High-dimensional multiple imputation (HDMI) for partially observed confounders including natural language processing-derived auxiliary covariates.

Multiple imputation (MI) models can be improved with auxiliary covariates (AC), but their performance in high-dimensional data remains unclear. We aimed to develop and compare high-dimensional MI (HDMI) methods using structured and natural language processing (NLP)-derived AC in studies with partially observed confounders. We conducted a plasmode simulation with acute kidney injury as outcome and simulated 100 cohorts with a null treatment effect, incorporating creatinine labs, atrial fibrillation (AFib), and other investigator-derived confounders in the outcome generation.

A simple Cox approach to estimating risk ratios without sharing individual-level data in multisite studies.

Epidemiologic studies frequently use risk ratios to quantify associations between exposures and binary outcomes. When the data are physically stored at the sites of multiple data partners, it can be challenging to perform individual-level analysis if data cannot be pooled centrally due to privacy constraints. Existing methods either require multiple file transfers between each data partner and an analysis center (eg, distributed regression) or only provide approximate estimation of the risk ratio (eg, meta-analysis).

A Principled Approach to Characterize and Analyze Partially Observed Confounder Data from Electronic Health Records.

Objective: Partially observed confounder data pose challenges to the statistical analysis of electronic health records (EHR) and systematic assessments of potentially underlying missingness mechanisms are lacking. We aimed to provide a principled approach to empirically characterize missing data processes and investigate performance of analytic methods.

Methods: Three empirical sub-cohorts of diabetic SGLT2 or DPP4-inhibitor initiators with complete information on HbA1c, BMI and smoking as confounders of interest (COI) formed the basis of data simulation under a plasmode framework.

Risk of Arterial and Venous Thrombotic Events Among Patients with COVID-19: A Multi-National Collaboration of Regulatory Agencies from Canada, Europe, and United States.

Purpose: Few studies have examined how the absolute risk of thromboembolism with COVID-19 has evolved over time across different countries. Researchers from the European Medicines Agency, Health Canada, and the United States (US) Food and Drug Administration established a collaboration to evaluate the absolute risk of arterial (ATE) and venous thromboembolism (VTE) in the 90 days after diagnosis of COVID-19 in the ambulatory (eg, outpatient, emergency department, nursing facility) setting from seven countries across North America (Canada, US) and Europe (England, Germany, Italy, Netherlands, and Spain) within periods before and during COVID-19 vaccine availability.

Patients And Methods: We conducted cohort studies of patients initially diagnosed with COVID-19 in the ambulatory setting from the seven specified countries.

smdi: an R package to perform structural missing data investigations on partially observed confounders in real-world evidence studies.

Objectives: Partially observed confounder data pose a major challenge in statistical analyses aimed to inform causal inference using electronic health records (EHRs). While analytic approaches such as imputation are available, assumptions on underlying missingness patterns and mechanisms must be verified. We aimed to develop a toolkit to streamline missing data diagnostics to guide choice of analytic approaches based on meeting necessary assumptions.

Risk of admission to hospital with arterial or venous thromboembolism among patients diagnosed in the ambulatory setting with covid-19 compared with influenza: retrospective cohort study.

Objective: To measure the 90 day risk of arterial thromboembolism and venous thromboembolism among patients diagnosed with covid-19 in the ambulatory (ie, outpatient, emergency department, or institutional) setting during periods before and during covid-19 vaccine availability and compare results to patients with ambulatory diagnosed influenza.

Design: Retrospective cohort study.

Setting: Four integrated health systems and two national health insurers in the US Food and Drug Administration's Sentinel System.

Association of COVID-19 vs Influenza With Risk of Arterial and Venous Thrombotic Events Among Hospitalized Patients.

Importance: The incidence of arterial thromboembolism and venous thromboembolism in persons with COVID-19 remains unclear.

Objective: To measure the 90-day risk of arterial thromboembolism and venous thromboembolism in patients hospitalized with COVID-19 before or during COVID-19 vaccine availability vs patients hospitalized with influenza.

Design, Setting, And Participants: Retrospective cohort study of 41 443 patients hospitalized with COVID-19 before vaccine availability (April-November 2020), 44 194 patients hospitalized with COVID-19 during vaccine availability (December 2020-May 2021), and 8269 patients hospitalized with influenza (October 2018-April 2019) in the US Food and Drug Administration Sentinel System (data from 2 national health insurers and 4 regional integrated health systems).

A cohort study to assess risk of cutaneous small vessel vasculitis among users of different oral anticoagulants.

Purpose: Cutaneous small vessel vasculitis (CSVV) was identified as a safety signal among patients treated with direct oral anticoagulants (DOAC). This study aimed to determine if CSVV risk differed among patients with atrial fibrillation (Afib) who newly initiated warfarin or a DOAC.

Methods: We identified enrollees aged ≥21 years diagnosed with Afib who newly initiated rivaroxaban, dabigatran, apixaban, and warfarin in the Sentinel Distributed Database from October 19, 2010 to February 29, 2020.

Association of Fluoroquinolones With the Risk of Aortic Aneurysm or Aortic Dissection.

Importance: Previous observational studies have suggested that fluoroquinolones are associated with aortic aneurysm or dissection, but these studies may be subject to confounding by indication or surveillance bias.

Objective: To assess the association of fluoroquinolones with risk of aortic aneurysm or aortic dissection (AA/AD) while accounting for potential confounding by fluoroquinolone indication and bias owing to differential surveillance.

Design, Setting, And Participants: In an observational cohort study using a US commercial claims database, 2 pairwise 1:1 propensity score-matched cohorts were identified: patients aged 50 years or older with a diagnosis of pneumonia 3 days or less before initiating treatment with a fluoroquinolone or azithromycin and patients aged 50 years or older with a urinary tract infection (UTI) diagnosis 3 days or less before initiating a fluoroquinolone or combined trimethoprim and sulfamethoxazole.

Improving measurement of binary covariates in claims data: A simulation study.

Purpose: When investigators have two claims-based definitions for a binary confounder, it is unclear whether to prefer the more sensitive or more specific definition. Our objective was to compare adjusting for the sensitive or specific definition alone vs two novel approaches combining both definitions: a "two-algorithm indicator" and a "two-algorithm restriction" approach.

Methods: Each simulated patient had a binary exposure, outcome, and confounder.

Non-Vitamin K Antagonist Oral Anticoagulants and Angioedema: A Cohort and Case-Crossover Study.

Introduction: Patients taking non-vitamin K antagonist oral anticoagulants (NOACs) such as dabigatran, rivaroxaban, and apixaban have reported experiencing angioedema in randomized trials and routine care.

Objective: The aim of this study was to quantify the association between NOACs and angioedema relative to warfarin among routinely treated patients with atrial fibrillation in a cohort study. We also compared warfarin users with non-users in a case-crossover study.

Comparative effectiveness of generic and brand-name medication use: A database study of US health insurance claims.

Background: To the extent that outcomes are mediated through negative perceptions of generics (the nocebo effect), observational studies comparing brand-name and generic drugs are susceptible to bias favoring the brand-name drugs. We used authorized generic (AG) products, which are identical in composition and appearance to brand-name products but are marketed as generics, as a control group to address this bias in an evaluation aiming to compare the effectiveness of generic versus brand medications.

Methods And Findings: For commercial health insurance enrollees from the US, administrative claims data were derived from 2 databases: (1) Optum Clinformatics Data Mart (years: 2004-2013) and (2) Truven MarketScan (years: 2003-2015).

Quantifying bias reduction with fixed-duration versus all-available covariate assessment periods.

Purpose: Implementing a cohort study in longitudinal healthcare databases requires looking back over some covariate assessment period (CAP) preceding cohort entry to measure confounders. We used simulations to compare fixed-duration versus all-available CAPs for confounder adjustment in the presence of differences in available baseline time between exposure groups.

Methods: We simulated cohorts of 10 000 patients with binary variables for a single confounder, exposure, and outcome.

Effect of Lawyer-Submitted Reports on Signals of Disproportional Reporting in the Food and Drug Administration's Adverse Event Reporting System.

Introduction: Lawyer-submitted reports may have unintended consequences on safety signal detection in spontaneous adverse event reporting systems.

Objective: Our objective was to assess the impact of lawyer-submitted reports primarily for one adverse event (AE) on the ability to detect a signal of disproportional reporting for another AE for the same drug in the US FDA Adverse Event Reporting System (FAERS).

Methods: FAERS reports from January 2004 to September 2015 were used to estimate yearly cumulative proportional reporting ratios (PRRs) for three known drug-AE pairs-isotretinoin-birth defects, atorvastatin-rhabdomyolysis, and rosuvastatin-rhabdomyolysis-with and without lawyer-submitted reports.

Development and application of two semi-automated tools for targeted medical product surveillance in a distributed data network.

Purpose Of Review: An important component of the Food and Drug Administration's Sentinel Initiative is the active post-market risk identification and analysis (ARIA) system, which utilizes semi-automated, parameterized computer programs to implement propensity-score adjusted and self-controlled risk interval designs to conduct targeted surveillance of medical products in the Sentinel Distributed Database. In this manuscript, we review literature relevant to the development of these programs and describe their application within the Sentinel Initiative.

Recent Findings: These quality-checked and publicly available tools have been successfully used to conduct rapid, replicable, and targeted safety analyses of several medical products.

Comparison of Calipers for Matching on the Disease Risk Score.

Previous studies have compared calipers for propensity score (PS) matching, but none have considered calipers for matching on the disease risk score (DRS). We used Medicare claims data to perform 3 cohort studies of medication initiators: a study of raloxifene versus alendronate in 1-year nonvertebral fracture risk, a study of cyclooxygenase 2 inhibitors versus nonselective nonsteroidal antiinflammatory medications in 6-month gastrointestinal bleeding, and a study of simvastatin + ezetimibe versus simvastatin alone in 6-month cardiovascular outcomes. The study periods for each cohort were 1998 through 2005, 1999 through 2002, and 2004 through 2005, respectively.

Thiazolidinediones and Parkinson Disease: A Cohort Study.

Thiazolidinediones, a class of medications indicated for the treatment of type 2 diabetes mellitus, reduce inflammation and have been shown to provide a therapeutic benefit in animal models of Parkinson disease. We examined the association between treatment with thiazolidinediones and the onset of Parkinson disease in older individuals. We performed a cohort study of 29,397 Medicare patients enrolled in state pharmaceutical benefits programs who initiated treatment with thiazolidinediones or sulfonylureas during the years 1997 through 2005 and had no prior diagnosis of Parkinson disease.

Metabolic monitoring for youths initiating use of second-generation antipsychotics, 2003-2011.

Objective: In 2004, the American Diabetes Association (ADA) released treatment guidelines recommending metabolic screening for children and adolescents before and after initiation of second-generation antipsychotics. Prior studies showed that the guidelines coincided with a small increase in glucose testing of children and adults but had limited follow-up. This study sought to evaluate changes in metabolic screening of children initiating second-generation antipsychotics around the time of the 2004 guidelines and in the following eight years.

A cross-national comparison of 17 countries' insulin glargine drug labels.

Purpose: Type 2 diabetes mellitus has reached epidemic proportions worldwide. Many patients with type 2 diabetes mellitus will require insulin, and the evidence-based use of insulin is described in the prescription drug label. Product labels in different countries may provide inconsistent information.

Patterns and trends in insulin intensification among patients with type 2 diabetes: a systematic review.

Type 2 diabetes (T2DM) diagnoses are skyrocketing, making treatment of this disease an increasing focus of primary care visits. Guidelines recommend insulin intensification over time to achieve HbA1c targets. We conducted a systematic review regarding patterns and trends of insulin intensification and barriers to intensification.

Effect of smoking on comparative efficacy of antiplatelet agents: systematic review, meta-analysis, and indirect comparison.

Objective: To evaluate whether smoking status is associated with the efficacy of antiplatelet treatment in the prevention of cardiovascular events.

Design: Systematic review, meta-analysis, and indirect comparisons.

Data Sources: Medline (1966 to present) and Embase (1974 to present), with supplementary searches in databases of abstracts from major cardiology conferences, the Cumulative Index to Nursing and Allied Health (CINAHL) and the CAB Abstracts databases, and Google Scholar.

Barriers to insulin progression among patients with type 2 diabetes: a systematic review.

Purpose: Treatment guidelines recommend insulin progression (switching from basal to a premixed insulin regimen, adding bolus doses, and/or increasing dosing frequency) to achieve A1C targets as type 2 diabetes progresses, but fewer patients are being progressed than would be indicated based on their disease status. This systematic review proposes 2 questions regarding insulin progression among patients with type 2 diabetes: (1) What are the patient, provider, and health system barriers to insulin progression? (2) Do insulin progression barriers differ between insulin-naive and insulin-experienced patients?

Methods: We conducted a systematic review in the MEDLINE, EMBASE, Science Citation Index, PsycINFO, CINAHL, and Cochrane Library databases through July 2011.

Results: Of 745 potentially relevant articles, 10 met inclusion criteria: 7 evaluated patient and 2 evaluated provider barriers, and 1 was an intervention to reduce barriers among physicians.

Production and characterization of a panel of monoclonal antibodies against native human cellular prion protein.

The human prion diseases, such as variant Creutzfeldt-Jakob disease (vCJD), are characterized by the conversion of the normal cellular prion protein (PrP(C)) into an abnormal disease associated form (PrP(Sc)). Monoclonal antibodies (MAbs) that recognize these different PrP isoforms are valuable reagents both in the diagnosis of these diseases and in prion disease research in general but we know of no attempts to raise MAbs against native human PrP(C). We immunized prion protein gene ablated (PrP(-/-)) mice with native human PrP(C) purified from platelets (pHuPrP) generating a predominantly IgG isotype anti-pHuPrP polyclonal antibody response in all mice.