Machine learning for improving high-dimensional proxy confounder adjustment in healthcare database studies: An overview of the current literature.

PURPOSE: Supplementing investigator-specified variables with large numbers of empirically identified features that collectively serve as 'proxies' for unspecified or unmeasured factors can often improve confounding control in studies utilizing administrative healthcare databases. Consequently, there has been a recent focus on the development of data-driven methods for high-dimensional proxy confounder adjustment in pharmacoepidemiologic research. In this paper, we survey current approaches and recent advancements for high-dimensional proxy confounder adjustment in healthcare database studies. METHODS: We discuss considerations underpinning three areas for high-dimensional proxy confounder adjustment: (1) feature generation-transforming raw data into covariates (or features) to be used for proxy adjustment; (2) covariate prioritization, selection, and adjustment; and (3) diagnostic assessment. We discuss challenges and avenues of future development within each area. RESULTS: There is a large literature on methods for high-dimensional confounder prioritization/selection, but relatively little has been written on best practices for feature generation and diagnostic assessment. Consequently, these areas have particular limitations and challenges. CONCLUSIONS: There is a growing body of evidence showing that machine-learning algorithms for high-dimensional proxy-confounder adjustment can supplement investigator-specified variables to improve confounding control compared to adjustment based on investigator-specified variables alone. However, more research is needed on best practices for feature generation and diagnostic assessment when applying methods for high-dimensional proxy confounder adjustment in pharmacoepidemiologic studies.

Using propensity scores to estimate effects of treatment initiation decisions: State of the science.

Confounding can cause substantial bias in nonexperimental studies that aim to estimate causal effects. Propensity score methods allow researchers to reduce bias from measured confounding by summarizing the distributions of many measured confounders in a single score based on the probability of receiving treatment. This score can then be used to mitigate imbalances in the distributions of these measured confounders between those who received the treatment of interest and those in the comparator population, resulting in less biased treatment effect estimates. This methodology was formalized by Rosenbaum and Rubin in 1983 and, since then, has been used increasingly often across a wide variety of scientific disciplines. In this review article, we provide an overview of propensity scores in the context of real-world evidence generation with a focus on their use in the setting of single treatment decisions, that is, choosing between two therapeutic options. We describe five aspects of propensity score analysis: alignment with the potential outcomes framework, implications for study design, estimation procedures, implementation options, and reporting. We add context to these concepts by highlighting how the types of comparator used, the implementation method, and balance assessment techniques have changed over time. Finally, we discuss evolving applications of propensity scores.

Prevalence of Eosinophilic Granulomatosis With Polyangiitis and Associated Health Care Utilization Among Patients With Concomitant Asthma in US Commercial Claims Database.

OBJECTIVE: To estimate the prevalence and associated disease burden of eosinophilic granulomatosis with polyangiitis (EGPA) in patients with asthma from a US claims database. METHODS: Two cohorts were defined using enrollees (aged ≥18 years) from the Optum deidentified Clinformatics Datamart claims database 2010-2014, based on validated EGPA case definitions with varying specificity: EGPA 1 (main cohort; more specific; patients with 2 codes [in any combination] within 12 months of each other for eosinophilia, vasculitis, or mononeuritis multiplex) and EGPA 2 (sensitivity analysis cohort; less specific; patients with 2 codes of above conditions and/or neurologic symptoms within 12 months of each other). Patients had 3 or more asthma medications in the 12-month baseline before index date (date of the second code). Eosinophilic granulomatosis with polyangiitis prevalence, asthma severity during the baseline period, oral corticosteroid (OCS) use, and health care utilization during the 12-month follow-up period were determined. RESULTS: Overall, 88 and 604 patients were included in main cohort EGPA 1 and sensitivity analysis cohort EGPA 2, respectively; corresponding annual EGPA prevalence rates were 3.2 to 5.9 and 23.4 to 30.7 cases/million patients. Approximately 75% of patients were prescribed OCS and ~30% experienced 1 or more hospitalization; 75% in EGPA 1 and 52% in EGPA 2 with 1 or more non-OCS prescription in the 90 days before index date had severe asthma. CONCLUSIONS: Eosinophilic granulomatosis with polyangiitis prevalence estimates varied based on specificity of the case definition but were generally consistent with previous country-specific estimates. Despite differences in prevalence, both cohorts displayed a generally similar, high burden of OCS use and health care utilization, highlighting the substantial disease burden among patients with EGPA and the need for specific treatments.

Real-world evidence: the devil is in the detail.

Much has been written about real-world evidence (RWE), a concept that offers an understanding of the effects of healthcare interventions using routine clinical data. The reflection of diverse real-world practices is a double-edged sword that makes RWE attractive but also opens doors to several biases that need to be minimised both in the design and analytical phases of non-experimental studies. Additionally, it is critical to ensure that researchers who conduct these studies possess adequate methodological expertise and ability to accurately implement these methods. Critical design elements to be considered should include a clearly defined research question using a causal inference framework, choice of a fit-for-purpose data source, inclusion of new users of a treatment with comparators that are as similar as possible to that group, accurately classifying person-time and deciding censoring approaches. Having taken measures to minimise bias 'by design', the next step is to implement appropriate analytical techniques (for example propensity scores) to minimise the remnant potential biases. A clear protocol should be provided at the beginning of the study and a report of the results after, including caveats to consider. We also point the readers to readings on some novel analytical methods as well as newer areas of application of RWE. While there is no one-size-fits-all solution to evaluating RWE studies, we have focused our discussion on key methods and issues commonly encountered in comparative observational cohort studies with the hope that readers are better equipped to evaluate non-experimental studies that they encounter in the future. Graphical abstract.

Linking electronic health data in pharmacoepidemiology: Appropriateness and feasibility.

PURPOSE: To provide guidance on data linkage appropriateness and feasibility to plan purposeful and sustainable new linkages that advance pharmacoepidemiology and healthcare research. Planning a new data linkage requires careful evaluation to weigh the resources required with the potential overall benefits. METHODS: In response to an International Society for Pharmacoepidemiology (ISPE) call for manuscripts, a working group comprised of members from academic, industry, and government determined priority content areas; appropriateness and feasibility of data linkage was selected. Within this topic, scientific and operational considerations were determined, reviewed, and formulated into key areas, and translated into 12 consensus recommendations. RESULTS: Guidance for feasibility assessment was categorized into five key areas: (1) research objectives and justification; (2) data quality and completeness; (3) the linkage process; (4) data ownership and governance; and (5) overall value added by linkage. Within these key areas, recommendations to consider prior to initiation were developed to evaluate suitability of the linkage to meet research objectives, assess source data completeness and population coverage, and ensure well-defined data governance standards and protections. When creating novel linked datasets, researchers must assess the feasibility of both scientific (data quality and linkage methods) and operational (access, data use and transfer, governance, and cost) aspects. CONCLUSIONS: The data linkage feasibility assessment considerations outlined can be used as a guide when designing sustainable linked data resources to generate actionable evidence in healthcare research. These recommendations were constructed for wide applicability and can be adapted depending on the geographic, structural, and data components of the linkage.

Impact of metformin use on the cardiovascular effects of dipeptidyl peptidase-4 inhibitors: An analysis of Medicare claims data from 2007 to 2015.

AIMS: To examine the outcomes of dipeptidyl peptidase-4 (DPP-4) inhibitor initiation with and without concurrent metformin treatment. MATERIALS AND METHODS: We identified Medicare enrollees initiating a DPP-4 inhibitor, a sulphonylurea or a thiazolidinedione. Using propensity-score-weighted Poisson models, we evaluated 1-year cardiovascular (CV) outcome incidence among initiators of DPP-4 inhibitors versus comparators in subgroups with and without concurrent metformin use, and assessed the interaction between initiation drug and metformin. Outcomes included mortality, non-fatal myocardial infarction (MI), stroke, and a composite outcome. RESULTS: For the DPP-4 inhibitor (n = 13 391) versus sulphonylurea (n = 33 206) comparison, rate differences in composite outcome incidence favoured DPP-4 inhibitors: -2.0/100 person-years among metformin users (95% confidence interval [CI] -2.7 to -1.3) and - 1.0/100 person-years (95% CI -1.8 to -0.2) among metformin non-users. Similar rate difference trends among metformin users and non-users were seen for mortality (-1.5/100 person-years [95% CI -2.1 to -0.9] and -0.7/100 person-years [95% CI -1.4 to 0.0]) and non-fatal MI (-0.5/100 person-years [95% CI -0.8, -0.3] and 0.1/100 person-years [95% CI -0.2 to 0.4]). The interaction between DPP-4 inhibitor initiation and metformin was statistically significant for non-fatal MI (P = 0.008). For the DPP-4 inhibitor (n = 22 210) versus thiazolidinedione (n = 9517) comparison, rate differences in composite outcome incidence for DPP-4 inhibitor initiation were -0.6/100 person-years (95% CI -1.5 to 0.2) among metformin users and 1.0 (95% CI 0.0 to 2.0) among metformin non-users. Similar rate difference trends among metformin users and non-users were seen for mortality (-0.5/100 person-years [95% CI -1.3 to 0.1] and 0.8/100 person-years [95% CI -0.0 to 1.7]) and non-fatal MI (-0.1/100 person-years [95% CI -0.4 to 0.2] and 0.2/100 person-years [95% CI -0.1 to 0.6]). The interaction between DPP-4 inhibitor initiation and metformin was statistically significant for the composite outcome (P = 0.024) and mortality (P = 0.023). CONCLUSION: Incidence rate differences in multiple CV outcomes appeared more favourable when DPP-4 inhibitor initiation occurred in the presence of metformin, suggesting a possible interaction between DPP-4 inhibitors and metformin.

Study design choices for evaluating the comparative safety of diabetes medications: An evaluation of pioglitazone use and risk of bladder cancer in older US adults with type-2 diabetes.

AIM: The aim of the study was to empirically demonstrate the effect of varying study designs when evaluating the safety of pioglitazone in treating bladder cancer. METHODS: We identified Medicare beneficiaries above 65 years of age with diabetes between 2008 and 2015 and with classified exposure (at least two claims within 180 days) to glucose-lowering drugs (GLD), pioglitazone or another drug. The effects of varying the following study design parameters on bladder cancer risk were assessed: use of a new vs existing drug, choice of referent (all non-users and users of GLDs, non-insulin GLDs and DPP-4s) and whether or not censoring accounted for treatment change. We used the Cox proportional hazards model to obtain adjusted HRs and 95% CIs. RESULTS: We included 1,510,212 patients classified as pioglitazone users (N = 135,188) or non-users (N = 1,375,024). Users had more diabetic complications than non-users, but fewer than insulin users. The HR ranged from 1.10 (1.01-1.20) to 1.13 (0.99-1.29) when censoring ignored treatment change, suggesting a weak association or none between pioglitazone and bladder cancer, probably under-estimating risk. However, the HR was 1.20 (1.01-1.42) when cohorts were restricted to new users, censored upon treatment change, and when DPP-4 was used as the referent, suggesting an increased risk of bladder cancer associated with pioglitazone. CONCLUSIONS: The continued demand for new GLDs indicates the need for more robust observational methods to improve the value of generating real-world evidence in equipping clinicians to make informed prescribing decisions. Although there is no one-size-fits-all approach, we recommend active comparator new user study designs that compare therapeutically equivalent drugs and account for treatment changes during follow-up to present the least biased comparative safety estimates.

Calendar time as an instrumental variable in assessing the risk of heart failure with antihyperglycemic drugs.

OBJECTIVE: In recent years, second-line diabetes treatment with dipeptidyl peptidase-4 inhibitors (DPP-4i) increased with a corresponding decrease in thiazolidinediones (TZDs). Using hospitalization for heart failure (HF) as a positive control outcome, we explored the use of calendar time as an instrumental variable (IV) and compared this approach to an active comparator new-user study. METHODS: We identified DPP-4i or TZD initiators after a 6-month washout using Medicare claims 2006-2013. The IV was defined as a binary variable comparing initiators during October 2010 to December 2013 (postperiod) versus January 2008 to May 2010 (preperiod). We examined IV strength and estimated risk differences (RDs) for HF using Kaplan-Meier curves, which were compared with propensity score (PS)-weighted RD for DPP-4i versus TZD. RESULTS: The IV compared 22 696 initiators (78% DPP-4i) in the postperiod versus 20 283 initiators (38% DPP-4i) in the preperiod, resulting in 40% compliance. The active-comparator (PS-weighted) approach compared 26 198 DPP-4i and 18 842 TZD initiators. Covariate balance across IV levels was slightly better than across treatments (standardized difference, 3% vs 4.5%). The 1- and 2-year local average treatment effects of RD of HF per 100 patients in the "compliers" (95% confidence intervals) were -0.62 (-0.99 to -0.25) and -0.88 (-1.46 to -0.25). Corresponding PS-weighted results were -0.20 (-0.33 to -0.05) and -0.18 (-0.30 to 0.03). CONCLUSION: Both approaches indicated lesser risk of HF hospitalizations among DPP-4i vs TZD initiators. The magnitude of the estimated effects may differ due to differences in the target populations and assumptions. Calendar time can be leveraged as an IV when market dynamics lead to profound changes in treatments.

No increased risk of cardiovascular events in older adults initiating dipeptidyl peptidase-4 inhibitors vs therapeutic alternatives.

AIM: To compare the cardiovascular (CV) risk associated with dipeptidyl peptidase-4 (DPP-4) inhibitors relative to sulphonylureas (SUs) and thiazolidinediones (TZDs). METHODS: During 2007 to 2013, using Medicare data for beneficiaries aged >65 years, we identified the following 2 cohorts of new-users, who had not been exposed to the drugs being compared in the 6 months before initiation: (1) DPP-4 inhibitor vs SU initiators and (2) DPP-4 inhibitor vs TZD initiators. Using propensity-score-adjusted Cox models accounting for competing risk by death, we estimated the hazard ratios (HRs), risk differences and 95% confidence intervals (CIs) for myocardial infarction (MI), stroke, hospitalization for heart failure (HF), and a combined outcome (MI, stroke, all-cause mortality). RESULTS: In the DPP-4 inhibitor vs SU comparison, there were 30 130 DPP-4 inhibitor initiators and 68 382 SU initiators. Their mean age was 75 years, 41% were men and 55% had a baseline CV condition. The HR for the composite outcome was 0.75 (95% CI 0.72-0.79) over a median treatment duration of 1 year, but the 1-year risks of MI were 1.00 (95% CI 0.89-1.12) and 1.47 (95% CI 1.38-1.56) per 100 patients for DPP-4 inhibitors and SUs, respectively, and the corresponding stroke risks were 0.98 (95% CI 0.87-1.10) and 1.09 (95% CI 1.01-1.17). For the DPP-4 inhibitor vs TZD comparison, there were 20 596 DPP-4 inhibitor initiators and 13 526 TZD initiators without previous HF. Their mean age was 74 years, 42% were men and 30% had a baseline CV event. The composite outcome HR was 0.94 (95% CI 0.86-1.02) over a median treatment duration of 1 year. The 1-year risk for MI was ~0.90 and for stroke it was ~0.80 per 100 patients in both DPP-4 inhibitor and TZD initiators. CONCLUSION: Although limited by the short treatment period, the present study suggests there is no increased short-term risk of MI, stroke or HF with DPP-4 inhibitors vs SUs/TZDs.

Effect of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors on colorectal cancer incidence and its precursors.

AIMS: Incretin-based antihyperglycemic therapies increase intestinal mucosal expansion and polyp growth in mouse models. We aimed to evaluate the effect of dipeptidyl peptidase-4 inhibitors (DPP-4i) or glucagon-like peptide-1 receptor agonists (GLP-1ra) initiation on colorectal cancer incidence. METHODS: We conducted a cohort study on US Medicare beneficiaries over age 66 from 2007 to 2013 without prevalent cancer. We identified three active-comparator and new-user cohorts: DPP-4i versus thiazolidinediones (TZD), DPP-4i versus sulphonylureas (SU), and GLP-1ra versus long acting insulin (LAI). Follow-up started from 6 months post-second prescription and ended 6 months after stopping (primary as-treated analysis). We estimated hazard ratios (HR) and 95 % confidence intervals (CI) for incident colorectal cancer adjusting for measured confounders using propensity score weighting. RESULTS: The median duration of treatment ranged 0.7-0.9 years among DPP-4i cohorts. Based on 104 events among 39,334 DPP-4i and 63 events among 25,786 TZD initiators, there was no association between DPP-4i initiation and colorectal cancer (adjusted HR = 1.17 (CI 0.88, 1.71)). There were 73 events among 27,047 DPP-4i and 266 events among 76,012 SU initiators with the adjusted HR 0.98 (CI 0.74, 1.30). We identified 5600 GLP-1ra and 54,767 LAI initiators and the median duration of treatment was 0.8 and 1.2 years, respectively. The adjusted HR was 0.82 (CI 0.42, 1.58) based on <11 events among GLP-1ra versus 276 events among LAI initiators. CONCLUSION: Although limited by the short duration of treatment, our analyses based on real-world drug utilization patterns provide evidence of no short-term effect of incretin-based agents on colorectal cancer.

More realistic power estimation for new user, active comparator studies: an empirical example.

PURPOSE: Pharmacoepidemiologic studies are often expected to be sufficiently powered to study rare outcomes, but there is sequential loss of power with implementation of study design options minimizing bias. We illustrate this using a study comparing pancreatic cancer incidence after initiating dipeptidyl-peptidase-4 inhibitors (DPP-4i) versus thiazolidinediones or sulfonylureas. METHODS: We identified Medicare beneficiaries with at least one claim of DPP-4i or comparators during 2007-2009 and then applied the following steps: (i) exclude prevalent users, (ii) require a second prescription of same drug, (iii) exclude prevalent cancers, (iv) exclude patients age <66 years and (v) censor for treatment changes during follow-up. Power to detect hazard ratios (effect measure strongly driven by the number of events) ≥ 2.0 estimated after step 5 was compared with the naïve power estimated prior to step 1. RESULTS: There were 19,388 and 28,846 DPP-4i and thiazolidinedione initiators during 2007-2009. The number of drug initiators dropped most after requiring a second prescription, outcomes dropped most after excluding patients with prevalent cancer and person-time dropped most after requiring a second prescription and as-treated censoring. The naïve power (>99%) was considerably higher than the power obtained after the final step (~75%). CONCLUSIONS: In designing new-user active-comparator studies, one should be mindful how steps minimizing bias affect sample-size, number of outcomes and person-time. While actual numbers will depend on specific settings, application of generic losses in percentages will improve estimates of power compared with the naive approach mostly ignoring steps taken to increase validity.

Comparison of diagnostic evaluations for cough among initiators of angiotensin converting enzyme inhibitors and angiotensin receptor blockers.

PURPOSE: Differential diagnostic evaluation associated with a drug may bias effect estimates because of an increased detection of preclinical outcomes. Persistent cough is a common side effect with angiotensin-converting enzyme inhibitors (ACEI), and we hypothesized that ACEI initiators would undergo more diagnostic evaluations, potentially leading to diagnosis of preclinical lung cancer. We compared the incidence of cough-related diagnostic evaluations and lung cancer among ACEI versus angiotensin receptor blockers (ARB) initiators. METHODS: Using a 20% sample of Medicare claims 2007-2012, we identified initiators of ACEI or ARB, age 66-99 years. Incidence of diagnostic evaluation and lung cancer were compared using adjusted Cox models. Monthly probabilities of workup were compared using proportion differences. RESULTS: There were 342 611 and 108 116 ACEI and ARB initiators, respectively. Monthly probability of chest X-rays ranged from minimum 4.7% to maximum 21.2% in the 6 months pre and post-initiation. Differences in incidence of diagnostic procedures in the 6 months after initiation were only minimal (chest X-rays hazard ratio (HR) = 1.12; 95% CI: 1.10-1.14), chest-MRI (0.86, 95% CI: 0.74-0.99), CT-scans (1.09, 95% CI: 0.99-1.18) or bronchoscopies (1.03, 95% CI: 0.83-1.29). Proportion differences for chest X-rays peaked in the month pre-initiation (8.4%, 95% CI: 8.1-8.6) but negligible thereafter. There was no difference in the incidence of lung cancer among ACEI versus ARB initiators (HR = 0.99, 95% CI: 0.84-1.16). CONCLUSION: Results indicate minimal differential chest workup after ACEI versus ARB initiation and no difference in lung cancer incidence, but suggest differential workup in the month before the first recorded prescription. The latter may reflect drug use before the first observed pharmacy claim or increased workup before initiation of ACEI therapy. Copyright © 2016 John Wiley & Sons, Ltd.

Clinical characteristics associated with Mycoplasma genitalium among female sex workers in Nairobi, Kenya.

The prevalence of Mycoplasma genitalium is high in vulnerable populations of women in low-resource settings. However, the epidemiology of infection in these populations is not well established. To determine the prevalence of Mycoplasma genitalium and its association with cervical cytology and other correlates, we recruited 350 female sex workers (FSW) who were 18 to 50 years old in Nairobi, Kenya, for a cross-sectional study. A questionnaire was administered at baseline to obtain information on sociodemographics and sexual behaviors. Women underwent a pelvic exam, during which a physician collected cervical-exfoliation samples for conventional cytology and sexually transmitted infection (STI) testing. Samples were tested for M. genitalium and other STI organisms (Chlamydia trachomatis, Neisseria gonorrhoeae, Trichomonas vaginalis) and the E6/E7 mRNA of human papillomavirus (HPV) by Aptima nucleic amplification assays. The prevalence of M. genitalium was 12.9%. FSW who engaged in sexual intercourse during menses were less likely to have M. genitalium infection than those who did not (odds ratio [OR], 0.3; 95% confidence interval [95% CI], 0.1, 0.9). M. genitalium was also less prevalent among FSW who had worked in prostitution for >5 years (6.2%) than among those who had worked for <3 years (17.6%) (OR, 0.3; 95% CI, 0.1, 0.8). FSW who reported more frequent condom use were more likely to be infected with M. genitalium than those who reported less frequent use (OR, 3.8; 95% CI, 1.2, 11.6). These correlates differ from those found in M. genitalium studies conducted with FSW from West Africa and China. Further longitudinal analyses assessing associations with persistent M. genitalium infection are needed.

Assessing the impact of propensity score estimation and implementation on covariate balance and confounding control within and across important subgroups in comparative effectiveness research.

PURPOSE: Researchers are often interested in estimating treatment effects in subgroups controlling for confounding based on a propensity score (PS) estimated in the overall study population. OBJECTIVE: To evaluate covariate balance and confounding control in sulfonylurea versus metformin initiators within subgroups defined by cardiovascular disease (CVD) history comparing an overall PS with subgroup-specific PSs implemented by 1:1 matching and stratification. METHODS: We analyzed younger patients from a US insurance claims database and older patients from 2 Medicare (Humana Medicare Advantage, fee-for-service Medicare Parts A, B, and D) datasets. Confounders and risk factors for acute myocardial infarction were included in an overall PS and subgroup PSs with and without CVD. Covariate balance was assessed using the average standardized absolute mean difference (ASAMD). RESULTS: Compared with crude estimates, ASAMD across covariates was improved 70%-94% for stratification for Medicare cohorts and 44%-99% for the younger cohort, with minimal differences between overall and subgroup-specific PSs. With matching, 75%-99% balance improvement was achieved regardless of cohort and PS, but with smaller sample size. Hazard ratios within each CVD subgroup differed minimally among PS and cohorts. CONCLUSIONS: Both overall PSs and CVD subgroup-specific PSs achieved good balance on measured covariates when assessing the relative association of diabetes monotherapy with nonfatal myocardial infarction. PS matching generally led to better balance than stratification, but with smaller sample size. Our study is limited insofar as crude differences were minimal, suggesting that the new user, active comparator design identified patients with some equipoise between treatments.

Characteristics, treatment patterns, and outcomes in patients with high-risk locally advanced cervical cancer.

OBJECTIVE: To characterize the real-world treatment patterns and outcomes of patients with high-risk locally advanced cervical cancer (HR-LACC). METHODS: This retrospective study identified and randomly selected adults diagnosed between 2010 and 2018 from the ConcertAI Oncology Dataset. For patients initially treated with concurrent chemoradiotherapy (CCRT), we estimated real-world progression-free survival (rwPFS) among those with persistent disease, real-world time on CCRT, and recurrence-free survival (rwRFS) using Kaplan-Meier methods. RESULTS: The cohort included 300 patients. Median age at diagnosis was 51 years. 53.7 % were White and 30.0 % were Black; 52.0 % were premenopausal; 89.3 % had squamous cell histology; 75.3 % had stage III disease, and 92.7 % had no evidence of performance status impairment. Initial treatment included CCRT (N = 229), surgery (N = 28), antineoplastics only (N = 11), and radiation only (N = 5). Twenty-seven patients were untreated. Baseline characteristics for the CCRT-first patients were similar to the overall cohort; their median real-world time on treatment was 1.6 months; 78.2 % received cisplatin for a median of 1.2 months; 28.4 % received antineoplastics after CCRT, and 11.8 % initiated a second antineoplastic therapy. Of the CCRT-first patients, 27/143 with a complete response had subsequent recurrent disease (median rwRFS not reached). 179 patients had persistent disease, among whom median (95 % confidence interval [CI]) rwPFS was 29.7 (16.9-59.3) months. CONCLUSION: In this study of United States-based clinical practices, most HR-LACC patients received CCRT as initial treatment. Many patients developed persistent disease after CCRT indicating a need for improved first treatment and maintenance options.

Patient profiles, treatment patterns, and outcomes among persistent, recurrent, or metastatic cervical cancer patients under routine care in the United States.

OBJECTIVE: Patients with persistent, recurrent, or metastatic cervical cancer have poor prognosis. While recent advances have expanded treatment options, real-world data on treatment patterns and outcomes in this population are lacking. METHODS: This retrospective study identified adult females with persistent, recurrent, or metastatic cervical cancer from the ConcertAI Oncology Dataset who received systemic therapy on or after August 15, 2014. Patients were followed from persistent, recurrent, or metastatic diagnosis through third-line (3 L) therapy, death, end of record, or study end (June 2021). Data collection included patient characteristics, treatment patterns, and clinical outcomes. Kaplan-Meier methods were used for the three most common first-line (1 L) regimens to analyze real-world time on treatment (rwToT), real-world progression-free survival (rwPFS), and real-world overall survival (rwOS). Analyses were stratified by bevacizumab receipt by treatment line. RESULTS: 307 patients were included (mean [standard deviation] age 51.5 [13.2] years, 70.7% White). 91.2% of patients had metastatic disease, 8.5% had persistent disease, and <1% had recurrent disease. The most common 1 L regimen was carboplatin+paclitaxel+bevacizumab (40.7%) with median (95% confidence interval [CI]) rwToT of 3.5 (2.9-4.4) months. 57.0% of patients proceeded to second line (2 L), and 25.7% went to 3 L. Median (95% CI) rwPFS was 7.2 (6.4-8.1) months, and median (95% CI) rwOS was 16.5 (14.2-19.9) months, from initiation of 1 L. CONCLUSIONS: 1 L regimens received in patients with persistent, recurrent, or metastatic cervical cancer generally followed clinical guidelines, and the rwOS agrees with clinical trials. This study highlights the burden of disease and unmet need for specific treatments in these patients.

Long-COVID-19 clinical and health outcomes: an umbrella review.

Background: A growing interest in long-term sequelae of COVID-19 has prompted several systematic literature reviews (SLRs) to evaluate long-COVID-19 effects. However, many of these reviews lack in-depth information on the timing, duration, and severity of these conditions. Objectives: Our aim was to synthesize both qualitative and quantitative evidence on prevalence and outcomes of long-term effect of COVID-19 through an umbrella review. Design: Umbrella review of relevant SLRs on long-COVID-19 in terms of prolonged symptoms and clinical conditions, and comprehensively synthesized the latest existing evidence. Data Sources and Methods: We systematically identified and appraised prior systematic reviews/meta-analyses using MEDLINE, Embase, and Cochrane database of systematic review from 2020 to 2021 following the preferred reporting items for systematic reviews and meta-analyses guidance. We summarized and categorized all relevant clinical symptoms and outcomes in adults with COVID-19 using the Medical Dictionary for Regulatory Activities System Organ Class (MedDRA SOC). Results: We identified 967 systematic reviews/meta-analyses; 36 were retained for final data extraction. The most prevalent SOC were social circumstances (40%), blood and lymphatic system disorders (39%), and metabolism and nutrition disorder (38%). The most frequently reported SOC outcomes within each MedDRA category were poor quality of life (59%), wheezing and dyspnea (19-49%), fatigue (30-64%), chest pain (16%), decreased or loss of appetite (14-17%), abdominal discomfort or digestive disorder (12-18%), arthralgia with or without myalgia (16-24%), paresthesia (27%) and hair loss (14-25%), and hearing loss or tinnitus (15%). Conclusion: This study confirmed a high prevalence of several long COVID-19 outcomes according to the MedDRA categories and indicated that the majority of evidence was rated as moderate to low. Registration: The review was registered at PROSPERO (https://www.crd.york.ac.uk/prospero/) (CRD42022303557).

Prognostic Factors of COVID-19: An Umbrella Review Endorsed by the International Society for Pharmacoepidemiology.

During the coronavirus disease 2019 (COVID-19) pandemic, the urgency for updated evidence to inform public health and clinical care placed systematic literature reviews (SLRs) at the cornerstone of research. We aimed to summarize evidence on prognostic factors for COVID-19 outcomes through published SLRs and to critically assess quality elements in the findings' interpretation. An umbrella review was conducted via electronic databases from January 2020 to April 2022. All SLRs (and meta-analyses) in English were considered. Data screening and extraction were conducted by two independent reviewers. AMSTAR 2 tool was used to assess SLR quality. The study was registered with PROSPERO (CRD4202232576). Out of 4,564 publications, 171 SLRs were included of which 3 were umbrella reviews. Our primary analysis included 35 SLRs published in 2022, which incorporated studies since the beginning of the pandemic. Consistent findings showed that, for adults, older age, obesity, heart disease, diabetes, and cancer were more strongly predictive of risk of hospitalization, intensive care unit admission, and mortality due to COVID-19. Male sex was associated with higher risk of short-term adverse outcomes, but female sex was associated with higher risk of long COVID. For children, socioeconomic determinants that may unravel COVID-19 disparities were rarely reported. This review highlights key prognostic factors of COVID-19, which can help clinicians and health officers identify high-risk groups for optimal care. Findings can also help optimize confounding adjustment and patient phenotyping in comparative effectiveness research. A living SLR approach may facilitate dissemination of new findings. This paper is endorsed by the International Society for Pharmacoepidemiology.

Prescription-acquired acetaminophen use and potential overuse patterns: 2001-2008.

BACKGROUND: Food and Drug Administration advisory committees recently made some recommendations to address acetaminophen (APAP)-related toxicity. OBJECTIVES: To study the proportion of APAP users potentially consuming APAP over the currently recommended dosage (4 g/day) and a toxic dosage (10 g/day). To explore the impact of substituting the APAP strength in combination prescriptions to 325 mg on potential APAP overuse patterns. METHODS: Using the 2001-2008 pharmacy claims from IMS LifeLink Health Plans, APAP potential maximum daily dose (PMDD), potential cumulative dose, and potential average daily dose (PADD) were calculated annually for APAP users. The proportion of users with potential APAP use above 4 g/day and 10 g/day are reported. Analyses were repeated by substituting the maximum APAP strength in combination prescriptions to 325 mg. Ordinary least squares regression was used to detect linear trends in APAP use/overuse. RESULTS: 790 188 of 2 656 161 study subjects were prescribed APAP in one or more years from 2001 to 2008. 32.62% and 26.84% of the adult APAP users had a PMDD > 4 gm/day in 2001 and 2008 while 1.88% and 3.17% had a PMDD > 10 gm/day. If the maximum APAP strength in combination prescriptions was 325 mg, the proportion of APAP users with PMDD > 4 g would be 14.08% in 2001 and 13.67% in 2008, whereas the proportion of those with PMDD > 10 g would be 0.21% and 2.30%, respectively. CONCLUSION: About one in four APAP users have a PMDD > 4 g/day, whereas 2-3% have a PMDD > 10 g based exclusively on prescription data, which is concerning. These proportions could reduce by over half if the maximum APAP strength in combination prescriptions is 325 mg. Additional monitoring of opioid prescription-patterns, physician and pharmacist cognizance in prescribing APAP-containing combination products, and dose-reduction strategies should be considered to reduce APAP overuse.

Framework for the synthesis of non-randomised studies and randomised controlled trials: a guidance on conducting a systematic review and meta-analysis for healthcare decision making.

INTRODUCTION: High-quality randomised controlled trials (RCTs) provide the most reliable evidence on the comparative efficacy of new medicines. However, non-randomised studies (NRS) are increasingly recognised as a source of insights into the real-world performance of novel therapeutic products, particularly when traditional RCTs are impractical or lack generalisability. This means there is a growing need for synthesising evidence from RCTs and NRS in healthcare decision making, particularly given recent developments such as innovative study designs, digital technologies and linked databases across countries. Crucially, however, no formal framework exists to guide the integration of these data types. OBJECTIVES AND METHODS: To address this gap, we used a mixed methods approach (review of existing guidance, methodological papers, Delphi survey) to develop guidance for researchers and healthcare decision-makers on when and how to best combine evidence from NRS and RCTs to improve transparency and build confidence in the resulting summary effect estimates. RESULTS: Our framework comprises seven steps on guiding the integration and interpretation of evidence from NRS and RCTs and we offer recommendations on the most appropriate statistical approaches based on three main analytical scenarios in healthcare decision making (specifically, 'high-bar evidence' when RCTs are the preferred source of evidence, 'medium,' and 'low' when NRS is the main source of inference). CONCLUSION: Our framework augments existing guidance on assessing the quality of NRS and their compatibility with RCTs for evidence synthesis, while also highlighting potential challenges in implementing it. This manuscript received endorsement from the International Society for Pharmacoepidemiology.