies and meta- analyses have yielded contradictory results regarding the association between inherited thrombophilia and P-EC/hemolysis, elevated liver enzymes, low platelets syndrome. Although studies published until 2002 reported on an increased prevalence of inherited thrombophilia in pre-eclamptic women, most subsequent studies did not. Inconsistency of data may be due to numerous confounders such as ethnicity, different definitions of P-EC, severity of illness, and methods of testing. Mild P-EC is unlikely to be associated with thrombophilic gene defects, whereas severe and early-onset P-EC is significantly related to inherited and acquired thrombophilia. Thrombophilic patients with severe P-EC appear to have an increased risk of overall maternal morbidity and recurrences of P-EC compared with pre-eclamptic women without thrombophilia. It remains a matter of debate if women with a previous history of (severe) P-EC should be screened for inherited thrombophilias and if the administration of low molecular weight heparin should be recommended in women with positive results to prevent adverse outcomes in subsequent pregnancies. Large prospective studies are urgently needed to determine the benefits and risks of prophylactic strategies. [ABSTRACT FROM AUTHOR]

Introduction: The question of whether patellar replacement should be performed in the case of total knee arthroplasty has been a subject of controversial discussion for years. Materials and methods: A structured literature analysis was conducted, including clinical studies and worldwide register data, with the revision rate as the main parameter, in order to study the impact of patellar resurfacing on the outcome in different sources of scientific content. Results: In comparison with register data, statistically significant deviations were found in the clinical literature. For patient groups not subjected to primary patellar resurfacing, the clinical literature shows increased revision rates. These results deviate statistically significantly from both register data and the outcome in patients not treated with a patellar component at primary surgery. Discussion: No evidence can be derived from the data as regards the superiority of either surgical technique. Other factors, such as the implant system used, seem to have greater influence on the outcome. [ABSTRACT FROM AUTHOR]

The article focuses on the cancer cases that are occupational in origin, the cofounders and the confusion it implicates. It mentions cofounders of cancer such as smoking and diet that can mislead the analysis of the origin of the disease. It suggests that medical literature should focus on latency and accumulative dose and must not dismiss a case at once and concludes that the cofounders are responsible for it will mislead the gauge on the attributed risk an occupation has.

The article presents a study that examines validity of reported risk factors for mortality rates of elderly cervical spine injury (CSI) patients. The study assesses articles on CSI treatments and evaluates its validity through analysis of mortality outcomes, causes of death and consideration of study design, injury type, and duration. Result shows that most study underreports death causes and concomitant injuries, suggesting less validity of reported risk factors for mortality assessment.

Imprinting is critical to understanding disease expression. It can be detected using linkage information, but the effects of potential confounders (heterogeneity, sex-specific penetrance, and sex-biased ascertainment) have not been explored. We examine power and confounders in two imprinting detection approaches, and we explore imprinting-linkage interaction. One method (PP) models imprinting by maximising lod scores w.r.t. parent-specific penetrances. The second (DRF) approximates imprinting by maximising lods over differential male-female recombination fractions. We compared power, type 1 error, and confounder effects in these two methods, using computer-simulated data. We varied heterogeneity, penetrance, family and dataset size, and confounders that might mimic imprinting. Without heterogeneity, PP had more imprinting-detecting power than DRF. PP's power increased when parental affectedness status was ignored, but decreased with heterogeneity. With heterogeneity, type 1 error increased dramatically for both methods. However, DRF's power also increased under heterogeneity, more than was attributable to inflated type 1 error. Sex-specific penetrance could increase false positives for PP but not for DRF. False positives did not increase on ascertainment through an affected “mother”. For PP, non-penetrant individuals increased information, arguing against using affecteds-only methods. The high type 1 error levels under some circumstances means these methods must be used cautiously. [ABSTRACT FROM AUTHOR]

Associations between occupational styrene exposures and impairment of visual functions were investigated with a view to answering three questions: (1) are the published findings for colour vision deficiencies and impaired contrast sensitivity to reproduce in a new study approach, (2) if such effects exist, are they related to current or chronic exposures and (3) if effects exist, are there reductions in the effects during an exposure-free period? Workers from a boat building plant were examined in groups of current low [ n = 97, mean mandelic acid (MA) + phenylglyoxylic acid (PGA) = 51 mg/g creatinine], medium ( n = 115, mean = 229 mg/g creatinine) and high ( n = 30, mean = 977 mg/g creatinine) level exposure to styrene. Job tenure was about 6 years. In addition, subgroups chronically exposed to low-short ( n = 34, lifetime weighted mean 200 mg/g creatinine for 6 years) and high-long ( n = 17, mean = 660 mg/g creatinine, 15 years) styrene levels were analysed. The examinations were carried out during normal working days and during the company holidays. Colour vision was investigated with the Lanthony desaturated panel D-15d using the colour confusion index (CCI) as a relevant variable. Contrast sensitivity was investigated with the Vistech charts VCTS 6500 using frequency-related results as well as total scores as variables. Co-variance analyses with repeated measurements and multiple linear regressions were used for statistical analysis. There was no evidence of significant associations between exposure parameters and CCI. This is true for the analyses with all participants as well as for those with the subgroups with high-long versus low-short exposure. Thus, no exposure related changes in the relevant variables were found during the exposure-free period. The analyses for contrast sensitivity show similar results. The largest portions of the variances in both tests were explained by age. German as mother tongue covered a considerable portion of the CCI variances. Education, long-term alcohol use and job tenure explain only partly significant portions of the test variances exhibited. Both acute styrene exposure levels of 40 ppm (range of standard deviation up to 54 ppm) and long term exposures to 27 ppm (range of standard deviation up to 44 ppm with higher exposure levels in the past) for a period of about 15 years were not identified as causing elevated risks for the investigated parameters of colour vision and contrast sensitivity. This statement contradicts the published results for styrene-related colour vision deficiencies but it seems to be compatible with published results for contrast sensitivity due to styrene exposure. [ABSTRACT FROM AUTHOR]

Recent studies on air pollution and disease have been based on millions of participants within a region or country, relying entirely on register-based confounder adjustment. We aimed to investigate the effects of increasing adjustment for register- and questionnaire-based covariates on the association between air pollution and cardiometabolic diseases. In a population-based cohort of 246,766 eligible participants randomly selected across Denmark in 2010 and 2013 and followed up until December 31, 2017, we identified 3,247 myocardial infarction (MI) cases, 4,166 stroke cases and 6,366 type 2 diabetes cases. Based on historical address-information, we calculated 5-year time-weighted exposure to PM 2.5 and NO 2 modelled using a validated air pollution model. We used Cox proportional hazards models to calculate hazard ratios (HR) with increasing adjustment for a number of individual- and area-level register-based covariates as well as lifestyle covariates assessed through questionnaires. We found that a 5 μg/m3 higher PM 2.5 was associated with HRs (95% CI) for MI, stroke and diabetes, of respectively, 1.18 (0.91–1.52), 1.11 (0.88–1.40) and 1.24 (1.03–1.50) in the fully adjusted models. For all three diseases, adjustment for either individual-level, area-level or lifestyle covariates, or combinations of these resulted in higher HRs compared to HRs adjusted only for age, sex and calendar-year, most marked for MI and diabetes. Further adjustment for lifestyle in models with full register-based individual- and area-level adjustment resulted in only minor changes in HRs for all three diseases. Our findings suggest that in studies of air pollution and cardiometabolic disease, which use an adjustment strategy with a broad range of register-based socioeconomic variables, there is no effect on risk estimates from subsequent lifestyle adjustment. • Results from strictly register-based studies may be biased by unmeasured confounders. • We investigated impact of different adjustment strategies in a cohort selected randomly across Denmark. • PM 2.5 and NO 2 seemed positively associated with risk of myocardial infarction, stroke and diabetes. • Crude adjustment models produced different results than more comprehensive register-based adjustment models. • With comprehensive register-based adjustment additional adjustment for lifestyle had limited effect on risk estimates. [ABSTRACT FROM AUTHOR]

Research on the relationship between body mass index (BMI) and mortality has led to conflicting results; a lack of agreement about how to adjust for confounders, such as smoking status, has added to the problem. Complicating such analyses is the fact that the BMI–mortality association is not a symmetric quadratic relationship; the distribution tends to be skewed to the right, causing the optimal BMI—where mortality is at a minimum—to be overestimated. One way to overcome this problem is by transformation of the BMI distribution to normality. The authors suggest several approaches for doing so, including the use of 1/BMI, or lean body mass index, instead of BMI in modeling. Data sets on 50 cohorts from approximately 30 international studies were used to examine the association (direct, inverse, quadratic or none) between BMI and mortality and to investigate the possible interaction of smoking status. Of the 50 cohorts, 36 showed a quadratic association between BMI and mortality, 10 showed no association and 1 showed a direct association between lean BMI and mortality. Only three cohorts showed a significant interaction between BMI and smoking, which was approximately what one would expect from a 5% significance test, even if no interaction existed. The association between BMI and mortality is not changed when smoking status is ignored in a model or when data on smokers are excluded from analysis. The methodology used in this study could be extended to look for other interactions.International Journal of Obesity (2008) 32, S52–S55; doi:10.1038/ijo.2008.86 [ABSTRACT FROM AUTHOR]

Suppose, in contrast to the fact, in 1950, we had put the cohort of 18-year-old non-smoking American men on a stringent mandatory diet that guaranteed that no one would ever weigh more than their baseline weight established at the age of 18 years. How would the counterfactual mortality of these 18 year olds have compared to their actual observed mortality through 2007? We describe in detail how this counterfactual contrast could be estimated from longitudinal epidemiologic data similar to that stored in the electronic medical records of a large health maintenance organization (HMO) by applying g-estimation to a novel of structural nested model (SNM). Our analytic approach differs from any alternative approach in that, in the absence of model misspecification, it can successfully adjust for (i) measured time-varying confounders such as exercise, hypertension and diabetes that are simultaneously intermediate variables on the causal pathway from weight gain to death and determinants of future weight gain, (ii) unmeasured confounding by undiagnosed preclinical disease (that is, reverse causation) that can cause both poor weight gain and premature mortality (provided an upper bound can be specified for the maximum length of time a subject may suffer from a subclinical illness severe enough to affect his weight without the illness becomes clinically manifest) and (iii) the presence of particular identifiable subgroups, such as those suffering from serious renal, liver, pulmonary and/or cardiac disease, in whom confounding by unmeasured prognostic factors is so severe as to render useless any attempt at direct analytic adjustment. However, (ii) and (iii) limit the ability to empirically test whether the SNM is misspecified. The other two g-methods—the parametric g-computation algorithm and inverse probability of treatment weighted estimation of marginal structural models—can adjust for potential bias due to (i) but not due to (ii) or (iii).International Journal of Obesity (2008) 32, S15–S41; doi:10.1038/ijo.2008.83 [ABSTRACT FROM AUTHOR]

Under usual practice in epidemiologic research, covariate adjustment would be used to control for confounding effects. Exclusions, on the other hand, are justified as a part of an analytic strategy when there is evidence of an interaction altering the shape or direction of the exposure–-outcome relationship across strata. This distinction applies with particular relevance in the analysis of the BMI–-mortality relationship. Both covariate adjustment and exclusions have been used, with the need to control for interaction usually justified by concerns of reverse causality. The concern of reverse causality arises when conditions prevalent at baseline are thought to be associated with both lower average body weight and higher mortality risk, as would be the case with smokers. In the analysis, the choice must be made of whether to control for smoking status or exclude smokers altogether. Unfortunately, reverse causality is difficult to test for directly in observational data as deletions of very large subsets of the data can also lead to a different result, by chance alone. Findings that result after large-scale exclusions must therefore be tested in the standard statistical framework that can distinguish any new result observed after exclusions from one that could have occurred solely by chance. In statistical tests focused specifically on this question, the weight of the evidence suggests that interactions are not present in this context and that exclusion of subgroups (e.g., by smoking status, age, sex, use of alcohol) leaves the shape of the mortality curve unchanged, although it may alter the absolute level of risk. Unless some special question is being asked about subgroups, the author advises against large-scale exclusions for a common trait in analyses of the BMI–-mortality relationship and emphasizes using representative study samples with measured exposure variables. A large-scale social experiment is cited that gives some evidence on the effect of a population-wide downward shift in BMI.International Journal of Obesity (2008) 32, S47–S51; doi:10.1038/ijo.2008.85 [ABSTRACT FROM AUTHOR]

Abstract: Methylmercury (MeHg) is a widespread environmental and food toxicant which has long been known to affect neurodevelopment in both humans and experimental animals. Risk assessment for MeHg is mainly based on human data coming from the massive episodes of poisoning in Japan and Iraq, as well as from large scale epidemiological studies concerning childhood development and neurotoxicity in relation to in utero exposure in various fish eating communities around the world. Despite the extensive literature and research, the threshold dose for MeHg neurotoxic effects is still unclear, in particular when it comes to subtle effects on neurobehaviour. In this article clinical and epidemiological findings concerning the neurodevelopmental toxicity of MeHg are reviewed. Much attention is focussed on the potential impact of factors, such as diet and nutrition, gender, pattern of exposure and co-exposure to other neurotoxic pollutants, which may modulate MeHg toxic effects. These factors, together with the notion that some symptoms may ensue or exacerbate with aging, contribute to the difficulties in the definition of safe levels for developmental exposure. [Copyright &y& Elsevier]

Objective To assess factors related to recorded vaccine uptake, which may confound the evaluation of vaccine impact. Methods Analysis of documented vaccination histories of children under 5 years and demographic and socio-economic characteristics collected by a demographic surveillance system in Karonga District, Malawi. Associations between deviations from the standard vaccination schedule and characteristics that are likely to be associated with increased mortality were determined by multivariate logistic regression. Results Approximately 78% of children aged 6–23 months had a vaccination document, declining to <50% by 5 years of age. Living closer to an under-5 clinic, having a better educated father, and both parents being alive were associated with having a vaccination document. For a small percentage of children, vaccination records were incomplete and/or faulty. Vaccination uptake was high overall, but delayed among children living further from the nearest under-5 clinic or from poorer socio-economic backgrounds. Approximately 9% of children had received their last dose of DPT with or after measles vaccine. These children were from relatively less educated parents, and were more likely to have been born outside the health services. Conclusions Though overall coverage in this community was high and variation in coverage according to child or parental characteristics small, there was strong evidence of more timely coverage among children from better socio-economic conditions and among those who lived closer to health facilities. These factors are likely to be strong confounders in the association of vaccinations with mortality, and may offer an alternative explanation for the non-specific mortality impact of vaccines described by other studies. [ABSTRACT FROM AUTHOR]

Sleep deprivation (or=140/90 mm Hg or regular use of antihypertensive medications. In cross-sectional analyses at phase 5 (n=5766), short duration of sleep (

Aims To examine whether there is evidence of an independent association between childhood sexual abuse (CSA) and nicotine disorder in youth and to explore the mechanisms underlying this association in a prospective cohort study. Design Birth cohort study followed-up to 21 years. Setting One of two major obstetric hospitals in Brisbane, Australia. Participants The Mater-University of Queensland Study of Pregnancy involves a prospective birth cohort from a population-based sample involving 7223 singletons whose mothers were enrolled between 1981 and 1984 at the first antenatal visit. The present cohort consisted of a subgroup of 2571 youth who completed the life-time version of the Composite International Diagnostic Interview—computerized version (CIDI-Auto) at the 21-year follow-up. Measurements Nicotine disorder was measured based on Diagnostic and Statistical Manual version IV (DSM-IV) diagnostic criteria and measures of CSA, including retrospective self-reports of rape, were obtained at 21 years. Results Of 2571 young adults, 16.6% met the criteria for either dependence (12.8%) or withdrawal (8.5%). Non-penetrative sexual abuse was reported by 15.5% of respondents and 8.0% reported penetrative sexual abuse. For any types of sexual abuse including non-penetrative, penetrative and self-reported rape before age 16 years, young adults had significantly higher rates of nicotine disorder than young adults who did not experience CSA. This relationship was independent and appeared direct after adjustment for a range of potential confounding and mediating factors. Conclusions This study shows that CSA is associated with young adult nicotine disorder. The results extend the public health significance of findings in this area and highlight the importance of not only intensifying public health efforts to address substance use problems among those who have experienced CSA, but of early intervention, so that emerging risky behaviours may be targeted in the earliest stages. [ABSTRACT FROM AUTHOR]

The article presents a study which compares the in-hospital mortality for patients with myocardial infraction in rural and urban hospitals in Iowa. Since patients in the rural hospitals have higher mortality rates than in urban, the authors utilized the unadjusted and risk-adjusted mortality rates using logistic regression models to assess the relative factors to such incident. Results revealed that the unmeasured confounding factors such as the health care services attribute to the situation.

Multiple genome-wide expression studies of bipolar disorder have been published. However, a unified picture of the genomic basis for the disease has not yet emerged. Genes identified in one study often fail to be identified in other studies, prompting the question of whether microarray studies in the brain are inherently unreliable. To answer this question, we performed a meta-analysis of 12 microarray studies of bipolar disorder. These studies included >500 individual array samples, on a range of microarray platforms and brain regions. Although we confirmed that individual studies showed some differences in results, clear and striking regulation patterns emerged across the studies. These patterns were found at the individual gene level, at the functional level, and at the broader pathway level. The patterns were generally found to be reproducible across platform and region, and were highly statistically significant. We show that the seeming discordance between the studies was primarily a result of the following factors, which are also typical for other brain array studies: (1) Sample sizes were, in retrospect, too small; (2) criteria were at once too restrictive (generally focusing on fold changes >1.5) and too broad (generally using p<0.05 or p<0.01 as criteria for significance); and (3) statistical adjustments were not consistently applied for confounders. In addition to these general conclusions, we also summarize the primary biological findings of the meta-analysis, focusing on areas that confirm previous research and also on novel findings. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Prior studies have suggested that oral contraceptives (OCs) may be associated with an increased fracture risk. However, the previous studies have only performed a limited adjustment for other potential risk factors. Subjects and Methods: All women with a fracture (n=64,548) in the year 2000 in Denmark served as cases. For each case, three age-matched controls were randomly drawn from the general population (n=193,641). Exposure was use of OCs between January 1, 1996, and December 31, 2000. Adjustments were made for use of other drugs, pregnancy, prior fracture, other diseases and social variables. Results: In the unadjusted analysis, use of OCs in low dose was associated with a small increase in overall fracture risk. However, upon adjustment, no increase in fracture risk could be demonstrated in any age or dose group. Conclusion: Oral contraceptives are not associated with an increase or a decrease in fracture risk. Any change in fracture risk may be due to confounders. [Copyright &y& Elsevier]

Recently, Chlamydia pneumoniae is the microorganism frequently implicated in the infection-based inflammatory atherogenous hypothesis. Although in vitro experimental data and initial sero-epidemiologic, pathologybased studies and antibiotic trials supported this interesting hypothesis, later data are conflicting. Some confounding factors are the causes of uncertainty; lacking of standard methods for C. pneumoniae detection, co-existence of other atherosclerotic risk factors and anti-inflammatory effects of antibiotics used in clinical trials seem to be the principal ones. Standardization of methodology used, antibiotic trials with a different orientation-design and a vaccine preparation that eventually will be tested in clinical trials with a long follow-up, should provide a definite answer regarding the probability C. pneumoniae to be a main, a secondary or an irrelevant factor to atherosclerosis. Studies linking C. pneumoniae to inflammation and accelerated atherosclerosis in renal failure patients are accumulated but limitations are similar to the above mentioned. [ABSTRACT FROM AUTHOR]

Presents abstracts of several studies about the genital organs, presented at the 2002 Biennial Meeting of the American Society for Colposcopy and Cervical Pathology. "Vulvar Intraepithelial Neoplasia 3: Posttherapeutic Management," by K. Moller, et al; "cMyc-Induced Dihydrofolate Reductase (DHFR) Gene Amplification as Genomic Biomaker in Cervical Neoplasia," by F. Guijon, et al; "Triage of ASCUS Pap Smears With Hybrid Capture II in Patient Undergoing Colposcopy and Tissue-Based HPV PCR Analysis," by N. M. Lonky, et al.

To compare hospitals' hip fracture patient mortality in a quality of care registry, correction for patient characteristics is needed. This study evaluates in 39,374 patients which characteristics are associated with 30 and 90-day mortality, and showed how using these characteristics in a case mix-model changes hospital comparisons within the Netherlands., Purpose: Mortality rates after hip fracture surgery are considerable and may be influenced by patient characteristics. This study aims to evaluate hospital variation regarding patient demographics and disease burden, to develop a case-mix adjustment model to analyse differences in hip fracture patients' mortality to calculate case-mix adjusted hospital-specific mortality rates., Methods: Data were derived from 64 hospitals participating in the Dutch Hip Fracture Audit (DHFA). Adult hip fracture patients registered in 2017-2019 were included. Variation of case-mix factors between hospitals was analysed, and the association between case-mix factors and mortality at 30 and 90 days was determined through regression models., Results: There were 39,374 patients included. Significant variation in case-mix factors amongst hospitals was found for age ≥ 80 (range 25.8-72.1% p < 0.001), male gender (12.0-52.9% p < 0.001), nursing home residents (42.0-57.9% p < 0.001), pre-fracture mobility aid use (9.9-86.7% p < 0,001), daily living dependency (27.5-96.5% p < 0,001), ASA-class ≥ 3 (25.8-83.3% p < 0.001), dementia (3.6-28.6% p < 0.001), osteoporosis (0.0-57.1% p < 0.001), risk of malnutrition (0.0-29.2% p < 0.001) and fracture types (all p < 0.001). All factors were associated with 30- and 90-day mortality. Eight hospitals showed higher and six showed lower 30-day mortality than expected based on their case-mix. Six hospitals showed higher and seven lower 90-day mortality than expected. The specific outlier hospitals changed when correcting for case-mix factors., Conclusions: Dutch hospitals show significant case-mix variation regarding hip fracture patients. Case-mix adjustment is a prerequisite when comparing hospitals' 30-day and 90-day hip fracture patients' mortality. Adjusted mortality may serve as a starting point for improving hip fracture care., (© 2022. The Author(s).)

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by pruritus, skin pain, and sleep disturbances. Currently, dupilumab is the only systemic therapy and biologic medication approved by the United States Food and Drug Administration for moderate-to-severe AD in adults and children. There is a sparsity of literature available on determining treatment failure with dupilumab and the next steps health care providers can take to treat AD. Individual goals and quality of life and not just body surface area should be considered when defining treatment failure. Possible confounding dermatoses also should be ruled out. Early identification of dupilumab-induced adverse events is important. For most patients, dupilumab can be continued while treatment for the adverse event is initiated. Adjusting the frequency of dupilumab dosing also may be considered in some circumstances. Adjuvant therapies, such as methotrexate, azathioprine, mycophenolate mofetil, cyclosporine, or phototherapy can be added but the safety and efficacy of these combination treatments are not known at this time., Competing Interests: Conflicts of interest Dr Narla has no conflicts of interest to report. Dr Silverberg has received honoraria as a consultant and/or advisory board member for Abbvie, Afyx, Arena, Asana, BioMX, Bluefin, Bodewell, Boehringer-Ingelheim, Celgene, Dermavant, Dermira, Eli Lilly, Galderma, GlaxoSmithKline, Incyte, Kiniksa, Leo, Luna, Menlo, Novartis, Pfizer, RAPT, Regeneron, Sanofi; data safety monitoring committee member for Afyx, Hoth, Morphosys; speaker for Pfizer, Regeneron, Sanofi-Genzyme; and Dr Silverberg's institution received grants from Galderma. Dr Simpson reports grants and fees for participation as a consultant and principal investigator for Eli Lilly and Company, LEO Pharma, Pfizer, and Regeneron; grants for participation as a principal investigator from Galderma and Merck; and fees for consultant services from AbbVie, Boehringer-Ingelheim, Dermavant Incyte, Forte Bio, Pierre Fabre Dermo, and Sanofi-Genzyme., (Copyright © 2021 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

The promise of machine learning (ML) to extract insights from high-dimensional datasets is tempered by confounding variables. It behooves scientists to determine if a model has extracted the desired information or instead fallen prey to bias. Due to features of natural phenomena and experimental design constraints, bioscience datasets are often organized in nested hierarchies that obfuscate the origins of confounding effects and render confounder amelioration methods ineffective. We propose a non-parametric statistical method called the rank-to-group (RTG) score that identifies hierarchical confounder effects in raw data and ML-derived embeddings. We show that RTG scores correctly assign the effects of hierarchical confounders when linear methods fail. In a public biomedical image dataset, we discover unreported effects of experimental design. We then use RTG scores to discover crossmodal correlated variability in a multi-phenotypic biological dataset. This approach should be generally useful in experiment-analysis cycles and to ensure confounder robustness in ML models., Competing Interests: This work was fully supported by Herophilus, Inc. A.R. and P.R. are employees of Herophilus, Inc. S.K. and G.S.E. are co-founders of Herophilus, Inc. A.R., P.R., R.B., S.K., and G.S.E. have equity interests in Herophilus, Inc., (© 2022 The Author(s).)

Cerebral autoregulation is a complex mechanism that serves to keep cerebral blood flow relatively constant within a wide range of cerebral perfusion pressures. The mean flow index (Mx) is one of several methods to assess dynamic cerebral autoregulation, but its reliability and validity have never been assessed systematically. The purpose of the present systematic review was to evaluate the methodology, reliability and validity of Mx.Based on 128 studies, we found inconsistency in the pre-processing of the recordings and the methods for calculation of Mx. The reliability in terms of repeatability and reproducibility ranged from poor to excellent, with optimal repeatability when comparing overlapping recordings. The discriminatory ability varied depending on the patient populations; in general, those with acute brain injury exhibited a higher Mx than healthy volunteers. The prognostic ability in terms of functional outcome and mortality ranged from chance result to moderate accuracy.Since the methodology was inconsistent between studies, resulting in varying reliability and validity estimates, the results were difficult to compare. The optimal method for deriving Mx is currently unknown.

Alzheimer's disease is a progressive form of dementia that results in problems with memory, thinking, and behavior. It often starts with abnormal aggregation and deposition of β amyloid and tau, followed by neuronal damage such as atrophy of the hippocampi, leading to Alzheimers Disease (AD). The aim of this paper is to map the genetic-imaging-clinical pathway for AD in order to delineate the genetically-regulated brain changes that drive disease progression based on the Alzheimers Disease Neuroimaging Initiative (ADNI) dataset. We develop a novel two-step approach to delineate the association between high-dimensional 2D hippocampal surface exposures and the Alzheimers Disease Assessment Scale (ADAS) cognitive score, while taking into account the ultra-high dimensional clinical and genetic covariates at baseline. Analysis results suggest that the radial distance of each pixel of both hippocampi is negatively associated with the severity of behavioral deficits conditional on observed clinical and genetic covariates. These associations are stronger in Cornu Ammonis region 1 (CA1) and subiculum subregions compared to Cornu Ammonis region 2 (CA2) and Cornu Ammonis region 3 (CA3) subregions. Supplementary materials for this article, including a standardized description of the materials available for reproducing the work, are available as an online supplement.