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The World Health Organization specifies that sexual health requires the potential for pleasurable and safe sexual experiences. Yet epidemiologic research into sexual pleasure and other positive sexual outcomes has been scant. In this commentary, we aim to support the development and adoption of sex-positive epidemiology, which we define as epidemiology that incorporates the study of pleasure and other positive features alongside sexually transmitted infections and other familiar negative outcomes. We first call epidemiologists' attention to the potential role that stigma plays in the suppression of sex-positive research. We further describe existing measures of sex-positive constructs that may be useful in epidemiologic research. Finally, the study of sex-positive constructs is vulnerable to biases that are well-known to epidemiologists, especially selection bias, information bias, and confounding. We outline how these biases influence existing research and identify opportunities for future research. Epidemiologists have the potential to contribute a great deal to the study of sexuality by bringing their considerable methodological expertise to long-standing challenges in the field. We hope to encourage epidemiologists to broaden their sexual health research to encompass positive outcomes and pleasure. [ABSTRACT FROM AUTHOR]

Administrative claims databases often do not capture date or fact of death, so studies using these data may inappropriately treat death as a censoring event—equivalent to other withdrawal reasons—rather than a competing event. We examined 1-, 3-, and 5-year inverse-probability-of-treatment weighted cumulative risks of a composite cardiovascular outcome among 34 527 initiators of telmisartan (exposure) and ramipril (referent), who were aged ≥55 years, in Optum (United States) claims data from 2003 to 2020. Differences in cumulative risks of the cardiovascular endpoint due to censoring of death (cause-specific), as compared with treating death as a competing event (subdistribution), increased with greater follow-up time and older age, where event and mortality risks were higher. Among ramipril users, 5-year cause-specific and subdistribution cumulative risk estimates per 100, respectively, were 16.4 (95% CI, 15.3-17.5) and 16.2 (95% CI, 15.1-17.3) among ages 55-64 (difference = 0.2) and were 43.2 (95% CI, 41.3-45.2) and 39.7 (95% CI, 37.9-41.4) among ages ≥75 (difference = 3.6). Plasmode simulation results demonstrated the differences in cause-specific versus subdistribution cumulative risks to increase with increasing mortality rate. We suggest researchers consider the cohort's baseline mortality risk when deciding whether real-world data with incomplete death information can be used without concern. This article is part of a Special Collection on Pharmacoepidemiology. [ABSTRACT FROM AUTHOR]

Epidemiologists are attempting to address research questions of increasing complexity by developing novel methods for combining information from diverse sources. Cole et al. (Am J Epidemiol. 2023;192(3)467–474) provide 2 examples of the process of combining information to draw inferences about a population proportion. In this commentary, we consider combining information to learn about a target population as an epidemiologic activity and distinguish it from more conventional meta-analyses. We examine possible rationales for combining information and discuss broad methodological considerations, with an emphasis on study design, assumptions, and sources of uncertainty. [ABSTRACT FROM AUTHOR]

Understanding characteristics of patients with propensity scores in the tails of the propensity score (PS) distribution has relevance for inverse-probability-of-treatment–weighted and PS-based estimation in observational studies. Here we outline a method for identifying variables most responsible for extreme propensity scores. The approach is illustrated in 3 scenarios: 1) a plasmode simulation of adult patients in the National Ambulatory Medical Care Survey (2011–2015) and 2) timing of dexamethasone initiation and 3) timing of remdesivir initiation in patients hospitalized for coronavirus disease 2019 from February 2020 through January 2021. PS models were fitted using relevant baseline covariates, and tails of the PS distribution were defined using asymmetric first and 99th percentiles. After fitting of the PS model in each original data set, values of each key covariate were permuted and model-agnostic variable importance measures were examined. Visualization and variable importance techniques were helpful in identifying variables most responsible for extreme propensity scores and may help identify individual characteristics that might make patients inappropriate for inclusion in a study (e.g. off-label use). Subsetting or restricting the study sample based on variables identified using this approach may help investigators avoid the need for trimming or overlap weights in studies. [ABSTRACT FROM AUTHOR]

Suicide rates in the United States have increased over the past 15 years, with substantial geographic variation in these increases; yet there have been few attempts to cluster counties by the magnitude of suicide rate changes according to intercept and slope or to identify the economic precursors of increases. We used vital statistics data and growth mixture models to identify clusters of counties by their magnitude of suicide growth from 2008 to 2020 and examined associations with county economic and labor indices. Our models identified 5 clusters, each differentiated by intercept and slope magnitude, with the highest-rate cluster (4% of counties) being observed mainly in sparsely populated areas in the West and Alaska, starting the time series at 25.4 suicides per 100,000 population, and exhibiting the steepest increase in slope (0.69/100,000/year). There was no cluster for which the suicide rate was stable or declining. Counties in the highest-rate cluster were more likely to have agricultural and service economies and less likely to have urban professional economies. Given the increased burden of suicide, with no clusters of counties improving over time, additional policy and prevention efforts are needed, particularly targeted at rural areas in the West. [ABSTRACT FROM AUTHOR]

Propensity score analysis is a common approach to addressing confounding in nonrandomized studies. Its implementation, however, requires important assumptions (e.g. positivity). The disease risk score (DRS) is an alternative confounding score that can relax some of these assumptions. Like the propensity score, the DRS summarizes multiple confounders into a single score, on which conditioning by matching allows the estimation of causal effects. However, matching relies on arbitrary choices for pruning out data (e.g. matching ratio, algorithm, and caliper width) and may be computationally demanding. Alternatively, weighting methods, common in propensity score analysis, are easy to implement and may entail fewer choices, yet none have been developed for the DRS. Here we present 2 weighting approaches: One derives directly from inverse probability weighting; the other, named target distribution weighting , relates to importance sampling. We empirically show that inverse probability weighting and target distribution weighting display performance comparable to matching techniques in terms of bias but outperform them in terms of efficiency (mean squared error) and computational speed (up to >870 times faster in an illustrative study). We illustrate implementation of the methods in 2 case studies where we investigate placebo treatments for multiple sclerosis and administration of aspirin in stroke patients. [ABSTRACT FROM AUTHOR]

Variable selection in regression models is a particularly important issue in epidemiology, where one usually encounters observational studies. In contrast to randomized trials or experiments, confounding is often not controlled by the study design, but has to be accounted for by suitable statistical methods. For instance, when risk factors should be identified with unconfounded effect estimates, multivariable regression techniques can help to adjust for confounders. We investigated the current practice of variable selection in 4 major epidemiologic journals in 2019 and found that the majority of articles used subject-matter knowledge to determine a priori the set of included variables. In comparison with previous reviews from 2008 and 2015, fewer articles applied data-driven variable selection. Furthermore, for most articles the main aim of analysis was hypothesis-driven effect estimation in rather low-dimensional data situations (i.e. large sample size compared with the number of variables). Based on our results, we discuss the role of data-driven variable selection in epidemiology. [ABSTRACT FROM AUTHOR]

In this paper, we advocate and expand upon a previously described monitoring strategy for efficient and robust estimation of disease prevalence and case numbers within closed and enumerated populations such as schools, workplaces, or retirement communities. The proposed design relies largely on voluntary testing, which is notoriously biased (e.g. in the case of coronavirus disease 2019) due to nonrepresentative sampling. The approach yields unbiased and comparatively precise estimates with no assumptions about factors underlying selection of individuals for voluntary testing, building on the strength of what can be a small random sampling component. This component enables the use of a recently proposed "anchor stream" estimator, a well-calibrated alternative to classical capture-recapture (CRC) estimators based on 2 data streams. We show that this estimator is equivalent to a direct standardization based on "capture," that is, selection (or not) by the voluntary testing program, made possible by means of a key parameter identified by design. This equivalency simultaneously allows for novel 2-stream CRC-like estimation of general mean values (e.g. means of continuous variables like antibody levels or biomarkers). For inference, we propose adaptations of Bayesian credible intervals when estimating case counts and bootstrapping when estimating means of continuous variables. We use simulations to demonstrate significant precision benefits relative to random sampling alone. [ABSTRACT FROM AUTHOR]

In this study, we compared location data from a dedicated Global Positioning System (GPS) device with location data from smartphones. Data from the Interventions, Equity, and Action in Cities Team (INTERACT) Study, a study examining the impact of urban-form changes on health in 4 Canadian cities (Victoria, Vancouver, Saskatoon, and Montreal), were used. A total of 337 participants contributed data collected for about 6 months from the Ethica Data smartphone application (Ethica Data Inc. Toronto, Ontario, Canada) and the SenseDoc dedicated GPS (MobySens Technologies Inc. Montreal, Quebec, Canada) during the period 2017–2019. Participants recorded an average total of 14,781 Ethica locations (standard deviation, 19,353) and 197,167 SenseDoc locations (standard deviation, 111,868). Dynamic time warping and cross-correlation were used to examine the spatial and temporal similarity of GPS points. Four activity-space measures derived from the smartphone app and the dedicated GPS device were compared. Analysis showed that cross-correlations were above 0.8 at the 125-m resolution for the survey and day levels and increased as cell size increased. At the day or survey level, there were only small differences between the activity-space measures. Based on our findings, we recommend dedicated GPS devices for studies where the exposure and the outcome are both measured at high frequency and when the analysis will not be aggregate. When the exposure and outcome are measured or will be aggregated to the day level, the dedicated GPS device and the smartphone app provide similar results. [ABSTRACT FROM AUTHOR]

Deep learning methods are increasingly being applied to problems in medicine and health care. However, few epidemiologists have received formal training in these methods. To bridge this gap, this article introduces the fundamentals of deep learning from an epidemiologic perspective. Specifically, this article reviews core concepts in machine learning (e.g. overfitting, regularization, and hyperparameters); explains several fundamental deep learning architectures (convolutional neural networks, recurrent neural networks); and summarizes training, evaluation, and deployment of models. Conceptual understanding of supervised learning algorithms is the focus of the article; instructions on the training of deep learning models and applications of deep learning to causal learning are out of this article's scope. We aim to provide an accessible first step towards enabling the reader to read and assess research on the medical applications of deep learning and to familiarize readers with deep learning terminology and concepts to facilitate communication with computer scientists and machine learning engineers. [ABSTRACT FROM AUTHOR]

Systematic error from selection bias, uncontrolled confounding, and misclassification is ubiquitous in epidemiologic research but is rarely quantified using quantitative bias analysis (QBA). This gap may in part be due to the lack of readily modifiable software to implement these methods. Our objective is to provide computing code that can be tailored to an analyst's dataset. We briefly describe the methods for implementing QBA for misclassification and uncontrolled confounding and present the reader with example code for how such bias analyses, using both summary-level data and individual record-level data, can be implemented in both SAS and R. Our examples show how adjustment for uncontrolled confounding and misclassification can be implemented. Resulting bias-adjusted point estimates can then be compared to conventional results to see the impact of this bias in terms of its direction and magnitude. Further, we show how 95% simulation intervals can be generated that can be compared to conventional 95% confidence intervals to see the impact of the bias on uncertainty. Having easy to implement code that users can apply to their own datasets will hopefully help spur more frequent use of these methods and prevent poor inferences drawn from studies that do not quantify the impact of systematic error on their results. [ABSTRACT FROM AUTHOR]

The aim of this study was to update and validate the Pregnancy Physical Activity Questionnaire (PPAQ), using novel and innovative accelerometer and wearable camera measures in a free-living setting, to improve the measurement performance of this method for self-reporting physical activity. A prospective cohort of 50 eligible pregnant women were enrolled in early pregnancy (mean = 14.9 weeks' gestation). In early, middle, and late pregnancy, participants completed the updated PPAQ and, for 7 days, wore an accelerometer (GT3X-BT; ActiGraph, Pensacola, Florida) on the nondominant wrist and a wearable camera (Autographer; OMG Life (defunct)). At the end of the 7-day period, participants repeated the PPAQ. Spearman correlations between the PPAQ and accelerometer data ranged from 0.37 to 0.44 for total activity, 0.17 to 0.53 for moderate- to vigorous-intensity activity, 0.19 to 0.42 for light-intensity activity, and 0.23 to 0.45 for sedentary behavior. Spearman correlations between the PPAQ and wearable camera data ranged from 0.52 to 0.70 for sports/exercise and from 0.26 to 0.30 for transportation activity. Reproducibility scores ranged from 0.70 to 0.92 for moderate- to vigorous-intensity activity and from 0.79 to 0.91 for sports/exercise, and were comparable across other domains of physical activity. The PPAQ is a reliable instrument and a valid measure of a broad range of physical activities during pregnancy. [ABSTRACT FROM AUTHOR]

Epidemiologic studies of low-frequency exposures or outcomes using metabolomics analyses of neonatal dried blood spots (DBS) often require assembly of samples with substantial differences in duration of storage. Independent assessment of stability of metabolites in archived DBS will enable improved design and interpretation of epidemiologic research utilizing DBS. Neonatal DBS routinely collected and stored as part of the California Genetic Disease Screening Program between 1983 and 2011 were used. The study population included 899 children without cancer before age 6 years, born in California. High-resolution metabolomics with liquid-chromatography mass spectrometry was performed, and the relative ion intensities of common metabolites and selected xenobiotic metabolites of nicotine (cotinine and hydroxycotinine) were evaluated. In total, we detected 26,235 mass spectral features across 2 separate chromatography methods (C18 hydrophobic reversed-phase chromatography and hydrophilic-interaction liquid chromatography). For most of the 39 metabolites related to nutrition and health status, we found no statistically significant annual trends across the years of storage. Nicotine metabolites were captured in the DBS with relatively stable intensities. This study supports the usefulness of DBS stored long-term for epidemiologic studies of the metabolome. -Omics-based information gained from DBS may also provide a valuable tool for assessing prenatal environmental exposures in child health research. [ABSTRACT FROM AUTHOR]

Prior applications of machine learning to population health have relied on conventional model assessment criteria, limiting the utility of models as decision support tools for public health practitioners. To facilitate practitioners' use of machine learning as a decision support tool for area-level intervention, we developed and applied 4 practice-based predictive model evaluation criteria (implementation capacity, preventive potential, health equity, and jurisdictional practicalities). We used a case study of overdose prevention in Rhode Island to illustrate how these criteria could inform public health practice and health equity promotion. We used Rhode Island overdose mortality records from January 2016–June 2020 (n  = 1,408) and neighborhood-level US Census data. We employed 2 disparate machine learning models, Gaussian process and random forest, to illustrate the comparative utility of our criteria to guide interventions. Our models predicted 7.5%–36.4% of overdose deaths during the test period, illustrating the preventive potential of overdose interventions assuming 5%–20% statewide implementation capacities for neighborhood-level resource deployment. We describe the health equity implications of use of predictive modeling to guide interventions along the lines of urbanicity, racial/ethnic composition, and poverty. We then discuss considerations to complement predictive model evaluation criteria and inform the prevention and mitigation of spatially dynamic public health problems across the breadth of practice. This article is part of a Special Collection on Mental Health. [ABSTRACT FROM AUTHOR]

Accurate forecasts can inform response to outbreaks. Most efforts in influenza forecasting have focused on predicting influenza-like activity, with fewer on influenza-related hospitalizations. We conducted a simulation study to evaluate a super learner's predictions of 3 seasonal measures of influenza hospitalizations in the United States: peak hospitalization rate, peak hospitalization week, and cumulative hospitalization rate. We trained an ensemble machine learning algorithm on 15,000 simulated hospitalization curves and generated weekly predictions. We compared the performance of the ensemble (weighted combination of predictions from multiple prediction algorithms), the best-performing individual prediction algorithm, and a naive prediction (median of a simulated outcome distribution). Ensemble predictions performed similarly to the naive predictions early in the season but consistently improved as the season progressed for all prediction targets. The best-performing prediction algorithm in each week typically had similar predictive accuracy compared with the ensemble, but the specific prediction algorithm selected varied by week. An ensemble super learner improved predictions of influenza-related hospitalizations, relative to a naive prediction. Future work should examine the super learner's performance using additional empirical data on influenza-related predictors (e.g. influenza-like illness). The algorithm should also be tailored to produce prospective probabilistic forecasts of selected prediction targets. [ABSTRACT FROM AUTHOR]

Unlike parametric regression, machine learning (ML) methods do not generally require precise knowledge of the true data-generating mechanisms. As such, numerous authors have advocated for ML methods to estimate causal effects. Unfortunately, ML algorithms can perform worse than parametric regression. We demonstrate the performance of ML-based singly and doubly robust estimators. We used 100 Monte Carlo samples with sample sizes of 200, 1,200, and 5,000 to investigate bias and confidence-interval coverage under several scenarios. In a simple confounding scenario, confounders were related to the treatment and the outcome via parametric models. In a complex confounding scenario, the simple confounders were transformed to induce complicated nonlinear relationships. In the simple scenario, when ML algorithms were used, double-robust estimators were superior to singly robust estimators. In the complex scenario, single-robust estimators with ML algorithms were at least as biased as estimators using misspecified parametric models. Doubly robust estimators were less biased, but coverage was well below nominal. The use of sample splitting, inclusion of confounder interactions, reliance on a richly specified ML algorithm, and use of doubly robust estimators was the only explored approach that yielded negligible bias and nominal coverage. Our results suggest that ML-based singly robust methods should be avoided. [ABSTRACT FROM AUTHOR]

Background Studies examining the potential impact of mothers' health during pregnancy on the health of their offspring often rely on self-reported information gathered several years later. To assess the validity of this approach, we analysed data from a national case–control study of childhood cancer (diagnosed <15 years) that collected health information from both interviews and medical records. Methods Mothers' interview reports of infections and medications in pregnancy were compared with primary care records. Taking clinical diagnoses and prescriptions as the reference, sensitivity and specificity of maternal recall along with kappa coefficients of agreement were calculated. Differences in the odd ratios estimated using logistic regression for each information source were assessed using the proportional change in the odds ratio (OR). Results Mothers of 1624 cases and 2524 controls were interviewed ∼6 years (range 0–18 years) after their child's birth. Most drugs and infections were underreported; in general practitioner records, antibiotic prescriptions were nearly three times higher and infections >40% higher. Decreasing with increasing time since pregnancy, sensitivity was ⩽40% for most infections and all drugs except 'anti-epileptics and barbiturates' (sensitivity 80% among controls). ORs associated with individual drug/disease categories that were based on self-reported data varied from 26% lower to 26% higher than those based on medical records; reporting differences between mothers of cases and controls were not systematically in the same direction. Conclusions The findings highlight the scale of under-reporting and poor validity of questionnaire-based studies conducted several years after pregnancy. Future research using prospectively collected data should be encouraged to minimize measurement errors. [ABSTRACT FROM AUTHOR]

The Environmental Influences on Child Health Outcomes (ECHO)-Wide Cohort Study (EWC), a collaborative research design comprising 69 cohorts in 31 consortia, was funded by the National Institutes of Health (NIH) in 2016 to improve children's health in the United States. The EWC harmonizes extant data and collects new data using a standardized protocol, the ECHO-Wide Cohort Data Collection Protocol (EWCP). EWCP visits occur at least once per life stage, but the frequency and timing of the visits vary across cohorts. As of March 4, 2022, the EWC cohorts contributed data from 60,553 children and consented 29,622 children for new EWCP data and biospecimen collection. The median (interquartile range) age of EWCP-enrolled children was 7.5 years (3.7–11.1). Surveys, interviews, standardized examinations, laboratory analyses, and medical record abstraction are used to obtain information in 5 main outcome areas: pre-, peri-, and postnatal outcomes; neurodevelopment; obesity; airways; and positive health. Exposures include factors at the level of place (e.g. air pollution, neighborhood socioeconomic status), family (e.g. parental mental health), and individuals (e.g. diet, genomics). [ABSTRACT FROM AUTHOR]

Inverse probability weighting (IPW), a well-established method of controlling for confounding in observational studies with binary exposures, has been extended to analyses with continuous exposures. Methods developed for continuous exposures may not apply when the exposure is quasicontinuous because of irregular exposure distributions that violate key assumptions. We used simulations and cluster-randomized clinical trial data to assess 4 approaches developed for continuous exposures—ordinary least squares (OLS), covariate balancing generalized propensity scores (CBGPS), nonparametric covariate balancing generalized propensity scores (npCBGPS), and quantile binning (QB)—and a novel method, a cumulative probability model (CPM), in quasicontinuous exposure settings. We compared IPW stability, covariate balance, bias, mean squared error, and standard error estimation across 3,000 simulations with 6 different quasicontinuous exposures, varying in skewness and granularity. In general, CBGPS and npCBGPS resulted in excellent covariate balance, and npCBGPS was the least biased but the most variable. The QB and CPM approaches had the lowest mean squared error, particularly with marginally skewed exposures. We then successfully applied the IPW approaches, together with missing-data techniques, to assess how session attendance (out of a possible 15) in a partners-based clustered intervention among pregnant couples living with human immunodeficiency virus in Mozambique (2017–2022) influenced postpartum contraceptive uptake. [ABSTRACT FROM AUTHOR]

Dimitris et al. (Am J Epidemiol. 2022;191(6):980–986) outline how the coronavirus disease 2019 (COVID-19) pandemic has, with mixed results, put epidemiology under the spotlight. While epidemiologic theory and methods have been critical in many successes, the ongoing global death toll from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the sometimes chaotic public messaging underscore that epidemiology as a field has room for improvement. Here, we use examples from psychiatric epidemiologic studies conducted during the COVID-19 era to reflect on errors driven by overlooking specific major methodological advances of modern epidemiology. We focus on: 1) use of nonrepresentative sampling in online surveys, which limits the potential knowledge to be gained from descriptive studies and amplifies collider stratification bias in causal studies; and 2) failure to acknowledge multiple versions of exposures (e.g. lockdown, school closure) and differences in prevalence of effect measure modifiers across contexts, which causes violations of the consistency assumption and lack of effect transportability. We finish by highlighting: 1) the heterogeneity of psychiatric epidemiologic results during the pandemic across place and sociodemographic groups and over time; 2) the importance of following the foundational advancements of modern epidemiology even in emergency settings; and 3) the need to limit the role of political agendas in cherry-picking and reporting epidemiologic evidence. [ABSTRACT FROM AUTHOR]

Background: Traditionally, heritability has been estimated using family-based methods such as twin studies. Advancements in molecular genomics have facilitated the development of methods that use large samples of (unrelated or related) genotyped individuals.Methods: Here, we provide an overview of common methods applied in genetic epidemiology to estimate heritability, i.e. the proportion of phenotypic variation explained by genetic variation. We provide a guide to key genetic concepts required to understand heritability estimation methods from family-based designs (twin and family studies), genomic designs based on unrelated individuals [linkage disequilibrium score regression, genomic relatedness restricted maximum-likelihood (GREML) estimation] and family-based genomic designs (sibling regression, GREML-kinship, trio-genome-wide complex trait analysis, maternal-genome-wide complex trait analysis, relatedness disequilibrium regression).Results: We describe how heritability is estimated for each method and the assumptions underlying its estimation, and discuss the implications when these assumptions are not met. We further discuss the benefits and limitations of estimating heritability within samples of unrelated individuals compared with samples of related individuals.Conclusions: Overall, this article is intended to help the reader determine the circumstances when each method would be appropriate and why. [ABSTRACT FROM AUTHOR]

In diagnostic medicine, the true disease status of a patient is often represented on an ordinal scale—for example, cancer stage (0, I, II, III, or IV) or coronary artery disease severity measured using the Coronary Artery Disease Reporting and Data System (CAD-RADS) scale (none, minimal, mild, moderate, severe, or occluded). With advances in quantitation of diagnostic images and in artificial intelligence (AI), both supervised and unsupervised algorithms are being developed to help physicians correctly grade disease. Most of the diagnostic accuracy literature deals with binary disease status (disease present or absent); however, tests diagnosing ordinal-scaled diseases should not be reduced to a binary status just to simplify diagnostic accuracy testing. In this paper, we propose different characterizations of ordinal-scale accuracy for different clinical use scenarios, along with methods for comparing tests. In the simplest scenario, just the proportion of correct grades is considered; other scenarios address the magnitude and direction of misgrading; and at the other extreme, a weighted accuracy measure with weights based on the relative costs of different types of misgrading is presented. The various scenarios are illustrated using a coronary artery disease example where the accuracy of AI algorithms in providing patients with the correct CAD-RADS grade is assessed. [ABSTRACT FROM AUTHOR]

The All of Us Research Program, a health and genetics epidemiologic data collection program, has been substantially affected by the coronavirus disease 2019 (COVID-19) pandemic. Although the program is highly digital in nature, certain aspects of the data collection require in-person interaction between staff and participants. Before the pandemic, the program was enrolling approximately 12,500 participants per month at more than 400 clinical sites. In March 2020, because of the pandemic, all in-person activity at program sites and by engagement partners was paused to develop processes and procedures for in-person activities that incorporated strict safety protocols. In addition, the program adopted new data collection methodologies to reduce the need for in-person activities. Through February 2022, a total of 224 clinical sites had reactivated in-person activity, and all enrollment and engagement partners have adopted new data collection methods that can be used remotely. As the COVID-19 pandemic persists, the program continues to require safety procedures for in-person activity and continues to generate and pilot methodologies that reduce risk and make it easier for participants to provide information. [ABSTRACT FROM AUTHOR]

There have been calls for race to be denounced as a biological variable and for a greater focus on racism, instead of solely race, when studying racial health disparities in the United States. These calls are grounded in extensive scholarship and the rationale that race is not a biological variable, but instead socially constructed, and that structural/institutional racism is a root cause of race-related health disparities. However, there remains a lack of clear guidance for how best to incorporate these assertions about race and racism into tools, such as causal diagrams, that are commonly used by epidemiologists to study population health. We provide clear recommendations for using causal diagrams to study racial health disparities that were informed by these calls. These recommendations consider a health disparity to be a difference in a health outcome that is related to social, environmental, or economic disadvantage. We present simplified causal diagrams to illustrate how to implement our recommendations. These diagrams can be modified based on the health outcome and hypotheses, or for other group-based differences in health also rooted in disadvantage (e.g. gender). Implementing our recommendations may lead to the publication of more rigorous and informative studies of racial health disparities. [ABSTRACT FROM AUTHOR]

A covariate-adjusted estimate of an exposure-outcome association may be biased if the exposure variable suffers measurement error. We propose an approach to correct for exposure measurement error in a covariate-adjusted estimate of the association between a continuous exposure variable and outcome of interest. Our proposed approach requires data for a reference population in which the exposure was a priori set to some known level (e.g. 0, and is therefore unexposed); however, our approach does not require an exposure validation study or replicate measures of exposure, which are typically needed when addressing bias due to exposure measurement error. A key condition for this method, which we refer to as "partial population exchangeability," requires that the association between a measured covariate and outcome in the reference population equals the association between that covariate and outcome in the target population in the absence of exposure. We illustrate the approach using simulations and an example. [ABSTRACT FROM AUTHOR]

Dengue is a serious public health concern in Brazil and globally. In the absence of a universal vaccine or specific treatments, prevention relies on vector control and disease surveillance. Accurate and early forecasts can help reduce the spread of the disease. In this study, we developed a model for predicting monthly dengue cases in Brazilian cities 1 month ahead, using data from 2007–2019. We compared different machine learning algorithms and feature selection methods using epidemiologic and meteorological variables. We found that different models worked best in different cities, and a random forests model trained on monthly dengue cases performed best overall. It produced lower errors than a seasonal naive baseline model, gradient boosting regression, a feed-forward neural network, or support vector regression. For each city, we computed the mean absolute error between predictions and true monthly numbers of dengue cases on the test data set. The median error across all cities was 12.2 cases. This error was reduced to 11.9 when selecting the optimal combination of algorithm and input features for each city individually. Machine learning and especially decision tree ensemble models may contribute to dengue surveillance in Brazil, as they produce low out-of-sample prediction errors for a geographically diverse set of cities. [ABSTRACT FROM AUTHOR]

Epidemiology has traditionally used quantitative approaches to characterizing disease prevalence and studying the effects of medical and public health interventions. Despite the power of such methods, they leave important gaps in understanding population health that can be addressed using qualitative and mixed methods. In this commentary, I describe philosophical differences in qualitative and quantitative approaches to research and explain how they can be used together to strengthen epidemiologic inquiry. [ABSTRACT FROM AUTHOR]

Ensuring that patients with opioid use disorder (OUD) have access to optimal medication therapies is a critical challenge in substance use epidemiology. Rudolph et al. (Am J Epidemiol. 2023;XXX(X):XXXX-XXXX) demonstrated that sophisticated data-adaptive statistical techniques can be used to learn optimal, individualized treatment rules that can aid providers in choosing a medication treatment modality for a particular patient with OUD. This important work also highlights the effects of the mathematization of epidemiologic research. Here, we define mathematization and demonstrate how it operates in the context of effectiveness research on medications for OUD using the paper by Rudolph et al. as a springboard. In particular, we address the normative dimension of mathematization and how it tends to resolve a fundamental tension in epidemiologic practice between technical sophistication and public health considerations in favor of more technical solutions. The process of mathematization is a fundamental part of epidemiology; we argue not for eliminating it but for balancing mathematization and technical demands equally with practical and community-centric public health needs. [ABSTRACT FROM AUTHOR]

There is growing acknowledgement of the legacy of White supremacy and racism in the discipline of epidemiology. Our department in the University of Washington School of Public Health undertook a systematic effort to begin addressing institutionalized racism and inclusive teaching in our courses. In July 2020, we introduced a new tool (the "Course Development Plan" (CDP)) to advance our curriculum. The CDP includes 2 components: 1) a guideline document that provides strategies on how to modify curricula and classroom teaching to incorporate antiracism and principles of equity, diversity, and inclusion (EDI); and 2) a structured worksheet for instructors to share EDI and antiracism practices they already incorporate and practices they plan to incorporate into their classes. Worksheets for each class are submitted prior to the beginning of the quarter and are reviewed by a peer faculty member and at least 1 epidemiology student; reviewers provide written feedback on the CDP worksheet. Further evaluation to assess the impact of the CDP process on classroom climate is ongoing. In this commentary, we discuss our department's efforts, the challenges we faced, and our hopes for next steps. [ABSTRACT FROM AUTHOR]

Measurement error is pervasive in epidemiologic research. Epidemiologists often assume that mismeasurement of study variables is nondifferential with respect to other analytical variables and then rely on the heuristic that "nondifferential misclassification will bias estimates towards the null." However, there are many exceptions to the heuristic for which bias towards the null cannot be assumed. In this paper, we compile and characterize 7 exceptions to this rule and encourage analysts to take a more critical and nuanced approach to evaluating and discussing bias from nondifferential mismeasurement. [ABSTRACT FROM AUTHOR]

Simulation methods are a powerful set of tools that can allow researchers to better characterize phenomena from the real world. As such, the ability to simulate data represents a critical set of skills that epidemiologists should use to better understand epidemiologic concepts and ensure that they have the tools to continue to self-teach even when their formal instruction ends. Simulation methods are not always taught in epidemiology methods courses, whereas causal directed acyclic graphs (DAGs) often are. Therefore, this paper details an approach to building simulations from DAGs and provides examples and code for learning to perform simulations. We recommend using very simple DAGs to learn the procedures and code necessary to set up a simulation that builds on key concepts frequently of interest to epidemiologists (e.g. mediation, confounding bias, M bias). We believe that following this approach will allow epidemiologists to gain confidence with a critical skill set that may in turn have a positive impact on how they conduct future epidemiologic studies. [ABSTRACT FROM AUTHOR]

In this paper, we consider methods for generating draws of a binary random variable whose expectation conditional on covariates follows a logistic regression model with known covariate coefficients. We examine approximations for finding a "balancing intercept," that is, a value for the intercept of the logistic model that leads to a desired marginal expectation for the binary random variable. We show that a recently proposed analytical approximation can produce inaccurate results, especially when targeting more extreme marginal expectations or when the linear predictor of the regression model has high variance. We then formulate the balancing intercept as a solution to an integral equation, implement a numerical approximation for solving the equation based on Monte Carlo methods, and show that the approximation works well in practice. Our approach to the basic problem of the balancing intercept provides an example of a broadly applicable strategy for formulating and solving problems that arise in the design of simulation studies used to evaluate or teach epidemiologic methods. [ABSTRACT FROM AUTHOR]

Data collected from a validation substudy permit calculation of a bias-adjusted estimate of effect that is expected to equal the estimate that would have been observed had the gold standard measurement been available for the entire study population. In this paper, we develop and apply a framework for adaptive validation to determine when sufficient validation data have been collected to yield a bias-adjusted effect estimate with a prespecified level of precision. Prespecified levels of precision are decided a priori by the investigator, based on the precision of the conventional estimate and allowing for wider confidence intervals that would still be substantively meaningful. We further present an applied example of the use of this method to address exposure misclassification in a study of transmasculine/transfeminine youth and self-harm. Our method provides a novel approach to effective and efficient estimation of classification parameters as validation data accrue, with emphasis on the precision of the bias-adjusted estimate. This method can be applied within the context of any parent epidemiologic study design in which validation data will be collected and modified to meet alternative criteria given specific study or validation study objectives. [ABSTRACT FROM AUTHOR]

Observational studies of oseltamivir use and influenza complications could suffer from residual confounding. Using negative control risk periods and a negative control outcome, we examined confounding control in a health-insurance-claims–based study of oseltamivir and influenza complications (pneumonia, all-cause hospitalization, and dispensing of an antibiotic). Within the Food and Drug Administration's Sentinel System, we identified individuals aged ≥18 years who initiated oseltamivir use on the influenza diagnosis date versus those who did not, during 3 influenza seasons (2014–2017). We evaluated primary outcomes within the following 1–30 days (the primary risk period) and 61–90 days (the negative control period) and nonvertebral fractures (the negative control outcome) within days 1–30. We estimated propensity-score–matched risk ratios (RRs) per season. During the 2014–2015 influenza season, oseltamivir use was associated with a reduction in the risk of pneumonia (RR = 0.72, 95% confidence interval (CI): 0.70, 0.75) and all-cause hospitalization (RR = 0.54, 95% CI: 0.53, 0.55) in days 1–30. During days 61–90, estimates were near-null for pneumonia (RR = 1.04, 95% CI: 0.95, 1.15) and hospitalization (RR = 0.94, 95% CI: 0.91, 0.98) but slightly increased for antibiotic dispensing (RR = 1.14, 95% CI: 1.08, 1.21). The RR for fractures was near-null (RR = 1.09, 95% CI: 0.99, 1.20). Estimates for the 2016–2017 influenza season were comparable, while the 2015–2016 season had conflicting results. Our study suggests minimal residual confounding for specific outcomes, but results differed by season. [ABSTRACT FROM AUTHOR]

Racial residential segregation is associated with multiple adverse health outcomes in Black individuals. Yet, the influence of structural racism and racial residential segregation on brain aging is less understood. In this study, we investigated the association between cumulative exposure to racial residential segregation over 25 years (1985–2010) in young adulthood, as measured by the Getis-Ord Gi* statistic, and year 25 measures of brain volume (cerebral, gray matter, white matter, and hippocampal volumes) in midlife. We studied 290 Black participants with available brain imaging data who were enrolled in the Coronary Artery Risk Development in Young Adults (CARDIA) Study, a prospective cohort study. CARDIA investigators originally recruited 2,637 Black participants aged 18–30 years from 4 field centers across the United States. We conducted analyses using marginal structural models, incorporating inverse probability of treatment weighting and inverse probability of censoring weighting. We found that compared with low/medium segregation, greater cumulative exposure to a high level of racial residential segregation throughout young adulthood was associated with smaller brain volumes in general (e.g. for cerebral volume, β = –0.08, 95% confidence interval: −0.15, −0.02) and with a more pronounced reduction in hippocampal volume, though results were not statistically significant. Our findings suggest that exposure to segregated neighborhoods may be associated with worse brain aging. [ABSTRACT FROM AUTHOR]

In their recent article, Ogburn et al. (Am J Epidemiol. 2021;190(6):1142–1147) raised a cautionary tale for epidemiologic data fusion: Bias may occur if a variable that is completely missing in the primary data set is imputed according to a regression model estimated from an auxiliary data set. However, in some specific settings, a solution may exist. Focusing on a linear outcome regression model with a missing covariate, we show that the bias can be eliminated if the underlying imputation model for the missing covariate is nonlinear in the common variables measured in both data sets. Otherwise, we describe 2 alternative approaches existing in the data fusion literature that could partially resolve this issue: One fits the outcome model by leveraging an additional validation data set containing joint observations of the outcome and the missing covariate, and the other offers informative bounds for the outcome regression coefficients without using validation data. We justify these 3 methods in a linear outcome model and briefly discuss their extension to general settings. [ABSTRACT FROM AUTHOR]

Predictors of opioid overdose death in neighborhoods are important to identify, both to understand characteristics of high-risk areas and to prioritize limited prevention and intervention resources. Machine learning methods could serve as a valuable tool for identifying neighborhood-level predictors. We examined statewide data on opioid overdose death from Rhode Island (log-transformed rates for 2016–2019) and 203 covariates from the American Community Survey for 742 US Census block groups. The analysis included a least absolute shrinkage and selection operator (LASSO) algorithm followed by variable importance rankings from a random forest algorithm. We employed double cross-validation, with 10 folds in the inner loop to train the model and 4 outer folds to assess predictive performance. The ranked variables included a range of dimensions of socioeconomic status, including education, income and wealth, residential stability, race/ethnicity, social isolation, and occupational status. The R 2 value of the model on testing data was 0.17. While many predictors of overdose death were in established domains (education, income, occupation), we also identified novel domains (residential stability, racial/ethnic distribution, and social isolation). Predictive modeling with machine learning can identify new neighborhood-level predictors of overdose in the continually evolving opioid epidemic and anticipate the neighborhoods at high risk of overdose mortality. [ABSTRACT FROM AUTHOR]

To determine potential measurement error related to the assessment of lifetime discrimination, Van Dyke et al. (Am J Epidemiol. 2022;191(3):370–378) investigated inconsistencies in reporting of racial, socioeconomic status, and sex discrimination over time among Black and White adults enrolled in the Coronary Artery Risk Development in Young Adults (CARDIA) Study. The authors found that "ever" reports of discrimination (as assessed by the Experiences of Discrimination Scale) decreased over time and that populations who most experience discrimination (i.e. Black/African-American people, younger persons, persons of low socioeconomic status, and women) were often also the most likely to inconsistently report discrimination over the course of the study period (from 1992 to 2010). The authors have raised an important issue related to the potential underestimation of lifetime discrimination that may depend on when discrimination is assessed, as well as the social identity of individuals surveyed. With implications for health inequities, these findings highlight study design and methodological issues that should be addressed to accurately estimate the true burden discrimination places on health. In this commentary, we further illuminate potential methodological challenges and opportunities to consider when investigating the impact of discrimination on health. [ABSTRACT FROM AUTHOR]

Data-sharing improves epidemiologic research, but the sharing of data frustrates epidemiologic researchers. The inefficiencies of current methods and options for data-sharing are increasingly documented and easily understood by any study group that has shared its data and any researcher who has received shared data. In this issue of the Journal , Temprosa et al. (Am J Epidemiol. 2021;191(1):147–158) describe how the Consortium of Metabolomics Studies (COMETS) developed and deployed a flexible analytical platform to eliminate key pain points in large-scale metabolomics research. COMETS Analytics includes an online tool, but its cloud computing and technology are the supporting rather than the leading actors in this script. The COMETS team identified the need to standardize diverse and inconsistent metabolomics and covariate data and models across its many participating cohort studies, and then developed a flexible tool that gave its member studies choices about how they wanted to meet the consortium's analytical requirements. Different specialties will have different specific research needs and will probably continue to use and develop an array of diverse analytical and technical solutions for their projects. COMETS Analytics shows how important—and enabling—the upstream attention to data standards and data consistency is to producing high-quality metabolomics, consortia-based, and large-scale epidemiology research. [ABSTRACT FROM AUTHOR]

Observational epidemiologic studies typically face challenges of exposure measurement error and confounding. Consider an observational study of the association between a continuous exposure and an outcome, where the exposure variable of primary interest suffers from classical measurement error (i.e. the measured exposures are distributed around the true exposure with independent error). In the absence of exposure measurement error, it is widely recognized that one should control for confounders of the association of interest to obtain an unbiased estimate of the effect of that exposure on the outcome of interest. However, here we show that, in the presence of classical exposure measurement error, the net bias in an estimate of the association of interest may increase upon adjustment for confounders. We offer an analytical expression for calculating the change in net bias in an estimate of the association of interest upon adjustment for a confounder in the presence of classical exposure measurement error, and we illustrate this problem using simulations. [ABSTRACT FROM AUTHOR]

Effect measure modification is often evaluated using parametric models. These models, although efficient when correctly specified, make strong parametric assumptions. While nonparametric models avoid important functional form assumptions, they often require larger samples to achieve a given accuracy. We conducted a simulation study to evaluate performance tradeoffs between correctly specified parametric and nonparametric models to detect effect modification of a binary exposure by both binary and continuous modifiers. We evaluated generalized linear models and doubly robust (DR) estimators, with and without sample splitting. Continuous modifiers were modeled with cubic splines, fractional polynomials, and nonparametric DR-learner. For binary modifiers, generalized linear models showed the greatest power to detect effect modification, ranging from 0.42 to 1.00 in the worst and best scenario, respectively. Augmented inverse probability weighting had the lowest power, with an increase of 23% when using sample splitting. For continuous modifiers, the DR-learner was comparable to flexible parametric models in capturing quadratic and nonlinear monotonic functions. However, for nonlinear, nonmonotonic functions, the DR-learner had lower integrated bias than splines and fractional polynomials, with values of 141.3, 251.7, and 209.0, respectively. Our findings suggest comparable performance between nonparametric and correctly specified parametric models in evaluating effect modification. [ABSTRACT FROM AUTHOR]

Although observational studies have identified modifiable risk factors for Alzheimer disease and related dementias (ADRD), randomized controlled trials (RCTs) of risk factor modification for ADRD prevention have been inconsistent or inconclusive. This finding suggests a need to improve translation between observational studies and RCTs. However, many common features of observational studies reduce their relevance to designing related RCTs. Observational studies routinely differ from RCTs with respect to eligibility criteria, study population, length of follow-up, treatment conditions, outcomes, and effect estimates. Using the motivating example of blood pressure reduction for ADRD prevention, we illustrate the need for a tighter connection between observational studies and RCTs, discuss barriers to using typically reported observational evidence in developing RCTs, and highlight methods that may be used to make observational research more relevant to clinical trial design. We conclude that the questions asked and answered by observational research can be made more relevant to clinical trial design and that better use of observational data may increase the likelihood of successful, or at least definitive, trials. Although we focus on improving translation of observational studies on risk factors for ADRD to RCTs in ADRD prevention, the overarching themes are broadly applicable to many areas of biomedical research. [ABSTRACT FROM AUTHOR]

An increasing number of recent studies have suggested that doubly robust estimators with cross-fitting should be used when estimating causal effects with machine learning methods. However, not all existing programs that implement doubly robust estimators support machine learning methods and cross-fitting, or provide estimates on multiplicative scales. To address these needs, we developed AIPW , a software package implementing augmented inverse probability weighting (AIPW) estimation of average causal effects in R (R Foundation for Statistical Computing, Vienna, Austria). Key features of the AIPW package include cross-fitting and flexible covariate adjustment for observational studies and randomized controlled trials (RCTs). In this paper, we use a simulated RCT to illustrate implementation of the AIPW estimator. We also perform a simulation study to evaluate the performance of the AIPW package compared with other doubly robust implementations, including CausalGAM , npcausal , tmle , and tmle3. Our simulation showed that the AIPW package yields performance comparable to that of other programs. Furthermore, we also found that cross-fitting substantively decreases the bias and improves the confidence interval coverage for doubly robust estimators fitted with machine learning algorithms. Our findings suggest that the AIPW package can be a useful tool for estimating average causal effects with machine learning methods in RCTs and observational studies. [ABSTRACT FROM AUTHOR]

Lash et al. (Am J Epidemiol. 2021;190(8):1604–1612) have presented detailed critiques of 3 bias analyses that they identify as "suboptimal." This identification raises the question of what "optimal" means for bias analysis, because it is practically impossible to do statistically optimal analyses of typical population studies—with or without bias analysis. At best the analysis can only attempt to satisfy practice guidelines and account for available information both within and outside the study. One should not expect a full accounting for all sources of uncertainty; hence, interval estimates and distributions for causal effects should never be treated as valid uncertainty assessments—they are instead only example analyses that follow from collections of often questionable assumptions. These observations reinforce those of Lash et al. and point to the need for more development of methods for judging bias-parameter distributions and utilization of available information. [ABSTRACT FROM AUTHOR]

Quantitative bias analysis comprises the tools used to estimate the direction, magnitude, and uncertainty from systematic errors affecting epidemiologic research. Despite the availability of methods and tools, and guidance for good practices, few reports of epidemiologic research incorporate quantitative estimates of bias impacts. The lack of familiarity with bias analysis allows for the possibility of misuse, which is likely most often unintentional but could occasionally include intentional efforts to mislead. We identified 3 examples of suboptimal bias analysis, one for each common bias. For each, we describe the original research and its bias analysis, compare the bias analysis with good practices, and describe how the bias analysis and research findings might have been improved. We assert no motive to the suboptimal bias analysis by the original authors. Common shortcomings in the examples were lack of a clear bias model, computed example, and computing code; poor selection of the values assigned to the bias model's parameters; and little effort to understand the range of uncertainty associated with the bias. Until bias analysis becomes more common, community expectations for the presentation, explanation, and interpretation of bias analyses will remain unstable. Attention to good practices should improve quality, avoid errors, and discourage manipulation. [ABSTRACT FROM AUTHOR]

Machine learning is gaining prominence in the health sciences, where much of its use has focused on data-driven prediction. However, machine learning can also be embedded within causal analyses, potentially reducing biases arising from model misspecification. Using a question-and-answer format, we provide an introduction and orientation for epidemiologists interested in using machine learning but concerned about potential bias or loss of rigor due to use of "black box" models. We conclude with sample software code that may lower the barrier to entry to using these techniques. [ABSTRACT FROM AUTHOR]

To extend previous simulations on the performance of propensity score (PS) weighting and trimming methods to settings without and with unmeasured confounding, Poisson outcomes, and various strengths of treatment prediction (PS c statistic), we simulated studies with a binary intended treatment T as a function of 4 measured covariates. We mimicked treatment withheld and last-resort treatment by adding 2 "unmeasured" dichotomous factors that directed treatment to change for some patients in both tails of the PS distribution. The number of outcomes Y was simulated as a Poisson function of T and confounders. We estimated the PS as a function of measured covariates and trimmed the tails of the PS distribution using 3 strategies ("Crump," "Stürmer," and "Walker"). After trimming and reestimation, we used alternative PS weights to estimate the treatment effect (rate ratio): inverse probability of treatment weighting, standardized mortality ratio (SMR)-treated, SMR-untreated, the average treatment effect in the overlap population (ATO), matching, and entropy. With no unmeasured confounding, the ATO (123%) and "Crump" trimming (112%) improved relative efficiency compared with untrimmed inverse probability of treatment weighting. With unmeasured confounding, untrimmed estimates were biased irrespective of weighting method, and only Stürmer and Walker trimming consistently reduced bias. In settings where unmeasured confounding (e.g. frailty) may lead physicians to withhold treatment, Stürmer and Walker trimming should be considered before primary analysis. [ABSTRACT FROM AUTHOR]

New-user designs restricting to treatment initiators have become the preferred design for studying drug comparative safety and effectiveness using nonexperimental data. This design reduces confounding by indication and healthy-adherer bias at the cost of smaller study sizes and reduced external validity, particularly when assessing a newly approved treatment compared with standard treatment. The prevalent new-user design includes adopters of a new treatment who switched from or previously used standard treatment (i.e. the comparator), expanding study sample size and potentially broadening the study population for inference. Previous work has suggested the use of time-conditional propensity-score matching to mitigate prevalent user bias. In this study, we describe 3 "types" of initiators of a treatment: new users, direct switchers, and delayed switchers. Using these initiator types, we articulate the causal questions answered by the prevalent new-user design and compare them with those answered by the new-user design. We then show, using simulation, how conditioning on time since initiating the comparator (rather than full treatment history) can still result in a biased estimate of the treatment effect. When implemented properly, the prevalent new-user design estimates new and important causal effects distinct from the new-user design. [ABSTRACT FROM AUTHOR]

In this study, we aimed to estimate the causal effect of normalized protein catabolic rate (nPCR) on mortality among end-stage renal disease (ESRD) patients in the presence of time-varying confounding affected by prior exposure using g-estimation. Information about 553 ESRD patients was retrospectively collected over an 8-year period (2011–2019) from hemodialysis facilities in Kerman, Iran. nPCR was dichotomized as <1.2 g/kg/day versus ≥1.2 g/kg/day. Then a standard time-varying accelerated failure time (AFT) Weibull model was built, and results were compared with those generated by g-estimation. After appropriate adjustment for time-varying confounders, weighted g-estimation yielded 78% shorter survival time (95% confidence interval (95% CI): −81, −73) among patients with a continuous nPCR <1.2 g/kg/day than among those who had nPCR ≥1.2 g/kg/day during follow-up, though it was 18% (95% CI: −57, 54) in the Weibull model. Moreover, hazard ratio estimates of 4.56 (95% CI: 3.69, 5.37) and 1.20 (95% CI: 0.66, 2.17) were obtained via weighted g-estimation and the Weibull model, respectively. G-estimation indicated that inadequate dietary protein intake characterized by nPCR increases all-cause mortality among ESRD patients, but the Weibull model provided an effect estimate that was substantially biased toward the null. [ABSTRACT FROM AUTHOR]

Observational pharmacoepidemiological studies using routinely collected healthcare data are increasingly being used in the field of nephrology to answer questions on the effectiveness and safety of medications. This review discusses a number of biases that may arise in such studies and proposes solutions to minimize them during the design or statistical analysis phase. We first describe designs to handle confounding by indication (e.g. active comparator design) and methods to investigate the influence of unmeasured confounding, such as the E-value, the use of negative control outcomes and control cohorts. We next discuss prevalent user and immortal time biases in pharmacoepidemiology research and how these can be prevented by focussing on incident users and applying either landmarking, using a time-varying exposure, or the cloning, censoring and weighting method. Lastly, we briefly discuss the common issues with missing data and misclassification bias. When these biases are properly accounted for, pharmacoepidemiological observational studies can provide valuable information for clinical practice. [ABSTRACT FROM AUTHOR]