Sebastian Schneeweiss

Brigham and Women's Hospital, Harvard Medical School · Department of Medicine, Div of Pharmacoepidemiology

Adjusting for large numbers of covariates ascertained from patients' health care claims data may improve control of confounding, as these variables may collectively be proxies for unobserved factors. Here, we develop and test an algorithm that empirically identifies candidate covariates, prioritizes covariates, and integrates them into a propensity...

Pharmacoepidemiologic and pharmacoeconomic analysis of health care databases has become a vital source of evidence to support health care decision making and efficient management of health care organizations. However, decision makers often consider studies done in nonrandomized health care databases more difficult to review than randomized trials b...

Real-world Evidence (RWE), the understanding of treatment effectiveness in clinical practice generated from longitudinal patient-level data from the routine operation of the healthcare system, is thought to complement evidence on the efficacy of medications from RCTs. RWE studies follow a structured approach: (1) A design layer decides on the study...

Studies that generate real-world evidence on the effects of medical products through analysis of digital data collected in clinical practice provide key insights for regulators, payers, and other healthcare decision-makers. Ensuring reproducibility of such findings is fundamental to effective evidence-based decision-making. We reproduce results for...

Importance: Nonrandomized studies using insurance claims databases can be analyzed to produce real-world evidence on the effectiveness of medical products. Given the lack of baseline randomization and measurement issues, concerns exist about whether such studies produce unbiased treatment effect estimates. Objective: To emulate the design of 30...

Purpose For observational cohort studies that employ matching by propensity scores ( PS ), preliminary stratification by consequential predictors of outcome better emulates stratified randomization and potentially reduces variance and bias through relaxed dependence on modeling assumptions. We assessed the impact of pre‐stratification in two real‐l...

The INVESTED trial did not show benefits of high‐dose (HD) vaccine vs. standard‐dose (SD) for a primary composite outcome of cardiopulmonary hospitalization or all‐cause mortality (hazard ratio [HR]=1.05;95% CI=0.96‐1.15) and its components (all‐cause mortality HR=1.01;0.84‐1.21, cardiopulmonary hospitalization HR=1.05;0.96‐1.16) during three influ...

Importance Observational (nonexperimental) studies that aim to emulate a randomized trial (ie, the target trial) are increasingly informing medical and policy decision-making, but it is unclear how these studies are reported in the literature. Consistent reporting is essential for quality appraisal, evidence synthesis, and translation of evidence t...

Real-world evidence (RWE) data is increasingly important to generate rapid insights to effectively manage patient populations. Disruptions like the coronavirus disease 2019 (COVID-19) pandemic may negatively impact the choice of medications used for managing chronic diseases such as psoriasis (PSO). Here, we explored the effect of the COVID-19 pand...

Background Observational studies are increasingly used to inform health decision-making when randomised trials are not feasible, ethical or timely. The target trial approach provides a framework to help minimise common biases in observational studies that aim to estimate the causal effect of interventions. Incomplete reporting of studies using the...

Objective: To evaluate the comparative cardiovascular effectiveness and safety of sodium-glucose cotransporter 2 inhibitors (SGLT-2is), glucagon-like peptide 1 receptor agonists (GLP-1RAs), and dipeptidyl peptidase 4 inhibitors (DPP-4is) in older adults with type 2 diabetes (T2D) across different frailty strata. Research design and methods: We p...

To the Editor: After dupilumab’s (interleukin 4 and interleukin 13 inhibitor) approval for atopic derma- titis (AD), case reports and cross-sectional studies have emerged, which report a possible association between dupilumab and arthritis. While this was not observed in the clinical trials, the US Food and Drug Administration label for dupilumab r...

The U.S. Food and Drug Administration and clinical guidelines use evidence from pharmacoepidemiology studies to inform prescribing decisions and fill evidence gaps left by randomized controlled trials (RCTs). The long-term safety and infrequent adverse reactions are not well-understood when RCTs are short and involve few patients, as is the case fo...

Objectives: While randomized controlled trials (RCTs) are considered a standard for evidence on the efficacy of medical treatments, non-randomized real-world evidence (RWE) studies using data from health insurance claims or electronic health records can provide important complementary evidence. The use of RWE to inform decision-making has been ques...

Trial results may not be generalizable to target populations treated in clinical practice with different distributions of baseline characteristics that modify the treatment effect. We used outcome models developed with trial data to predict treatment effects in Medicare populations. We used data from the Randomized Evaluation of Long-Term Anticoagu...

Aims: The effectiveness of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in patients with heart failure (HF) in routine clinical practice is not extensively studied. This study aimed to evaluate the comparative effectiveness of SGLT2i vs. sitagliptin in older adults with HF and type 2 diabetes and to investigate whether there were any differe...

Zusammenfassung Hintergrund Die Real World Evidence (RWE) liefert Erkenntnisse über die Wirksamkeit von Behandlungen im klinischen Versorgungsalltag auf Basis von patientenindividuellen Längsschnittdaten, die im Routinebetrieb des Gesundheitssystems anfallen und ergänzt Erkenntnisse aus randomisierten kontrollierten Studien. Fragestellung Das Zie...

Background: The Model for End-Stage Liver Disease (MELD) score predicts disease severity and mortality in cirrhosis. To improve cirrhosis phenotyping in administrative databases lacking laboratory data, we aimed to develop and externally validate claims-based MELD prediction models, using claims data linked to electronic health records (EHR). Met...

Current guidelines suggest off-label cyclosporine and systemic glucocorticoids as first-line systemic treatment in pregnant women with atopic dermatitis (AD). Dupilumab is the first systemic medication specifically approved for AD. This study sought to examine the use of systemic and topical AD medications in women during pregnancy since the approv...

Importance: Psoriasis in children is increasingly treated with systemic medications, yet their risk of serious infection is not well characterized in clinical practice. Pediatric clinical trials for these medications were often small and placebo controlled. Objective: To estimate the 6-month rate of infections among children with psoriasis who s...

Background Real-word evidence from diverse data sources is increasingly important in terms of generating rapid insights to effectively manage patient populations, especially during major public health disruptions such as the ongoing COVID-19 pandemic. Patients with chronic and inflammatory diseases - such as multiple sclerosis (MS) - were reported...

Objective: Some medications require specific medical procedures in the weeks before their start. Such procedures may meet the definition of instrumental variables (IVs). We examined how they may influence treatment effect estimation in propensity score (PS)-adjusted comparative studies, and how to remedy. Study design and setting: Different cova...

Background Many patients with cirrhosis have concurrent nonvalvular atrial fibrillation (NVAF). Data are lacking regarding recent oral anticoagulant (OAC) usage trends among US patients with cirrhosis and NVAF. Methods and Results Using MarketScan claims data (2012–2019), we identified patients with cirrhosis and NVAF eligible for OACs (CHA 2 DS 2...

We recently nominated cytokine signaling through the Janus-kinase-signal transducer and activator of transcription (JAK/STAT) pathway as a potential AD drug target. As hydroxychloroquine (HCQ) has recently been shown to inactivate STAT3, we hypothesized that it may impact AD pathogenesis and risk. Among 109,124 rheumatoid arthritis patients from ro...

Purpose: The patterns of dupilumab use, the first systemic drug approved for the treatment of atopic dermatitis (AD), is not well understood in the context of off-label systemic medications. Objective: To describe patterns of prescribing, switching and discontinuing systemic AD drugs, before and after the approval of dupilumab and understand var...

Natural language processing (NLP) tools turn free‐text notes (FTN) from electronic health records (EHR) into data features that can supplement confounding adjustment in pharmacoepidemiologic studies. However, current applications are difficult to scale. We used unsupervised NLP to generate high‐dimensional feature spaces from FTN to improve predict...

Introduction: While serious liver injury among statin users is extremely rare, baseline liver enzyme testing is still recommended prior to initiating therapy. The benefit of such screening should be reevaluated based on empirical evidence. This study compared the risk of severe acute liver injury (SALI) between statin initiators with an elevated AL...

In our cohort study, we sought to describe the utilization patterns of systemic immunomodulators in children with atopic dermatitis (AD) and how utilization changed after approval of dupilumab, the first systemic drug approved for the treatment of AD. Using US nationwide claims data, we identified children with AD who initiated a systemic therapy (...

Purpose: Oncology electronic health record (EHR) databases have increased in quality and availability over the past decade, yet it remains unclear whether these clinical practice data can be used to conduct reliable comparative effectiveness studies. We sought to emulate a clinical trial with EHR data in the advanced breast cancer population and c...

Real‐world evidence (RWE) used for regulatory, payer, and clinical decision‐making requires principled epidemiology in design and analysis, applying methods to minimize confounding given the lack of randomization. One technique to deal with potential confounding is propensity score (PS) analysis, which allows for the adjustment for measured pre‐exp...

Introduction: Limited information exists on the effectiveness of sodium-glucose cotransporter-2 inhibitors (SGLT2i) among patients with heart failure with preserved ejection fraction (HFpEF) in routine clinical care. Further, it remains uncertain if all agents in the SGLT2i class confer similar benefits in HFpEF. Methods: We compared initiators of...

Background: Identifying high data-continuity patients in an electronic health record (EHR) system may facilitate selecting cohorts with a lower degree of variable misclassification and promote study validity. We updated a previously developed algorithm for identifying patients with high EHR data-completeness by adding demographic and health utiliza...

Legislative and technological advancements over the past decade have given rise to the proliferation of healthcare data generated from routine clinical practice, often referred to as real‐world data (RWD). These data have piqued the interest of healthcare stakeholders due to their potential utility in generating evidence to support clinical and reg...

Importance Limited evidence is available on the comparative effectiveness of empagliflozin vs alternative second-line glucose-lowering agents in patients with type 2 diabetes (T2D) receiving routine care who have a broad spectrum of cardiorenal risk. Objective To evaluate the association of empagliflozin with cardiovascular outcomes relative to li...

Problem: Ambiguity in communication of key study parameters limits the utility of real-world evidence (RWE) studies in healthcare decision-making. Clear communication about data provenance, design, analysis, and implementation is needed. This would facilitate reproducibility, replication in independent data, and assessment of potential sources of b...

Background: The use of electronic health records (EHR) data to assess drug effectiveness in clinical oncology practice is of great interest to regulators, clinicians, and payers. However, the utility of EHR data in clinical effectiveness studies may be limited by missing data, unmeasured confounding, and imperfect outcome surveillance. This study...

We evaluated the hypothesis that phosphodiesterase-5 inhibitors, including sildenafil and tadalafil, may be associated with reduced incidence of Alzheimer’s disease and related dementia using a patient-level cohort study of Medicare claims and cell culture-based phenotypic assays. We compared incidence of Alzheimer’s disease and related dementia af...

Objectives: Ambiguity in communication of key study parameters limits the utility of real-world evidence (RWE) studies in healthcare decision-making. Clear communication about data provenance, design, analysis, and implementation is needed. This would facilitate reproducibility, replication in independent data, and assessment of potential sources...

OBJECTIVE To determine whether sodium–glucose cotransporter 2 (SGLT2) inhibitors, compared with glucagon-like peptide-1 receptor agonists (GLP-1RAs) or dipeptidyl peptidase-4 (DPP-4) inhibitors, are associated with an increased risk of early bladder cancer events. RESEARCH DESIGN AND METHODS We conducted a multisite, population-based, new-user, ac...

The durability of immune responses after COVID-19 vaccination will drive long-term vaccine effectiveness across settings and may differ by vaccine type. To determine durability of protection of COVID-19 vaccines (BNT162b2, mRNA-1273, and Ad26.COV2.S) following primary vaccination in the United States, a matched case-control study was conducted in t...

Objective Multiple database studies on the same question, conducted by different investigators using different approaches or different data sources can be considered sensitivity analyses for the same causal treatment effect question. We evaluated the contribution of alternative study design parameters and analysis choices to variation in estimates...

Background : The effect of sodium glucose cotransporter 2 inhibitors (SGLT2i) on the total (first and recurrent) burden of cardiovascular (CV) hospitalizations, including hospitalization for heart failure, myocardial infarction, and stroke, is poorly understood. Objective : To assess the effect of empagliflozin, an SGLT2i, on total CV hospitalizat...

Aims To assess the association between the use of sodium-glucose cotransporter-2 (SGLT2i) and cardiovascular outcomes and death as a function of obesity among patients with type 2 diabetes. Methods This new-user, active-comparator cohort study used U.K.’s Clinical Practice Research Datalink linked to Hospital Episodes Statistics repository and Off...

Transparency is increasingly promoted to instill trust in nonrandomized studies using real‐world data. Graphics and data visualizations support transparency by aiding communication and understanding, and can inform study design and analysis decisions. However, other than graphical representation of a study design and flow diagrams (e.g., a Consolid...

Background Medical and regulatory communities are increasingly interested in the utility of real-world evidence (RWE) for answering questions pertaining to drug safety and effectiveness but concerns about validity remain. A principled approach to conducting RWE studies may alleviate concerns and increase confidence in findings. This study sought to...

Introduction: Electronic health record (EHR) discontinuity (missing out-of-network encounters) can lead to information bias. We sought to construct an algorithm that identifies high EHR-continuity among oncology patients. Methods: Using a linked Medicare-EHR database and regression, we sought to 1) measure how often Medicare claims for outpatien...

Within the EMPRISE® monitoring program, we evaluated the cardiovascular effectiveness of empagliflozin (EMPA) vs. glucagon-like peptide-1 receptor agonists (GLP1RA) or liraglutide using data from Medicare and 2 U.S. commercial claims databases [2014- (2018 for Medicare) ]. We identified patients ≥18 years with type 2 diabetes initiating (i) EMPA vs...

EMPRISE is a 5-year monitoring program that evaluates the effectiveness and safety of empagliflozin (EMPA) using Medicare and 2 U.S. commercial claims [2014-20 (2018 for Medicare) ]. We identified 190,226 patients ≥18 years with type 2 diabetes initiating EMPA or a dipeptidyl peptidase-4 inhibitors (DPP-4i) , and followed them up for heart failure...

SGLT2 inhibitors (SGLT2is) have been shown to reduce the risk of cardiovascular and mortality events in large cardiovascular outcome trials in patients with type 2 diabetes. However, their safety profile is controversial, with some trials reporting imbalances in bladder cancer events, all of which occurred relatively soon after randomization. To ad...

Background: Sacubitril/valsartan is strongly supported in guidelines for the management of heart failure, but suboptimal adherence and treatment non-persistence may limit the population-level benefit that this therapy might otherwise offer. Methods: We identified a cohort of Medicare beneficiaries (2014-2017) initiating sacubitril/valsartan afte...

Background: Several studies linked various chronic inflammatory skin diseases (CISDs) with inflammatory bowel disease (IBD) in a range of data sources with mixed conclusions. Objective: We compared the incidence of IBD-ulcerative colitis (UC) and Crohn's disease (CD)- in patients with a CISD versus similar persons without a CISD. Methods: In t...

Background: Evidence on the risk for cardiovascular events associated with use of first-line sodium–glucose cotransporter-2 inhibitors (SGLT-2i) compared with metformin is limited. Objective: To assess cardiovascular outcomes among adults with type 2 diabetes (T2D) who initiated first-line treatment with SGLT-2i versus metformin. Design: Population...

These PowerPoint templates of longitudinal design diagrams expand on earlier design diagrams and now add illustration of data observability. Feel free to download and modify to your needs. You may want to consider referencing as: Wang SV, Schneeweiss S. A framework for visualizing study designs and data observability in electronic health record dat...

These PowerPoint templates of longitudinal design diagrams are related to our publication in the Annals of Internal Medicine in 2019 describing the use and utility of this form of study design visualization. Please feel free to use the slides for your study and publication. You may want to consider referencing as: Schneeweiss S, Rassen JA, Brown...

Background: There is growing interest in using evidence generated from clinical practice data to support regulatory, coverage and other healthcare decision-making. A graphical framework for depicting longitudinal study designs to mitigate this barrier was introduced and has found wide acceptance. We sought to enhance the framework to contain infor...

The propensity score has become a standard tool to control for large numbers of variables in healthcare database studies. However, little has been written on the challenge of comparing large-scale propensity score analyses that use different methods for confounder selection and adjustment. In these settings, balance diagnostics are useful but do no...

Importance: Cytokine signaling, including tumor necrosis factor (TNF) and interleukin (IL)-6, through the Janus-kinase (JAK)-signal transducer and activator of transcription pathway, was hypothesized to attenuate the risk of Alzheimer disease and related dementia (ADRD) in the Drug Repurposing for Effective Alzheimer Medicines (DREAM) initiative b...

Objective: While infliximab combined to thiopurines is more effective than infliximab monotherapy in patients with Crohn's disease (CD) and UC, the impact of adding thiopurines to vedolizumab remains controversial. We emulated two target trials comparing the effectiveness of combination therapy versus vedolizumab monotherapy in CD and UC. Design:...

Background Electric health record (EHR) discontinuity, that is, receiving care outside of a given EHR system, can lead to substantial information bias. We aimed to determine whether a previously described EHR-continuity prediction model can reduce the misclassification of 4 commonly used risk scores in pharmacoepidemiology. Methods The study cohor...

Importance: Vaccination against the SARS-CoV-2 virus is critical to control the pandemic. Randomized clinical trials demonstrated efficacy of the single-dose Ad26.COV2.S COVID-19 vaccine, but data on longer-term protection in clinical practice and effectiveness against variants are needed. Objective: To assess the association between receiving t...

Background: Dupilumab-associated conjunctivitis in patients with atopic dermatitis (AD) is not fully characterized. Objective: The aim of the study was to characterize the incidence of bacterial and nonbacterial conjunctivitis among patients with AD who initiated dupilumab. Methods: Pooling longitudinal claims data from 2 US databases, we iden...

Case reports and a pharmacovigilance analysis have linked glucagon-like peptide-1 receptor agonists (GLP-1 RAs) with anaphylactic reactions, but real-world evidence for this possible association is lacking. Using databases from the United Kingdom (Clinical Practice Research Datalink) and United States (Medicare, Optum, MarketScan), we used a new-us...

Purpose: The high-dimensional propensity score (HDPS) is a semi-automated procedure for confounder identification, prioritisation, and adjustment in large healthcare databases that requires investigators to specify data dimensions, prioritisation strategy, and tuning parameters. In practice, reporting of these decisions is inconsistent and this ca...

Background: Large health care utilization databases are frequently used to analyze unintended effects of prescription drugs and biologics. Confounders that require detailed information on clinical parameters, lifestyle, or over-the-counter medications are often not measured in such datasets, causing residual confounding bias. Objective: This paper...

Objectives: Determine durability of protection by the three currently available COVID-19 vaccines in the United States (US) following primary vaccination against breakthrough infections, hospitalizations, and intensive care unit (ICU) admissions. Methods: Using claims and laboratory data covering 168 million lives, we conducted a matched case-contr...

Purpose Sodium-glucose cotransporter-2 inhibitors (SGLT-2i) are increasingly being considered as first-line treatment for type 2 diabetes (T2D). The benefits of SGLT-2i from cardiovascular outcome trials may lead to preferential prescribing of SGLT-2i to patients at high cardiovascular risk, possibly causing confounding in non-randomized studies of...

IN RESPONSE: We agree with Dr. Bepo and colleagues that notall placebo-controlled cardiovascular outcome trials showedconsistent cardiovascular benefits in patients with T2D acrossindividual GLP-1 RAs and SGLT2 inhibitors. For example,among SGLT2 inhibitors, dapagliflozin and ertugliflozin did notshow a reduction in the risk for major adverse cardi...

The Sentinel System is a major component of the United States Food and Drug Administration’s (FDA) approach to active medical product safety surveillance. While Sentinel has historically relied on large quantities of health insurance claims data, leveraging longitudinal electronic health records (EHRs) that contain more detailed clinical informatio...

The past two decades have witnessed advances in the design and analysis of epidemiologic studies. This chapter introduces some of the approaches with a focus on confounding control, one of the major methodological challenges in pharmacoepidemiology. Pharmacoepidemiologists try to reduce bias by appropriate choices of study design and analytic strat...

The EMPA-REG OUTCOME trial showed cardioprotective effects of empagliflozin (EMPA) in patients with established cardiovascular diseases (CVD). Within the Empagliflozin Comparative Effectiveness and Safety (EMPRISE) multi-database study of patients in routine care, we evaluated the relative cardiovascular benefits of EMPA versus therapeutic alternat...

Background Non-interventional large-scale research on real-world patients who had a stroke requires the use of multiple data sources ensuring access to longitudinal data from large populations with clinically-detailed information. We sought to establish a framework for longitudinal research on patients hospitalised with stroke by linking informatio...

Objective: Over 99% of the EMPA-REG OUTCOME trial participants had established cardiovascular disease (CVD). We aimed to investigate effectiveness and safety outcomes among patients with type 2 diabetes (T2D) initiating empagliflozin vs dipeptidyl peptidase-4 inhibitor (DPP-4i) across the broad spectrum of cardiovascular risk. Methods: In a popu...

Dans EMPA-REG-OUTCOME, l’empagliflozine a réduit le risque de décès CV, décès toutes causes et hospitalisations pour insuffisance cardiaque (hIC) chez les patients DT2 avec maladie CV (MCV) établie. Nous avons évalué l’efficacité CV d’empagliflozine en vie réelle chez des DT2 avec et sans MCV dans EMPRISE, étude sur l’efficacité, la tolérance, l’ut...