Examining uncertainty in journal peer reviewers' recommendations: a cross-sectional study.

The peer review process is used throughout science but has often been criticized for being inconsistent, with decisions dependent on the peers who did the reviewing. Much of the decision inconsistency arises from the differences between reviewers in terms of their expertise, training and experience. Another source of uncertainty is within reviewers as they must make a single recommendation (e.g. 'Accept'), when they may have wavered between two (e.g. 'Accept' or 'Reject'). We estimated the size of within-reviewer uncertainty using post-review surveys at three journals. We asked reviewers to think outside the recommendation they gave (e.g. 'Accept') and assign percentages to all other recommendations (e.g. 'Major revision'). Reviewers who were certain could assign 100% to one recommendation. Twenty-three per cent of reviewers reported no uncertainty (95% confidence interval 19-27%). Women were associated with more uncertainty at one journal, and protocol papers were associated with more uncertainty at one journal. Reviewers commonly experience some uncertainty when peer-reviewing journal articles. This uncertainty is part of the variability in peer reviewers' recommendation.

ANTHROPOMETRIC MEASURES AMONG CHILDREN AND TEENS WITH CLASSIC 46,XX CONGENITAL ADRENAL HYPERPLASIA IN RELATION TO IMPROVEMENTS IN DIAGNOSIS AND CARE.

OBJECTIVES: 1) To examine anthropometric changes of patients with classic 46,XX CAH and matched referents; 2) To investigate the impact of improvements in diagnosis and care on growth patterns in these patients by comparing changes in anthropometric parameters before and after CAH consensus guidelines. METHODS: This was a retrospective cohort study nested within three large integrated health-systems. Seventy-six patients with classic 46XX CAH and 1,102 matched referents <21 years of age were identified. Anthropometric measurements including age-specific percentiles for height, weight, and body mass index were examined and compared between groups using linear mixed-effect models. Anthropometric trajectories were explored using latent class analyses (LCA). RESULTS: CAH patients had lower height percentiles than referents at all time points. Differences ranged from 10.7% to 28.4%. After age 5 differences in height were only significant among study participants born before the publication of CAH consensus guidelines. LCA of height detected a "gradual growth increase" pattern in 28% of CAH cases and only 4% of referents, and a "growth stunting" pattern was observed in 13% of CAH cases and 6% of referents. Height percentile measures did not differ in CAH patients with or without evidence of hormonal interventions (growth hormone and/or puberty blockers) used to increase adult height. CONCLUSIONS: There is substantial heterogeneity in growth trajectories of CAH patients. Although stunting may affect CAH patients, advances in diagnosis and care improved anthropometric outcomes in this population. Understanding the disease- and therapy-related mechanisms that explain the different growth patterns requires additional research.

Non-differential misclassification of outcome under (near)-perfect specificity: a simulation study.

Mismeasurement of a dichotomous outcome yields an unbiased risk ratio estimate when there are no false positive cases (perfect specificity) and when sensitivity is non-differential with respect to exposure status. In studies where these conditions are expected, quantitative bias analysis may be considered unnecessary. We conducted a simulation study to explore the robustness of this special case to small departures from perfect specificity and stochastic departures from non-differential sensitivity. We observed substantial bias of the risk ratio with specificity values as high at 99.8%. The magnitude of bias increased directly with the true underlying risk ratio and was markedly stronger at lower baseline risk. Stochastic departure from non-differential sensitivity also resulted in substantial bias in most simulated scenarios; downward bias prevailed when sensitivity was higher among unexposed compared with exposed, and upward bias prevailed when sensitivity was higher among exposed compared with unexposed. Our results show that seemingly innocuous departures from perfect specificity (e.g., 0.2%) and from non-differential sensitivity can yield substantial bias of the risk ratio under outcome misclassification. We present a web tool permitting easy exploration of this bias mechanism under user-specifiable study scenarios.

Genetic variants and social benefit receipt in premenopausal women with breast cancer treated with docetaxel: a Danish population-based cohort study.

PURPOSE: Breast cancer patients' need for social benefits may increase following taxane-based chemotherapy, due to long-lasting side effects. Specific single nucleotide polymorphisms (SNPs) may mediate such side effects. We investigated the association between SNPs related to taxane metabolism, transport, toxicity, or DNA and neural repair, and receipt of social benefits. METHODS: From the Danish Breast Cancer Group, we identified premenopausal women diagnosed with stage I-III breast cancer during 2007-2011 and treated with docetaxel-based chemotherapy. We genotyped 21 SNPs from archived breast tumors using TaqMan assays. We ascertained social benefit payments from 1 year before to 5 years after diagnosis, using nationwide, administrative registry data. For each week, we categorized women as receiving health-related benefits (including sick leave and disability pension), labor market-related benefits (including unemployment benefits), or as being self-supporting. We computed rate ratios (RRs) of social benefit receipt for variant carriers (heterozygotes plus homozygotes) vs. non-carriers, using negative binominal regression with robust variance estimation. RESULTS: Among 2430 women, 12% received health-related benefits before diagnosis, 80% at diagnosis, and ~ 24% 2 to 5 years after diagnosis. Labor market-related benefits were uncommon (3-6%). All RRs were near-null and/or imprecise. CONCLUSION: We found no clinically meaningful impact of the selected SNPs on social benefit receipt among premenopausal breast cancer survivors treated with docetaxel.

Comparative Cardiovascular Effectiveness of Empagliflozin Versus Dapagliflozin in Adults With Treated Type 2 Diabetes: A Target Trial Emulation.

BACKGROUND: Empagliflozin and dapagliflozin have proven cardiovascular benefits in people with type 2 diabetes at high cardiovascular risk, but their comparative effectiveness is unknown. METHODS: This study used nationwide, population-based Danish health registries to emulate a hypothetical target trial comparing empagliflozin versus dapagliflozin initiation, in addition to standard care, among people with treated type 2 diabetes from 2014 through 2020. The outcome was a composite of myocardial infarction, ischemic stroke, heart failure (HF), or cardiovascular death (major adverse cardiovascular event). Participants were followed until an outcome, emigration, or death occurred; 6 years after initiation; or December 31, 2021, whichever occurred first. Logistic regression was used to compute inverse probability of treatment and censoring weights, controlling for 57 potential confounders. In intention-to-treat analyses, 6-year adjusted risks, risk differences, and risk ratios considering noncardiovascular death competing risks were estimated. Analyses were stratified by coexisting atherosclerotic cardiovascular disease and HF. A per-protocol design was performed as a secondary analysis. RESULTS: There were 36 670 eligible empagliflozin and 20 606 eligible dapagliflozin initiators. In the intention-to-treat analysis, the adjusted 6-year absolute risk of major adverse cardiovascular event was not different between empagliflozin and dapagliflozin initiators (10.0% versus 10.0%; risk difference, 0.0% [95% CI, -0.9% to 1.0%]; risk ratio, 1.00 [95% CI, 0.91 to 1.11]). The findings were consistent in people with atherosclerotic cardiovascular disease (risk difference, -2.3% [95% CI, -8.2% to 3.5%]; risk ratio, 0.92 [95% CI, 0.74 to 1.14]) and without atherosclerotic cardiovascular disease (risk difference, 0.3% [95% CI, -0.6% to 1.2%]; risk ratio, 1.04 [95% CI, 0.93 to 1.16]) and in people with HF (risk difference, 1.1% [95% CI, -6.5% to 8.6%]; risk ratio, 1.04 [95% CI, 0.79 to 1.37]) and without HF (risk difference, -0.1% [95% CI, -1.0% to 0.8%]; risk ratio, 0.99 [95% CI, 0.90 to 1.09]). The 6-year risks of major adverse cardiovascular event were also not different in the per-protocol analysis (9.1% versus 8.8%; risk difference, 0.2% [95% CI, -2.1% to 2.5%]; risk ratio, 1.03 [95% CI, 0.80 to 1.32]). CONCLUSIONS: Empagliflozin and dapagliflozin initiators had no differences in 6-year cardiovascular outcomes in adults with treated type 2 diabetes with or without coexisting atherosclerotic cardiovascular disease or HF.

Quantitative bias analysis methods for summary-level epidemiologic data in the peer-reviewed literature: a systematic review.

OBJECTIVES: Quantitative bias analysis (QBA) methods evaluate the impact of biases arising from systematic errors on observational study results. This systematic review aimed to summarize the range and characteristics of QBA methods for summary-level data published in the peer-reviewed literature. STUDY DESIGN AND SETTING: We searched MEDLINE, Embase, Scopus, and Web of Science for English-language articles describing QBA methods. For each QBA method, we recorded key characteristics, including applicable study designs, bias(es) addressed; bias parameters, and publicly available software. The study protocol was preregistered on the Open Science Framework (https://osf.io/ue6vm/). RESULTS: Our search identified 10,249 records, of which 53 were articles describing 57 QBA methods for summary-level data. Of the 57 QBA methods, 53 (93%) were explicitly designed for observational studies, and 4 (7%) for meta-analyses. There were 29 (51%) QBA methods that addressed unmeasured confounding, 19 (33%) misclassification bias, 6 (11%) selection bias, and 3 (5%) multiple biases. Thirty-eight (67%) QBA methods were designed to generate bias-adjusted effect estimates and 18 (32%) were designed to describe how bias could explain away observed findings. Twenty-two (39%) articles provided code or online tools to implement the QBA methods. CONCLUSION: In this systematic review, we identified a total of 57 QBA methods for summary-level epidemiologic data published in the peer-reviewed literature. Future investigators can use this systematic review to identify different QBA methods for summary-level epidemiologic data. PLAIN LANGUAGE SUMMARY: Quantitative bias analysis (QBA) methods can be used to evaluate the impact of biases on observational study results. However, little is known about the full range and characteristics of available methods in the peer-reviewed literature that can be used to conduct QBA using information reported in manuscripts and other publicly available sources without requiring the raw data from a study. In this systematic review, we identified 57 QBA methods for summary-level data from observational studies. Overall, there were 29 methods that addressed unmeasured confounding, 19 that addressed misclassification bias, six that addressed selection bias, and three that addressed multiple biases. This systematic review may help future investigators identify different QBA methods for summary-level data.

The Population-level Effect of Adjuvant Therapies on Breast Cancer Recurrence: Application of the Trend-in-Trend Design.

PURPOSE: Breast cancer has an average 10-year relative survival reaching 84%. This favorable survival is due, in part, to the introduction of biomarker-guided therapies. We estimated the population-level effect of the introduction of two adjuvant therapies-tamoxifen and trastuzumab-on recurrence using the trend-in-trend pharmacoepidemiologic study design. METHODS: We ascertained data on women diagnosed with nonmetastatic breast cancer who were registered in the Danish Breast Cancer Group clinical database. We used the trend-in-trend design to estimate the population-level effect of the introduction of (1) tamoxifen for postmenopausal women with estrogen receptor (ER)-positive breast cancer in 1982, (2) tamoxifen for premenopausal women diagnosed with ER-positive breast cancer in 1999, and (3) trastuzumab for women <60 years diagnosed with human epidermal growth factor receptor 2-positive breast cancer in 2007. RESULTS: For the population-level effect of the introduction of tamoxifen among premenopausal women diagnosed with ER-positive breast cancer in 1999, the risk of recurrence decreased by nearly one-half (OR = 0.52), consistent with evidence from clinical trials; however, the estimate was imprecise (95% confidence interval [CI] = 0.25, 1.85). We observed an imprecise association between tamoxifen use and recurrence from the time it was introduced in 1982 (OR = 1.24 95% CI = 0.46, 5.11), inconsistent with prior knowledge from clinical trials. For the introduction of trastuzumab in 2007, the estimate was also consistent with trial evidence, though imprecise (OR = 0.51; 95% CI = 0.21, 22.4). CONCLUSIONS: We demonstrated how novel pharmacoepidemiologic analytic designs can be used to evaluate the routine clinical care and effectiveness of therapeutic advancements in a population-based setting while considering some limitations of the approach.

Real-World Risk of Severe Cytopenias in Multiple Myeloma Patients Sequentially Treated with Immunomodulatory Drugs.

INTRODUCTION: Most multiple myeloma (MM) patients experience cytopenias, likely driven by both disease and treatment-related factors. Immunomodulatory agents (IMiDs), which form the backbone of most anti-myeloma regimens, are known to cause higher grade cytopenias. In this context, the impact of sequential IMiD treatments on cytopenia risk is unknown. METHODS: We evaluated the cumulative risks of severe cytopenias following second line of therapy (LOT) initiation in 5,573 MM patients in the Flatiron Health database. Patients for whom both LOTs 1 and 2 contained IMiDs were considered "sequentially exposed"; those for whom neither contained IMiDs were "never exposed." RESULTS: For the neutropenia outcome, compared to the never exposed, the sequentially exposed had the highest 1-year risk (risk difference [RD] 12%), followed by those only recently exposed during LOT 2 (RD 8%), then by those with only past exposure during LOT 1 (RD 5%). A similar pattern was observed for leukopenia, but no meaningful differences were observed for anemia or thrombocytopenia. The associations between sequential exposure, versus never, with neutropenia and leukopenia were even stronger among those with a recent cytopenia history. CONCLUSION: Results suggest that sequential exposure to IMiDs is a risk factor for higher grade cytopenias. These findings have profound clinical implications in choosing newer LOTs with potential risks of cytopenia.

Association between gender-affirming hormone therapy and measures of glucose metabolism: A longitudinal study.

CONTEXT: The long-term effect of gender-affirming hormone therapy (GAHT) on glucose metabolism is an area of priority in transgender health research. OBJECTIVES: To evaluate the relation between GAHT and changes in fasting blood glucose (FG) and glycosylated hemoglobin (HbA1c) in transmasculine (TM) and transfeminine (TF) persons relative to the corresponding temporal changes in presumably cisgender persons (i.e. without any evidence of TGD status). DESIGN: Retrospective cohort study. SETTING: Three large integrated health systems. PARTICIPANTS: 2,425 TF and 2,127 TM persons compared with 33,995 cisgender males (CM) and 38,913 cisgender females (CF) enrolled in the same health plans. OUTCOMES/MEASURES: Temporal changes in FG and HbA1c levels examined using linear mixed models with main results expressed as ratios-of-ratios. RESULTS: The pre- versus post-GAHT ratios-of-ratio (95% confidence interval) estimates adjusted for age, race/ethnicity, study site, and body mass index in the model comparing TF and CM groups were 1.05 (1.01, 1.09) for FG and 1.03 (0.99, 1.06) for HbA1c. By contrast, the corresponding results in the models contrasting TM and cisgender cohort members were in the 0.99-1.00 range. The ratio-of-ratios comparing post-GAHT changes among transgender and cisgender persons were close to the null and without a discernable pattern. CONCLUSION: Though the within-transgender cohort data suggest an increase in the levels of FG and HbA1c following feminizing GAHT initiation, these changes were no longer evident when compared with the corresponding changes in cisgender referents. Based on these results, clinically important effects of GAHT on routine laboratory markers of glucose metabolism appear unlikely.

Influence of incomplete death information on cumulative risk estimates in US claims data.

Administrative claims databases often do not capture date or fact of death, so studies using these data may inappropriately treat death as a censoring event-equivalent to other withdrawal reasons-rather than a competing event. We examined 1-, 3-, and 5-year inverse-probability-of-treatment weighted cumulative risks of a composite cardiovascular outcome among 34 527 initiators of telmisartan (exposure) and ramipril (referent), who were aged ≥55 years, in Optum (United States) claims data from 2003 to 2020. Differences in cumulative risks of the cardiovascular endpoint due to censoring of death (cause-specific), as compared with treating death as a competing event (subdistribution), increased with greater follow-up time and older age, where event and mortality risks were higher. Among ramipril users, 5-year cause-specific and subdistribution cumulative risk estimates per 100, respectively, were 16.4 (95% CI, 15.3-17.5) and 16.2 (95% CI, 15.1-17.3) among ages 55-64 (difference = 0.2) and were 43.2 (95% CI, 41.3-45.2) and 39.7 (95% CI, 37.9-41.4) among ages ≥75 (difference = 3.6). Plasmode simulation results demonstrated the differences in cause-specific versus subdistribution cumulative risks to increase with increasing mortality rate. We suggest researchers consider the cohort's baseline mortality risk when deciding whether real-world data with incomplete death information can be used without concern. This article is part of a Special Collection on Pharmacoepidemiology.

Use of quantitative bias analysis to evaluate single-arm trials with real-world data external controls.

PURPOSE: Use of real-world data (RWD) for external controls added to single-arm trials (SAT) is increasingly prevalent in regulatory submissions. Due to inherent differences in the data-generating mechanisms, biases can arise. This paper aims to illustrate how to use quantitative bias analysis (QBA). METHODS: Advanced non-small cell lung cancer (NSCLC) serves as an example, where many small subsets of patients with molecular tumor subtypes exist. First, some sources of bias that may occur in oncology when comparing RWD to SAT are described. Second, using a hypothetical immunotherapy agent, a dataset is simulated based on expert input for survival analysis of advanced NSCLC. Finally, we illustrate the impact of three biases: missing confounder, misclassification of exposure, and outcome evaluation. RESULTS: For each simulated scenario, bias was induced by removing or adding data; hazard ratios (HRs) were estimated applying conventional analyses. Estimating the bias-adjusted treatment effect and uncertainty required carefully selecting the bias model and bias factors. Although the magnitude of each biased and bias-adjusted HR appeared moderate in all three hypothetical scenarios, the direction of bias was variable. CONCLUSION: These findings suggest that QBA can provide an intuitive framework for bias analysis, providing a key means of challenging assumptions about the evidence. However, the accuracy of bias analysis is itself dependent on correct specification of the bias model and bias factors. Ultimately, study design should reduce bias, but QBA allows us to evaluate the impact of unavoidable bias to assess the quality of the evidence.

Clinical factors associated with patterns of endocrine therapy adherence in premenopausal breast cancer patients.

INTRODUCTION: Patients with hormone receptor positive breast cancer are recommended at least five years of adjuvant endocrine therapy, but adherence to this treatment is often suboptimal. We investigated longitudinal trends in adjuvant endocrine therapy (AET) adherence among premenopausal breast cancer patients and identified clinical characteristics, including baseline comorbidities and non-cancer chronic medication use, associated with AET adherence. METHODS: We included stage I-III premenopausal breast cancer patients diagnosed during 2002-2011 and registered in the Danish Breast Cancer Group clinical database who initiated AET. We used group-based trajectory modeling to describe AET adherence patterns. We also linked patients to Danish population-based registries and fit multinomial logistic models to compute odds ratios (ORs) and 95% confidence intervals (95% CIs) associating clinical characteristics with AET adherence patterns. RESULTS: We identified three adherence patterns among 4,353 women-high adherers (57%), slow decliners (36%), and rapid decliners (6.9%). Women with stage I disease (vs. stage II; OR: 1.9, 95% CI 1.5, 2.5), without chemotherapy (vs. chemotherapy; OR: 4.3, 95% CI 3.0, 6.1), with prevalent comorbid disease (Charlson Comorbidity Index score ≥ 1 vs. 0; OR: 1.6, 95% CI 1.1, 2.3), and with a history of chronic non-cancer medication use (vs. none; OR: 1.3, 95% CI 1.0, 1.8) were more likely to be rapid decliners compared with high adherers. CONCLUSIONS: Women with stage I cancer, no chemotherapy, higher comorbidity burden, and history of chronic non-cancer medication use were less likely to adhere to AET. Taking steps to promote adherence in these groups of women may reduce their risk of recurrence.

Sex Differences in Psychopathology Following Potentially Traumatic Experiences.

Importance: Various psychopathology may follow trauma; however, sex differences in these ranging manifestations of posttraumatic psychopathology remain understudied. Objective: To investigate sex-specific incidence of posttraumatic psychopathology. Design, Setting, and Participants: This population-based cohort study of Danish national health registries included a cohort of individuals who experienced a potentially traumatic event (PTE) from 1994 to 2016. Individuals were further categorized by presence of any pretrauma psychopathology. A comparison group of individuals who experienced a nontraumatic stressor (nonsuicide death of a first-degree relative) was examined as a reference cohort. Exposures: At least 1 of 8 PTEs (eg, physical assault, transportation accident) derived through health registry International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) codes, with additional qualifiers to improve classification accuracy. Main Outcomes and Measures: Incidence of 9 categories of ICD-10 psychiatric disorders recorded in registries within 5 years of PTEs. The standardized morbidity ratios (SMRs) for psychopathology outcomes were also calculated to compare individuals experiencing PTEs with those experiencing a nontraumatic stressor. Results: This study included 1 398 026 individuals who had been exposed to trauma (475 280 males [34.0%]; 922 750 females [66.0%]). The group of males who had been exposed to trauma were evenly distributed across age, while most females in the trauma-exposed group were aged 16 to 39 years (592 385 [64.2%]). Males and females were equally distributed across income quartiles and predominantly single. Following PTEs, the most common diagnosis was substance use disorders for males (35 160 [7.4%]) and depressive disorders for females (29 255 [3.2%]); incidence proportions for these and other disorders were higher among males and females with any pretrauma psychopathology. Certain PTEs had elevated onset of various psychiatric disorders and some sex differences emerged. Following physical assault, associations were found with schizophrenia or psychotic disorders for males (SMR, 17.5; 95% CI, 15.9-19.3) and adult personality disorders for females (SMR, 16.3; 95% CI, 14.6-18.3). For noninterpersonal PTEs, males had larger SMRs for substance use, schizophrenia or psychotic disorders, and adult personality disorders (SMR, 43.4; 95% CI, 41.9-45.0), and females had larger SMRs for depressive disorders (SMR, 19.0; 95% CI, 18.6-19.4). Sex differences were also observed, particularly when considering pretrauma psychopathology. For example, among interpersonal PTEs, males were most likely to develop substance use disorders after physical assault, whereas females were more likely to develop various disorders, with stronger associations seen for females without pretrauma psychiatric diagnoses. Among noninterpersonal PTEs, exposure to toxic substance showed robust associations with psychopathology, particularly in those without pretrauma psychopathology, with sex-specific differences across psychiatric categories. Conclusions and Relevance: Mental disorders after trauma were wide-ranging for males and females, and sex differences in patterns of posttraumatic psychopathology were more pronounced when accounting for pretrauma psychopathology. Findings provide new insights for sex-relevant PTEs and their mental health consequences. It also outlines future directions for advancing understanding of a constellation of posttraumatic psychopathology in males and females.

Characterizing Fit-for-Purpose Real-World Data: An Assessment of a Mother-Infant Linkage in the Japan Medical Data Center Claims Database.

Purpose: Observational postapproval safety studies are needed to inform medication safety during pregnancy. Real-world databases can be valuable for supporting such research, but fitness for regulatory purpose must first be vetted. Here, we demonstrate a fit-for-purpose assessment of the Japan Medical Data Center (JMDC) claims database for pregnancy safety regulatory decision-making. Patients and Methods: The Duke-Margolis framework considers a database's fitness for regulatory purpose based on relevancy (capacity to answer the research question based on variable availability and a sufficiently sized, representative population) and quality (ability to validly answer the research question based on data completeness and accuracy). To assess these considerations, we examined descriptive characteristics of infants and pregnancies among females ages 12-55 years in the JMDC between January 2005 and March 2022. Results: For relevancy, we determined that critical data fields (maternal medications, infant major congenital malformations, covariates) are available. Family identification codes permitted linkage of 385,295 total mother-infant pairs, 57% of which were continuously enrolled during pregnancy. The prevalence of specific congenital malformation subcategories and maternal medical conditions were representative of the general population, but preterm births were below expectations (3.6% versus 5.6%) in this population. For quality, our methods are expected to accurately identify the complete set of mothers and infants with a shared health insurance plan. However, validity of gestational age information was limited given the high proportion (60%) of missing live birth delivery codes coupled with suppression of infant birth dates and inaccessibility of disease codes with gestational week information. Conclusion: The JMDC may be well suited for descriptive studies of pregnant people in Japan (eg, comorbidities, medication usage). More work is needed to identify a method to assign pregnancy onset and delivery dates so that in utero medication exposure windows can be defined more precisely as needed for many regulatory postapproval pregnancy safety studies.

Staging and clean room: Constructs designed to facilitate transparency and reduce bias in comparative analyses of real-world data.

PURPOSE: We describe constructs designed to protect the integrity of the results from comparative analyses using real-world data (RWD): staging and clean room. METHODS: Staging involves performing sequential preliminary analyses and evaluating the population size available and potential bias before conducting comparative analyses. A clean room involves restricted access to data and preliminary results, policies governing exploratory analyses and protocol deviations, and audit trail. These constructs are intended to allow decisions about protocol deviations, such as changes to design or model specification, to be made without knowledge of how they might affect subsequent analyses. We describe an example for implementing staging with a clean room. RESULTS: Stage 1 may involve selecting a data source, developing and registering a protocol, establishing a clean room, and applying inclusion/exclusion criteria. Stage 2 may involve attempting to achieve covariate balance, often through propensity score models. Stage 3 may involve evaluating the presence of residual confounding using negative control outcomes. After each stage, check points may be implemented when a team of statisticians, epidemiologists and clinicians masked to how their decisions may affect study outcomes, reviews the results. This review team may be tasked with making recommendations for protocol deviations to address study precision or bias. They may recommend proceeding to the next stage, conducting additional analyses to address bias, or terminating the study. Stage 4 may involve conducting the comparative analyses. CONCLUSIONS: The staging and clean room constructs are intended to protect the integrity and enhance confidence in the results of analyses of RWD.

Biomarkers predictive of a response to extended endocrine therapy in breast cancer: a systematic review and meta-analysis.

PURPOSE: Extension of adjuvant endocrine therapy beyond five years confers only modest survival benefit in breast cancer patients and carries risk of toxicities. This systematic review investigates the role of biomarker tests in predicting the clinical response to an extension of endocrine therapy. METHODS: We searched Ovid MEDLINE, Ovid Embase, Global Index Medicus, and the Cochrane Central Register of Controlled Trials using an iterative approach to identify full-text articles related to breast cancer, endocrine therapy, and biomarkers. RESULTS: Of the 1,217 unique reports identified, five studies were deemed eligible. Four investigated the Breast Cancer Index (BCI) assay in three distinct study populations. These studies consistently showed that BCI score was predictive of response to extended endocrine therapy among 1,946 combined patients, who were predominately non-Hispanic white and postmenopausal. CONCLUSIONS: Evidence in the setting of predictive tests for extended endocrine therapy is sparse. Most relevant studies investigated the use of BCI, but these study populations were largely restricted to a single age, race, and ethnicity group. Future studies should evaluate a variety of biomarkers in diverse populations. Without sufficient evidence, physicians and patients face a difficult decision in balancing the benefits and risks of endocrine therapy extension.

Prediction of Suicide Attempts Among Persons with Depression: A Population-Based Case Cohort Study.

Studies have highlighted the potential importance of modeling interactions for suicide attempt prediction. This case-cohort study identified risk factors for suicide attempts among persons with depression in Denmark using statistical approaches that do (random forests) or do not model interactions (least absolute shrinkage and selection operator regression [LASSO]). Cases made a non-fatal suicide attempt (n = 6,032) between 1995 and 2015. The comparison subcohort was a 5% random sample of all persons in Denmark on January 1, 1995 (n = 11,963). We used random forests and LASSO for sex-stratified prediction of suicide attempts from demographic variables, psychiatric and somatic diagnoses, and treatments. Poisonings, psychiatric disorders, and medications were important predictors for both sexes. Area under the receiver operating characteristic curve (AUC) values were higher in LASSO models (0.85 [95% CI = 0.84, 0.86] in men; 0.89 [95% CI = 0.88, 0.90] in women) than random forests (0.76 [95% CI = 0.74, 0.78] in men; 0.79 [95% CI = 0.78, 0.81] in women). Automatic detection of interactions via random forests did not result in better model performance than LASSO models that did not model interactions. Due to the complex nature of psychiatric comorbidity and suicide, modeling interactions may not always be the optimal statistical approach to enhancing suicide attempt prediction in high-risk samples.

Census Tracts Are Not Neighborhoods: Addressing Spatial Misalignment in Studies Examining the Impact of Historical Redlining on Present-day Health Outcomes.

BACKGROUND: Research examining the effects of historical redlining on present-day health outcomes is often complicated by the misalignment of contemporary census boundaries with the neighborhood boundaries drawn by the US Home Owners' Loan Corporation (HOLC) in the 1930s. Previous studies have used different approaches to assign historical HOLC grades to contemporary geographies, but how well they capture redlining exposure is unknown. METHODS: Our analysis included 7711 residences identified in the Multiple Listing Service database in Atlanta, Georgia (2017-2022). We evaluated the classification of HOLC grade assignment (A, B, C, D, or ungraded) when assigning exposure under four area-level approaches (centroid, majority land area, weighted score, and highest HOLC) compared with using complete address data (gold standard). We additionally compared approaches across three 2020 census geographies (tract, block group, and block). RESULTS: When comparing the use of census tracts to complete address data, sensitivity was highest for the weighted score approach, which correctly identified 77% of residences in truly A-D graded neighborhoods as compared with the majority land area (44%), centroid (54%), and highest HOLC (59%) approaches. Regarding specificity, the majority land area approach best-classified residences in truly ungraded neighborhoods (93%) as compared with the weighted score (65%), centroid (81%), and highest HOLC (54%) approaches. Classification improved regardless of approach when using census block compared with the census tract. CONCLUSIONS: Misclassification of historical redlining exposure is inevitable when using contemporary census geographies rather than complete address data. This study provides a framework for assessing spatial misalignment and selecting an approach for classification.

Risk of recurrent cancer-associated venous thromboembolism: A Danish nationwide cohort study.

BACKGROUND: Predictive factors for recurrent cancer-associated venous thromboembolism have been inconsistent across previous studies. To provide data for improved risk stratification, we described the risk of recurrent venous thromboembolism overall and across age, sex, calendar period, cancer type, Ottawa risk score, cancer stage, and cancer treatment in a nationwide cohort of patients with active cancer. METHODS: Using Danish administrative registries, we identified a cohort of all adult patients with active cancer and a first-time diagnosis of venous thromboembolism during 2003-2018. We accounted for the competing risk of death and calculated absolute risks of recurrent venous thromboembolism at six months. RESULTS: The population included 34,072 patients with active cancer and venous thromboembolism. Recurrence risks at six months were higher for patients with genitourinary cancer (6.5%), lung cancer (6.1%), gastrointestinal cancer (5.6%), brain cancer (5.2%), and hematological cancer (5.1%) than for patients with gynecological cancer (4.7%), breast cancer (4.1%), and other cancer types (4.8%). Recurrence risks were similar for men (5.2%) and women (4.9%), with and without chemotherapy (5.1%), across Ottawa risk score group (low: 5.0%; high: 5.1%) and across calendar periods but increased with increasing cancer stage. The overall six-month all-cause mortality risk was 26%, and highest for patients with lung cancer (49%) and lowest among breast cancer patients (4.1%). CONCLUSIONS: Six-month recurrence risk after first-time cancer-associated venous thromboembolism was high and varied by cancer type and patient characteristics. Refining risk stratification for recurrence may improve decision-making regarding treatment duration after cancer-associated thromboembolism.

Antihypertensive Medications and PTSD Incidence in a Trauma Cohort.

Objective: Antihypertensive medications have been examined as agents for posttraumatic stress disorder (PTSD) prevention in trauma-exposed individuals, given well-documented associations between PTSD and increased risk of cardiovascular disease and purported trauma-relevant mechanisms of action for these medications. Evidence regarding the effectiveness of such drugs for this purpose remains mixed.Methods: We conducted a national population-based cohort study using data from Danish national registries to assess whether 4 classes of antihypertensive drugs (beta-adrenoceptor blockers [beta blockers], angiotensin II receptor blockers [ARBs], angiotensin-converting enzyme [ACE] inhibitors, and calcium channel blockers) were associated with a decreased incidence of PTSD (diagnosed according to ICD-10) over a 22-year study period. Data for this study originated from a population-based cohort of over 1.4 million persons who experienced a traumatic event between 1994 and 2016 in Denmark. We calculated the incidence rate of PTSD per 100,000 person-years among persons who filled a prescription for each class of drug in the 60 days prior to a traumatic event and for corresponding unexposed comparison groups. We then used Cox proportional hazards regression to compare the rate of PTSD among persons who filled an antihypertensive medication prescription within 60 days before their trauma to the rate among persons who did not.Results: We found evidence that calcium channel blockers were associated with a decreased incidence of PTSD (adjusted hazard ratio = 0.63, 95% confidence interval [CI] = 0.34, 1.2); all other antihypertensive medication classes had null or near null associations.Conclusions: These findings lay a foundation for additional research focusing on antihypertensive medications that appear most effective in reducing PTSD incidence following trauma and for additional replication work aimed at continuing to clarify the disparate findings reported in the literature to date.