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...

Introduction: Progression-free survival (PFS), a common endpoint used in multiple myeloma (MM) trials, is defined as the time to the earliest occurrence of disease progression or death. Disease progression in MM is determined by the International Myeloma Working Group (IMWG) Uniform Response Criteria based on imaging and biomarkers from blood, urin...

Targeted systemic immune-modulating drugs (IMDs) to treat atopic dermatitis (AD) were highly efficacious in randomized trials. Trials with limited number of subjects leave questions about their safety. We describe a data and analytics structure for the production of timely, high-quality evidence on the comparative safety of recently approved IMDs i...

Purpose The US Food and Drug Administration's Sentinel Innovation Center aimed to establish a query‐ready, quality‐checked distributed data network containing electronic health records (EHRs) linked with insurance claims data for at least 10 million individuals to expand the utility of real‐world data for regulatory decision‐making. Methods In thi...

Importance The conditions required for health record data sources to accurately assess treatment effectiveness remain unclear. Emulation of randomized clinical trials (RCTs) with health record data and subsequent calibration of the results can help elucidate this. Objective To pilot an emulation of the KEYNOTE-189 RCT using a commercially availabl...

Summary • Many important clinical questions on medical products cannot be addressed by randomized controlled trials (RCTs). • The emulation of a hypothetical target trial using non-randomized data from clinical practice has been increasingly used and can avoid self-inflicted bias. • A methodological approach calibrating real-world evidence against...

Purpose: There is increasing recognition of the importance of transparency and reproducibility in scientific research. This study aimed to quantify the extent to which programming code is publicly shared in pharmacoepidemiology, and to develop a set of recommendations on this topic. Methods: We conducted a literature review identifying all studies...

Observational studies are increasingly used to provide real-world evidence in regulatory decision-making. The RCT-DUPLICATE initiative conducted observational studies emulating two trials in patients with asthma and three in COPD. For each trial, new-user cohorts were constructed from two US healthcare claims databases, comparing initiators of the...

Objectives To evaluate the concordance of results between the HORIZON-Pivotal Fracture Trial (PFT) and a non-randomized database study designed to emulate the trial. Methods HORIZON-PFT evaluated the efficacy of zoledronic acid vs placebo in reducing the risk of hip fractures and found a 41% risk reduction over a 3-year treatment period (HR = 0.59;...

Introduction: While randomized controlled trials remain the reference standard for evaluating treatment efficacy, there is an increased interest in the use of external control arms (ECA), namely in oncology, using real-world data (RWD). Challenges related to measurement of real-world oncology endpoints, like progression-free survival (PFS), are one...

Electronic health record (EHR) data are seen as an important source for Pharmacoepidemiology studies. In the US healthcare system, EHR systems often only identify fragments of patients’ health information across the care continuum, including primary care, specialist care, hospitalizations, and pharmacy dispensing. This leads to unobservable informa...

Aim: Non-randomized studies on bariatric surgery have reported large reductions in mortality within 6-12 months after surgery compared with non-surgical patients. It is unclear whether these findings are the result of bias. Study design and setting: We searched PubMed to identify all non-randomized studies investigating the effect of bariatric s...

Almost all external control arm analyses to contextualize findings of a single arm trial struggle with two key issues: the lack of baseline randomization, and equally important, the difference in data collection between the experimental arm with its primary data collection, and the external control arm using secondary data. We illustrate the data c...

OBJECTIVE We compared health care resource utilization (HCRU) and costs for inpatient and outpatient services and dispensed medications in older adults with type 2 diabetes initiating empagliflozin versus dipeptidyl peptidase 4 inhibitors (DPP-4is). RESEARCH DESIGN AND METHODS The study population included U.S. Medicare fee-for-service beneficiari...

Background: Unmeasured confounding is often raised as a source of potential bias during the design of non-randomized studies but quantifying such concerns is challenging. Methods: We developed a simulation-based approach to assess the potential impact of unmeasured confounding during the study design stage. The approach involved generation of hypot...

Multiple imputation (MI) models can be improved by including auxiliary covariates (AC), but their performance in high-dimensional data is not well understood. We aimed to develop and compare high-dimensional MI (HDMI) approaches using structured and natural language processing (NLP)-derived AC in studies with partially observed confounders. We cond...

Direct oral anticoagulants (DOACs) revolutionized the management of thromboembolic disorders. Clinical care may be further improved as Factor XIs undergo large-scale outcome trials. What role can non-randomized database studies play in expediting understanding of these drugs in clinical practice? The RCT-DUPLICATIVE Initiative emulated the design o...

This Viewpoint discusses the challenges involved with secondary health care data collection vs primary data collection and provides a list of suggested data checks before registration of a study protocol using secondary data.

Background: Accurately identifying alopecia in claims data is important to study this rare medication side effect. Objectives: To develop and validate a claims-based algorithm to identify alopecia in women of childbearing age. Methods: We linked electronic health records from a large healthcare system in Massachusetts (Mass General Brigham) with...

Purpose: There is increasing recognition of the importance of transparency and reproducibility in scientific research. This study aimed to quantify the extent to which programming code is publicly shared in pharmacoepidemiology, and to develop a set of recommendations on this topic. Methods: We conducted a literature review identifying all studies...

BACKGROUND Transcatheter left atrial appendage occlusion (LAAO) is an alternative to oral anticoagulants (OACs) for stroke prevention in patients with atrial fibrillation, but the predictors of LAAO use in routine care are unclear. We aimed to assess the utilization trends of LAAO and compare the change in characteristics of LAAO users versus OACs...

This report proposes a stepwise process covering the range of considerations to systematically consider key choices for study design and data analysis for non-interventional studies with the central objective of fostering generation of reliable and reproducible evidence. These steps include (1) formulating a well defined causal question via specifi...

Background No randomized clinical trials have directly compared the cardiorenal effectiveness of empagliflozin and GLP-1RA agents with demonstrated cardioprotective effects in patients with a broad spectrum of cardiovascular risk. We reported the final-year results of the EMPRISE study, a monitoring program designed to evaluate the cardiorenal effe...

Objective To explore how design emulation and population differences relate to variation in results between randomised controlled trials (RCT) and non-randomised real world evidence (RWE) studies, based on the RCT-DUPLICATE initiative (Randomised, Controlled Trials Duplicated Using Prospective Longitudinal Insurance Claims: Applying Techniques of E...

Importance Laboratory testing for the presence of tuberculosis, hepatitis, and other conditions before starting most systemic immunomodulatory agents is recommended in patients with chronic inflammatory skin diseases (CISD) but current testing patterns in the US are unclear. Objective To determine the prevalence of pretreatment testing that is rec...

Introduction: Immune checkpoint inhibitors (ICI) have improved the clinical outcomes of several cancers but have also been associated with a greater risk of cardiovascular adverse effects. Hypothesis: The use of combination ICI therapy is associated with an increased risk of myocarditis, compared to use of a single ICI. Methods: A cohort study was...

Introduction: Surgical treatment for obesity, a major risk factor for diabetes and cardiovascular disease, may lead to important improvements in cardiovascular health. Sleeve gastrectomy (SG) procedures have gained popularity over Roux-en-Y gastric bypass (RYGB), though it is unclear which procedure results in better cardiovascular (CV) outcomes. O...

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). Metho...

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...

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 utilizat...

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 ALT...

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...

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...

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...

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 so...

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...