Association between prolactin increasing antipsychotic use and the risk of breast cancer: a retrospective observational cohort study in a United States Medicaid population.

Introduction: Results of retrospective studies examining the relationship between prolactin increasing antipsychotics and incident breast cancer have been inconsistent. This study assessed the association between use of high prolactin increasing antipsychotics (HPD) and the incidence of breast cancer using best practices in pharmacoepidemiology. Methods: Using administrative claims data from the MarketScan Medicaid database, schizophrenia patients initiating antipsychotics were identified. Those initiating HPD were compared with new users of non/low prolactin increasing drugs (NPD). Two definitions of breast cancer, two at-risk periods, and two large-scale propensity score (PS) adjustment methods were used in separate analyses. PS models included all previously diagnosed conditions, medication use, demographics, and other available medical history. Negative control outcomes were used for empirical calibration. Results: Five analysis variants passed all diagnostics for sufficient statistical power and balance across all covariates. Four of the five variants used an intent-to-treat (ITT) approach. Between 4,256 and 6,341 patients were included in each group for the ITT analyses, and patients contributed approximately four years of follow-up time on average. There was no statistically significant association between exposure to HPD and risk of incident breast cancer in any analysis, and hazard ratios remained close to 1.0, ranging from 0.96 (95% confidence interval 0.62 - 1.48) to 1.28 (0.40 - 4.07). Discussion: Using multiple PS methods, outcome definitions and at-risk periods provided robust and consistent results which found no evidence of an association between use of HPD and risk of breast cancer.

Similar Risk of Kidney Failure among Patients with Blinding Diseases Who Receive Ranibizumab, Aflibercept, and Bevacizumab: An Observational Health Data Sciences and Informatics Network Study.

PURPOSE: To characterize the incidence of kidney failure associated with intravitreal anti-VEGF exposure; and compare the risk of kidney failure in patients treated with ranibizumab, aflibercept, or bevacizumab. DESIGN: Retrospective cohort study across 12 databases in the Observational Health Data Sciences and Informatics (OHDSI) network. SUBJECTS: Subjects aged ≥ 18 years with ≥ 3 monthly intravitreal anti-VEGF medications for a blinding disease (diabetic retinopathy, diabetic macular edema, exudative age-related macular degeneration, or retinal vein occlusion). METHODS: The standardized incidence proportions and rates of kidney failure while on treatment with anti-VEGF were calculated. For each comparison (e.g., aflibercept versus ranibizumab), patients from each group were matched 1:1 using propensity scores. Cox proportional hazards models were used to estimate the risk of kidney failure while on treatment. A random effects meta-analysis was performed to combine each database's hazard ratio (HR) estimate into a single network-wide estimate. MAIN OUTCOME MEASURES: Incidence of kidney failure while on anti-VEGF treatment, and time from cohort entry to kidney failure. RESULTS: Of the 6.1 million patients with blinding diseases, 37 189 who received ranibizumab, 39 447 aflibercept, and 163 611 bevacizumab were included; the total treatment exposure time was 161 724 person-years. The average standardized incidence proportion of kidney failure was 678 per 100 000 persons (range, 0-2389), and incidence rate 742 per 100 000 person-years (range, 0-2661). The meta-analysis HR of kidney failure comparing aflibercept with ranibizumab was 1.01 (95% confidence interval [CI], 0.70-1.47; P = 0.45), ranibizumab with bevacizumab 0.95 (95% CI, 0.68-1.32; P = 0.62), and aflibercept with bevacizumab 0.95 (95% CI, 0.65-1.39; P = 0.60). CONCLUSIONS: There was no substantially different relative risk of kidney failure between those who received ranibizumab, bevacizumab, or aflibercept. Practicing ophthalmologists and nephrologists should be aware of the risk of kidney failure among patients receiving intravitreal anti-VEGF medications and that there is little empirical evidence to preferentially choose among the specific intravitreal anti-VEGF agents. FINANCIAL DISCLOSURES: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Patterns of Comorbidities and Prescribing and Dispensing of Non-steroidal Anti-inflammatory Drugs (NSAIDs) Among Patients with Osteoarthritis in the USA: Real-World Study.

BACKGROUND: Osteoarthritis (OA) is a major cause of chronic pain. Non-steroidal anti-inflammatory drugs (NSAIDs) are analgesics commonly used for musculoskeletal pain; however, NSAIDs can increase the risk of certain adverse events, such as gastrointestinal bleeding, edema, heart failure, and hypertension. OBJECTIVE: The objective of this study was to characterize existing comorbidities among patients with OA. For patients with OA with and without a coexisting medical condition of interest (CMCOI), we estimated the prevalence of prescribing and dispensing NSAIDs pre-OA and post-OA diagnosis. METHODS: Data from three large administrative claims databases were used to construct an OA retrospective cohort. Databases leveraged were IBM MarketScan Medicare Supplemental Database (MDCR), IBM MarketScan Commercial Database (CCAE), and Optum's de-identified Clinformatics® Data Mart Database (Optum CDM). The OA study population was defined to be those patients who had an OA diagnosis from an inpatient or outpatient visit with at least 365 days of prior observation time in the database during January 2000 through May 2021. Asthma, cardiovascular disorders, renal impairment, and gastrointestinal bleeding risks were the CMCOI of interest. Patients with OA were then classified as having or not having evidence of a CMCOI. For both groups, NSAID dispensing patterns pre-OA and post-OA diagnosis were identified. Descriptive analysis was performed within the Observational Health Data Sciences and Informatics framework. RESULTS: In each database, the proportion of the OA population with at least one CMCOI was nearly 50% or more (48.0% CCAE; 74.4% MDCR; 68.6% Optum CDM). Cardiovascular disease was the most commonly observed CMCOI in each database, and in two databases, nearly one in four patients with OA had two or more CMCOI (23.2% MDCR; 22.6% Optum CDM). Among the OA population with CMCOI, NSAID utilization post-OA diagnosis ranged from 33.0 to 46.2%. Following diagnosis of OA, an increase in the prescribing and dispensing of NSAIDs was observed in all databases, regardless of patient CMCOI presence. CONCLUSIONS: This study provides real-world evidence of the pattern of prescribing and dispensing of NSAIDs among patients with OA with and without CMCOI, which indicates that at least half of patients with OA in the USA have a coexisting condition. These conditions may increase the risk of side effects commonly associated with NSAIDs. Yet, at least 32% of these patients were prescribed and dispensed NSAIDs. These data support the importance of shared decision making between healthcare professionals and patients when considering NSAIDs for the treatment of OA in patients with NSAID-relevant coexisting medical conditions.

Evaluating the impact of alternative phenotype definitions on incidence rates across a global data network.

Objective: Developing accurate phenotype definitions is critical in obtaining reliable and reproducible background rates in safety research. This study aims to illustrate the differences in background incidence rates by comparing definitions for a given outcome. Materials and Methods: We used 16 data sources to systematically generate and evaluate outcomes for 13 adverse events and their overall background rates. We examined the effect of different modifications (inpatient setting, standardization of code set, and code set changes) to the computable phenotype on background incidence rates. Results: Rate ratios (RRs) of the incidence rates from each computable phenotype definition varied across outcomes, with inpatient restriction showing the highest variation from 1 to 11.93. Standardization of code set RRs ranges from 1 to 1.64, and code set changes range from 1 to 2.52. Discussion: The modification that has the highest impact is requiring inpatient place of service, leading to at least a 2-fold higher incidence rate in the base definition. Standardization showed almost no change when using source code variations. The strength of the effect in the inpatient restriction is highly dependent on the outcome. Changing definitions from broad to narrow showed the most variability by age/gender/database across phenotypes and less than a 2-fold increase in rate compared to the base definition. Conclusion: Characterization of outcomes across a network of databases yields insights into sensitivity and specificity trade-offs when definitions are altered. Outcomes should be thoroughly evaluated prior to use for background rates for their plausibility for use across a global network.

Contextualising adverse events of special interest to characterise the baseline incidence rates in 24 million patients with COVID-19 across 26 databases: a multinational retrospective cohort study.

Background: Adverse events of special interest (AESIs) were pre-specified to be monitored for the COVID-19 vaccines. Some AESIs are not only associated with the vaccines, but with COVID-19. Our aim was to characterise the incidence rates of AESIs following SARS-CoV-2 infection in patients and compare these to historical rates in the general population. Methods: A multi-national cohort study with data from primary care, electronic health records, and insurance claims mapped to a common data model. This study's evidence was collected between Jan 1, 2017 and the conclusion of each database (which ranged from Jul 2020 to May 2022). The 16 pre-specified prevalent AESIs were: acute myocardial infarction, anaphylaxis, appendicitis, Bell's palsy, deep vein thrombosis, disseminated intravascular coagulation, encephalomyelitis, Guillain- Barré syndrome, haemorrhagic stroke, non-haemorrhagic stroke, immune thrombocytopenia, myocarditis/pericarditis, narcolepsy, pulmonary embolism, transverse myelitis, and thrombosis with thrombocytopenia. Age-sex standardised incidence rate ratios (SIR) were estimated to compare post-COVID-19 to pre-pandemic rates in each of the databases. Findings: Substantial heterogeneity by age was seen for AESI rates, with some clearly increasing with age but others following the opposite trend. Similarly, differences were also observed across databases for same health outcome and age-sex strata. All studied AESIs appeared consistently more common in the post-COVID-19 compared to the historical cohorts, with related meta-analytic SIRs ranging from 1.32 (1.05 to 1.66) for narcolepsy to 11.70 (10.10 to 13.70) for pulmonary embolism. Interpretation: Our findings suggest all AESIs are more common after COVID-19 than in the general population. Thromboembolic events were particularly common, and over 10-fold more so. More research is needed to contextualise post-COVID-19 complications in the longer term. Funding: None.

Reproducible variability: assessing investigator discordance across 9 research teams attempting to reproduce the same observational study.

OBJECTIVE: Observational studies can impact patient care but must be robust and reproducible. Nonreproducibility is primarily caused by unclear reporting of design choices and analytic procedures. This study aimed to: (1) assess how the study logic described in an observational study could be interpreted by independent researchers and (2) quantify the impact of interpretations' variability on patient characteristics. MATERIALS AND METHODS: Nine teams of highly qualified researchers reproduced a cohort from a study by Albogami et al. The teams were provided the clinical codes and access to the tools to create cohort definitions such that the only variable part was their logic choices. We executed teams' cohort definitions against the database and compared the number of subjects, patient overlap, and patient characteristics. RESULTS: On average, the teams' interpretations fully aligned with the master implementation in 4 out of 10 inclusion criteria with at least 4 deviations per team. Cohorts' size varied from one-third of the master cohort size to 10 times the cohort size (2159-63 619 subjects compared to 6196 subjects). Median agreement was 9.4% (interquartile range 15.3-16.2%). The teams' cohorts significantly differed from the master implementation by at least 2 baseline characteristics, and most of the teams differed by at least 5. CONCLUSIONS: Independent research teams attempting to reproduce the study based on its free-text description alone produce different implementations that vary in the population size and composition. Sharing analytical code supported by a common data model and open-source tools allows reproducing a study unambiguously thereby preserving initial design choices.

International cohort study indicates no association between alpha-1 blockers and susceptibility to COVID-19 in benign prostatic hyperplasia patients.

Purpose: Alpha-1 blockers, often used to treat benign prostatic hyperplasia (BPH), have been hypothesized to prevent COVID-19 complications by minimising cytokine storm release. The proposed treatment based on this hypothesis currently lacks support from reliable real-world evidence, however. We leverage an international network of large-scale healthcare databases to generate comprehensive evidence in a transparent and reproducible manner. Methods: In this international cohort study, we deployed electronic health records from Spain (SIDIAP) and the United States (Department of Veterans Affairs, Columbia University Irving Medical Center, IQVIA OpenClaims, Optum DOD, Optum EHR). We assessed association between alpha-1 blocker use and risks of three COVID-19 outcomes-diagnosis, hospitalization, and hospitalization requiring intensive services-using a prevalent-user active-comparator design. We estimated hazard ratios using state-of-the-art techniques to minimize potential confounding, including large-scale propensity score matching/stratification and negative control calibration. We pooled database-specific estimates through random effects meta-analysis. Results: Our study overall included 2.6 and 0.46 million users of alpha-1 blockers and of alternative BPH medications. We observed no significant difference in their risks for any of the COVID-19 outcomes, with our meta-analytic HR estimates being 1.02 (95% CI: 0.92-1.13) for diagnosis, 1.00 (95% CI: 0.89-1.13) for hospitalization, and 1.15 (95% CI: 0.71-1.88) for hospitalization requiring intensive services. Conclusion: We found no evidence of the hypothesized reduction in risks of the COVID-19 outcomes from the prevalent-use of alpha-1 blockers-further research is needed to identify effective therapies for this novel disease.

Phenotype Algorithms for the Identification and Characterization of Vaccine-Induced Thrombotic Thrombocytopenia in Real World Data: A Multinational Network Cohort Study.

INTRODUCTION: Vaccine-induced thrombotic thrombocytopenia (VITT) has been identified as a rare but serious adverse event associated with coronavirus disease 2019 (COVID-19) vaccines. OBJECTIVES: In this study, we explored the pre-pandemic co-occurrence of thrombosis with thrombocytopenia (TWT) using 17 observational health data sources across the world. We applied multiple TWT definitions, estimated the background rate of TWT, characterized TWT patients, and explored the makeup of thrombosis types among TWT patients. METHODS: We conducted an international network retrospective cohort study using electronic health records and insurance claims data, estimating background rates of TWT amongst persons observed from 2017 to 2019. Following the principles of existing VITT clinical definitions, TWT was defined as patients with a diagnosis of embolic or thrombotic arterial or venous events and a diagnosis or measurement of thrombocytopenia within 7 days. Six TWT phenotypes were considered, which varied in the approach taken in defining thrombosis and thrombocytopenia in real world data. RESULTS: Overall TWT incidence rates ranged from 1.62 to 150.65 per 100,000 person-years. Substantial heterogeneity exists across data sources and by age, sex, and alternative TWT phenotypes. TWT patients were likely to be men of older age with various comorbidities. Among the thrombosis types, arterial thrombotic events were the most common. CONCLUSION: Our findings suggest that identifying VITT in observational data presents a substantial challenge, as implementing VITT case definitions based on the co-occurrence of TWT results in large and heterogeneous incidence rate and in a cohort of patints with baseline characteristics that are inconsistent with the VITT cases reported to date.

Seek COVER: using a disease proxy to rapidly develop and validate a personalized risk calculator for COVID-19 outcomes in an international network.

BACKGROUND: We investigated whether we could use influenza data to develop prediction models for COVID-19 to increase the speed at which prediction models can reliably be developed and validated early in a pandemic. We developed COVID-19 Estimated Risk (COVER) scores that quantify a patient's risk of hospital admission with pneumonia (COVER-H), hospitalization with pneumonia requiring intensive services or death (COVER-I), or fatality (COVER-F) in the 30-days following COVID-19 diagnosis using historical data from patients with influenza or flu-like symptoms and tested this in COVID-19 patients. METHODS: We analyzed a federated network of electronic medical records and administrative claims data from 14 data sources and 6 countries containing data collected on or before 4/27/2020. We used a 2-step process to develop 3 scores using historical data from patients with influenza or flu-like symptoms any time prior to 2020. The first step was to create a data-driven model using LASSO regularized logistic regression, the covariates of which were used to develop aggregate covariates for the second step where the COVER scores were developed using a smaller set of features. These 3 COVER scores were then externally validated on patients with 1) influenza or flu-like symptoms and 2) confirmed or suspected COVID-19 diagnosis across 5 databases from South Korea, Spain, and the United States. Outcomes included i) hospitalization with pneumonia, ii) hospitalization with pneumonia requiring intensive services or death, and iii) death in the 30 days after index date. RESULTS: Overall, 44,507 COVID-19 patients were included for model validation. We identified 7 predictors (history of cancer, chronic obstructive pulmonary disease, diabetes, heart disease, hypertension, hyperlipidemia, kidney disease) which combined with age and sex discriminated which patients would experience any of our three outcomes. The models achieved good performance in influenza and COVID-19 cohorts. For COVID-19 the AUC ranges were, COVER-H: 0.69-0.81, COVER-I: 0.73-0.91, and COVER-F: 0.72-0.90. Calibration varied across the validations with some of the COVID-19 validations being less well calibrated than the influenza validations. CONCLUSIONS: This research demonstrated the utility of using a proxy disease to develop a prediction model. The 3 COVER models with 9-predictors that were developed using influenza data perform well for COVID-19 patients for predicting hospitalization, intensive services, and fatality. The scores showed good discriminatory performance which transferred well to the COVID-19 population. There was some miscalibration in the COVID-19 validations, which is potentially due to the difference in symptom severity between the two diseases. A possible solution for this is to recalibrate the models in each location before use.

Comparative Effectiveness of Famotidine in Hospitalized COVID-19 Patients.

INTRODUCTION: Famotidine has been posited as a potential treatment for coronavirus disease 2019 (COVID-19). We compared the incidence of COVID-19 outcomes (i.e., death and death or intensive services use) among hospitalized famotidine users vs proton pump inhibitors (PPIs) users, hydroxychloroquine users, or famotidine nonusers separately. METHODS: We constructed a retrospective cohort study using data from COVID-19 Premier Hospital electronic health records. The study population was COVID-19 hospitalized patients aged 18 years or older. Famotidine, PPI, and hydroxychloroquine exposure groups were defined as patients dispensed any medication containing 1 of the 3 drugs on the day of admission. The famotidine nonuser group was derived from the same source population with no history of exposure to any drug with famotidine as an active ingredient before or on the day of admission. Time at risk was defined based on the intention-to-treat principle starting 1 day after admission to 30 days after admission. For each study comparison group, we fit a propensity score model through large-scale regularized logistic regression. The outcome was modeled using a survival model. RESULTS: We identified 2,193 users of PPI, 5,950 users of the hydroxychloroquine, 1,816 users of famotidine, and 26,820 nonfamotidine users. After propensity score stratification, the hazard ratios (HRs) for death were as follows: famotidine vs no famotidine HR 1.03 (0.89-1.18), vs PPIs: HR 1.14 (0.94-1.39), and vs hydroxychloroquine: 1.03 (0.85-1.24). Similar results were observed for the risk of death or intensive services use. DISCUSSION: We found no evidence of a reduced risk of COVID-19 outcomes among hospitalized COVID-19 patients who used famotidine compared with those who did not or compared with PPI or hydroxychloroquine users.

Alpha-1 blockers and susceptibility to COVID-19 in benign prostate hyperplasia patients : an international cohort study.

Alpha-1 blockers, often used to treat benign prostate hyperplasia (BPH), have been hypothesized to prevent COVID-19 complications by minimising cytokine storms release. We conducted a prevalent-user active-comparator cohort study to assess association between alpha-1 blocker use and risks of three COVID-19 outcomes: diagnosis, hospitalization, and hospitalization requiring intensive services. Our study included 2.6 and 0.46 million users of alpha-1 blockers and of alternative BPH therapy during the period between November 2019 and January 2020, found in electronic health records from Spain (SIDIAP) and the United States (Department of Veterans Affairs, Columbia University Irving Medical Center, IQVIA OpenClaims, Optum DOD, Optum EHR). We estimated hazard ratios using state-of-the-art techniques to minimize potential confounding, including large-scale propensity score matching/stratification and negative control calibration. We found no differential risk for any of COVID-19 outcome, pointing to the need for further research on potential COVID-19 therapies.

Implementation of the COVID-19 Vulnerability Index Across an International Network of Health Care Data Sets: Collaborative External Validation Study.

BACKGROUND: SARS-CoV-2 is straining health care systems globally. The burden on hospitals during the pandemic could be reduced by implementing prediction models that can discriminate patients who require hospitalization from those who do not. The COVID-19 vulnerability (C-19) index, a model that predicts which patients will be admitted to hospital for treatment of pneumonia or pneumonia proxies, has been developed and proposed as a valuable tool for decision-making during the pandemic. However, the model is at high risk of bias according to the "prediction model risk of bias assessment" criteria, and it has not been externally validated. OBJECTIVE: The aim of this study was to externally validate the C-19 index across a range of health care settings to determine how well it broadly predicts hospitalization due to pneumonia in COVID-19 cases. METHODS: We followed the Observational Health Data Sciences and Informatics (OHDSI) framework for external validation to assess the reliability of the C-19 index. We evaluated the model on two different target populations, 41,381 patients who presented with SARS-CoV-2 at an outpatient or emergency department visit and 9,429,285 patients who presented with influenza or related symptoms during an outpatient or emergency department visit, to predict their risk of hospitalization with pneumonia during the following 0-30 days. In total, we validated the model across a network of 14 databases spanning the United States, Europe, Australia, and Asia. RESULTS: The internal validation performance of the C-19 index had a C statistic of 0.73, and the calibration was not reported by the authors. When we externally validated it by transporting it to SARS-CoV-2 data, the model obtained C statistics of 0.36, 0.53 (0.473-0.584) and 0.56 (0.488-0.636) on Spanish, US, and South Korean data sets, respectively. The calibration was poor, with the model underestimating risk. When validated on 12 data sets containing influenza patients across the OHDSI network, the C statistics ranged between 0.40 and 0.68. CONCLUSIONS: Our results show that the discriminative performance of the C-19 index model is low for influenza cohorts and even worse among patients with COVID-19 in the United States, Spain, and South Korea. These results suggest that C-19 should not be used to aid decision-making during the COVID-19 pandemic. Our findings highlight the importance of performing external validation across a range of settings, especially when a prediction model is being extrapolated to a different population. In the field of prediction, extensive validation is required to create appropriate trust in a model.

Comparative Risk Assessment of Severe Uterine Bleeding Following Exposure to Direct Oral Anticoagulants: A Network Study Across Four Observational Databases in the USA.

BACKGROUND: Antithrombotic therapies are associated with an increased bleeding risk. Abnormal uterine bleeding data have been reported in clinical trials of patients with venous thromboembolism (VTE), but data are limited for patients with atrial fibrillation (AF). OBJECTIVE: Using real-world data from four US healthcare databases (October 2010 to December 2018), we compared the occurrence of severe uterine bleeding among women newly exposed to rivaroxaban, apixaban, dabigatran, and warfarin stratified by indication. METHODS: To reduce potential confounding, patients in comparative cohorts were matched on propensity scores. Treatment effect estimates were generated using Cox proportional hazard models for each indication, in each database, and only for pairwise comparisons that met a priori study diagnostics. If estimates were homogeneous (I2 < 40%), a meta-analysis across databases was performed and pooled hazard ratios reported. RESULTS: Data from 363,919 women newly exposed to a direct oral anticoagulant or warfarin with a prior diagnosis of AF (60.8%) or VTE (39.2%) were analyzed. Overall incidence of severe uterine bleeding was low in the populations exposed to direct oral anticoagulants, although relatively higher in the younger VTE population vs the AF population (unadjusted incidence rates: 2.8-33.7 vs 1.9-10.0 events/1000 person-years). In the propensity score-matched AF population, a suggestive, moderately increased risk of severe uterine bleeding was observed for rivaroxaban relative to warfarin [hazard ratios and 95% confidence intervals from 0.83 (0.27-2.48) to 2.84 (1.32-6.23) across databases with significant heterogeneity], apixaban [pooled hazard ratio 1.45 (0.91-2.28)], and dabigatran [2.12 (1.01-4.43)], which were sensitive to the time-at-risk period. In the propensity score-matched VTE population, a consistent increased risk of severe uterine bleeding was observed for rivaroxaban relative to warfarin [2.03 (1.19-3.27)] and apixaban [2.25 (1.45-3.41)], which were insensitive to the time-at-risk period. CONCLUSIONS: For women who need antithrombotic therapy, personalized management strategies with careful evaluation of benefits and risks are required. CLINICALTRIALS. GOV REGISTRATION: NCT04394234; registered in May 2020.

Risk of depression, suicide and psychosis with hydroxychloroquine treatment for rheumatoid arthritis: a multinational network cohort study.

OBJECTIVES: Concern has been raised in the rheumatology community regarding recent regulatory warnings that HCQ used in the coronavirus disease 2019 pandemic could cause acute psychiatric events. We aimed to study whether there is risk of incident depression, suicidal ideation or psychosis associated with HCQ as used for RA. METHODS: We performed a new-user cohort study using claims and electronic medical records from 10 sources and 3 countries (Germany, UK and USA). RA patients ≥18 years of age and initiating HCQ were compared with those initiating SSZ (active comparator) and followed up in the short (30 days) and long term (on treatment). Study outcomes included depression, suicide/suicidal ideation and hospitalization for psychosis. Propensity score stratification and calibration using negative control outcomes were used to address confounding. Cox models were fitted to estimate database-specific calibrated hazard ratios (HRs), with estimates pooled where I2 <40%. RESULTS: A total of 918 144 and 290 383 users of HCQ and SSZ, respectively, were included. No consistent risk of psychiatric events was observed with short-term HCQ (compared with SSZ) use, with meta-analytic HRs of 0.96 (95% CI 0.79, 1.16) for depression, 0.94 (95% CI 0.49, 1.77) for suicide/suicidal ideation and 1.03 (95% CI 0.66, 1.60) for psychosis. No consistent long-term risk was seen, with meta-analytic HRs of 0.94 (95% CI 0.71, 1.26) for depression, 0.77 (95% CI 0.56, 1.07) for suicide/suicidal ideation and 0.99 (95% CI 0.72, 1.35) for psychosis. CONCLUSION: HCQ as used to treat RA does not appear to increase the risk of depression, suicide/suicidal ideation or psychosis compared with SSZ. No effects were seen in the short or long term. Use at a higher dose or for different indications needs further investigation. TRIAL REGISTRATION: Registered with EU PAS (reference no. EUPAS34497; http://www.encepp.eu/encepp/viewResource.htm? id=34498). The full study protocol and analysis source code can be found at https://github.com/ohdsi-studies/Covid19EstimationHydroxychloroquine2.

Characterising the background incidence rates of adverse events of special interest for covid-19 vaccines in eight countries: multinational network cohort study.

OBJECTIVE: To quantify the background incidence rates of 15 prespecified adverse events of special interest (AESIs) associated with covid-19 vaccines. DESIGN: Multinational network cohort study. SETTING: Electronic health records and health claims data from eight countries: Australia, France, Germany, Japan, the Netherlands, Spain, the United Kingdom, and the United States, mapped to a common data model. PARTICIPANTS: 126 661 070 people observed for at least 365 days before 1 January 2017, 2018, or 2019 from 13 databases. MAIN OUTCOME MEASURES: Events of interests were 15 prespecified AESIs (non-haemorrhagic and haemorrhagic stroke, acute myocardial infarction, deep vein thrombosis, pulmonary embolism, anaphylaxis, Bell's palsy, myocarditis or pericarditis, narcolepsy, appendicitis, immune thrombocytopenia, disseminated intravascular coagulation, encephalomyelitis (including acute disseminated encephalomyelitis), Guillain-Barré syndrome, and transverse myelitis). Incidence rates of AESIs were stratified by age, sex, and database. Rates were pooled across databases using random effects meta-analyses and classified according to the frequency categories of the Council for International Organizations of Medical Sciences. RESULTS: Background rates varied greatly between databases. Deep vein thrombosis ranged from 387 (95% confidence interval 370 to 404) per 100 000 person years in UK CPRD GOLD data to 1443 (1416 to 1470) per 100 000 person years in US IBM MarketScan Multi-State Medicaid data among women aged 65 to 74 years. Some AESIs increased with age. For example, myocardial infarction rates in men increased from 28 (27 to 29) per 100 000 person years among those aged 18-34 years to 1400 (1374 to 1427) per 100 000 person years in those older than 85 years in US Optum electronic health record data. Other AESIs were more common in young people. For example, rates of anaphylaxis among boys and men were 78 (75 to 80) per 100 000 person years in those aged 6-17 years and 8 (6 to 10) per 100 000 person years in those older than 85 years in Optum electronic health record data. Meta-analytic estimates of AESI rates were classified according to age and sex. CONCLUSION: This study found large variations in the observed rates of AESIs by age group and sex, showing the need for stratification or standardisation before using background rates for safety surveillance. Considerable population level heterogeneity in AESI rates was found between databases.

Risk of hydroxychloroquine alone and in combination with azithromycin in the treatment of rheumatoid arthritis: a multinational, retrospective study.

BACKGROUND: Hydroxychloroquine, a drug commonly used in the treatment of rheumatoid arthritis, has received much negative publicity for adverse events associated with its authorisation for emergency use to treat patients with COVID-19 pneumonia. We studied the safety of hydroxychloroquine, alone and in combination with azithromycin, to determine the risk associated with its use in routine care in patients with rheumatoid arthritis. METHODS: In this multinational, retrospective study, new user cohort studies in patients with rheumatoid arthritis aged 18 years or older and initiating hydroxychloroquine were compared with those initiating sulfasalazine and followed up over 30 days, with 16 severe adverse events studied. Self-controlled case series were done to further establish safety in wider populations, and included all users of hydroxychloroquine regardless of rheumatoid arthritis status or indication. Separately, severe adverse events associated with hydroxychloroquine plus azithromycin (compared with hydroxychloroquine plus amoxicillin) were studied. Data comprised 14 sources of claims data or electronic medical records from Germany, Japan, the Netherlands, Spain, the UK, and the USA. Propensity score stratification and calibration using negative control outcomes were used to address confounding. Cox models were fitted to estimate calibrated hazard ratios (HRs) according to drug use. Estimates were pooled where the I 2 value was less than 0·4. FINDINGS: The study included 956 374 users of hydroxychloroquine, 310 350 users of sulfasalazine, 323 122 users of hydroxychloroquine plus azithromycin, and 351 956 users of hydroxychloroquine plus amoxicillin. No excess risk of severe adverse events was identified when 30-day hydroxychloroquine and sulfasalazine use were compared. Self-controlled case series confirmed these findings. However, long-term use of hydroxychloroquine appeared to be associated with increased cardiovascular mortality (calibrated HR 1·65 [95% CI 1·12-2·44]). Addition of azithromycin appeared to be associated with an increased risk of 30-day cardiovascular mortality (calibrated HR 2·19 [95% CI 1·22-3·95]), chest pain or angina (1·15 [1·05-1·26]), and heart failure (1·22 [1·02-1·45]). INTERPRETATION: Hydroxychloroquine treatment appears to have no increased risk in the short term among patients with rheumatoid arthritis, but in the long term it appears to be associated with excess cardiovascular mortality. The addition of azithromycin increases the risk of heart failure and cardiovascular mortality even in the short term. We call for careful consideration of the benefit-risk trade-off when counselling those on hydroxychloroquine treatment. FUNDING: National Institute for Health Research (NIHR) Oxford Biomedical Research Centre, NIHR Senior Research Fellowship programme, US National Institutes of Health, US Department of Veterans Affairs, Janssen Research and Development, IQVIA, Korea Health Industry Development Institute through the Ministry of Health and Welfare Republic of Korea, Versus Arthritis, UK Medical Research Council Doctoral Training Partnership, Foundation Alfonso Martin Escudero, Innovation Fund Denmark, Novo Nordisk Foundation, Singapore Ministry of Health's National Medical Research Council Open Fund Large Collaborative Grant, VINCI, Innovative Medicines Initiative 2 Joint Undertaking, EU's Horizon 2020 research and innovation programme, and European Federation of Pharmaceutical Industries and Associations.

Longitudinal associations of gross motor development, motor milestone achievement and weight-for-length z score in a racially diverse cohort of US infants.

OBJECTIVES: To investigate longitudinal associations between gross motor development, motor milestone achievement and weight-for-length z scores in a sample of infants. In a secondary aim, we explored potential bidirectional relationships, as higher weight-for-length z scores may impede motor development, and poor motor development may lead to obesity. DESIGN: The design was an observational birth cohort. SETTING: We used data from the Nurture study, a birth cohort of predominately black women and their infants residing in the Southeastern USA. PARTICIPANTS: 666 women enrolled their infants in Nurture. We excluded infants with missing data on exposure, outcome or main covariates, leaving a total analytic sample of 425 infants. PRIMARY OUTCOME: The outcome was weight-for-length z score, measured when infants were 3, 6, 9 12 months. RESULTS: Among infants, 64.7% were black, 18.8% were white and 16.9% were other/multiple race. Mean (SD) breastfeeding duration was 17.6 (19.7) weeks. Just over one-third (38.5%) had an annual household income of < $20 000. After adjusting for potential confounders, higher motor development score was associated with lower weight-for-length z score (-0.004; 95% CI -0.001 to -0.007; p=0.01), mainly driven by associations among boys (-0.007; 95% CI -0.014 to -0.001; p=0.03) and not girls (0.001; 95% CI -0.005 to 0.008; p=0.62). Earlier crawling was the only milestone associated with a lower weight-for-length z score at 12 months (-0.328; 95% CI -0.585 to 0.072; p=0.012). However, this association appeared to be driven by male infants only (-0.461; 95% CI -0.825 to -0.096; p=0.01). Weight-for-length z score was unrelated to subsequent motor development score and was thus not bidirectional in our sample. CONCLUSIONS: Higher motor development score and earlier crawling were associated with lower subsequent weight-for-length z score. However, this was primary true for male infants only. These findings contribute to the growing body of evidence suggesting that delayed motor development may be associated with later obesity.

A multivariate discrete failure time model for the analysis of infant motor development.

We develop a multivariate discrete failure time model for the analysis of infant motor development. We use the model to jointly evaluate the time (in months) to achievement of three well-established motor milestones: sitting up, crawling, and walking. The model includes a subject-specific latent factor that reflects underlying heterogeneity in the population and accounts for within-subject dependence across the milestones. The factor loadings and covariate effects are allowed to vary flexibly across milestones, and the milestones are permitted to have unique at-risk intervals corresponding to different developmental windows. We adopt a Bayesian inferential approach and develop a convenient data-augmented Gibbs sampler for posterior computation. We conduct simulation studies to illustrate key features of the model and use the model to analyze data from the Nurture study, a birth cohort examining infant health and development during the first year of life.

The association between method of solicitation and patient permissions for use of surplus tissues and contact for future research.

OBJECTIVE: Obtaining patient permissions for research contact and for surplus tissue use as part of routine clinical practice can improve research participation. This study aims to investigate the difference in patient permissions for use of surplus tissues, and for direct contact for research, using 2 different methods of solicitation. METHODS: An opt-in, population-based approach for gathering research permissions was implemented in 2 methods. The first method, applied a 2-item patient questionnaire delivered through the electronic health record patient portal. The questionnaire composed of 2 questions (1) whether de-identified surplus specimens may be used for research and (2) whether patients could be contacted about research. In the second method, the same questionnaire was physically presented in clinic within the clinical workflow. We used 1 to 1 propensity score matching and multivariate logistic regression to estimate the odds of obtaining permission and the difference between the 2 methods of solicitation. RESULTS: The propensity score model matched 8044 observations (4114 submissions in each group). Among the in-clinic submission group, 70.13% provided permission for surplus tissue compared with 66.65% in the patient portal submission group (odds ratio [OR] = 1.20; 95% confidence interval [CI] 1.09-1.32; P < 0.001). Permission for future research contact was similar among in-clinic (65.07%) and patient portal submission (66.65%) groups (OR = 0.94; 95% CI 0.85-1.03; P = 0.175). These trends were consistent among European Americans and African American patients. However, among patients of other race, higher permission for both future contact (OR = 0.58; 95% CI 0.39-0.86; P < 0.007) and surplus tissue use (OR = 0.65; 95% CI 0.43-0.97; P = 0.036) was observed among patient portal submission. DISCUSSION: Our findings suggest that in-clinic solicitation of patient permissions may provide the same opportunity to patients who do not use patient portals and may be associated with higher permission rate for surplus tissue. However, this was primary true for European American and African Americans patients. Patients of other race minorities might respond better to online approaches. CONCLUSION: Adopting a patient-centric approach that combines in-clinic and portal-based administration may be feasible and promising. Further research is required in this area.

Research participation preferences as expressed through a patient portal: implications of demographic characteristics.

OBJECTIVE: As patient portals are increasingly used for research recruitment, it is important to examine the demographic makeup of research registries that are populated via portals and the factors that influence participation in these registries. METHODS: We examined the response to a routine research preference questionnaire among patients who were enrolled in a patient portal at an academic health center and characterized the sub-population that responded and was tracked in a research preferences registry. We examined the factors that influence choices in two research preferences: future contact for research opportunities and biobanking of de-identified specimens. RESULTS: Out of 79 834 patients to whom the questionnaire was sent, 32% responded. Of those 74% agreed to future contact and 77% to the biobank preference. We found significantly lower odds of agreement in both preferences in minority populations, especially in the population >65 years of age when stratified by race. Individuals with higher comorbidity indexes had significantly higher odds for agreement. DISCUSSION: The disparities in volunteerism as expressed by agreement to future contact and willingness to participate in biobanking are exacerbated by lower levels of enrollment in the patient portal by minorities, especially in the oldest age group. Future work should examine other socioeconomic factors and the differences across age groups, sicker individuals, and payer categories. CONCLUSION: Although patient portals can be more efficient for recruitment, researchers have to be cognizant of, and proactively address, potential biases when recruiting participants from these registries.