Study-level Differences Research Articles

BRCA1 and BRCA2 pathogenic variants and prostate cancer risk: systematic review and meta-analysis

BackgroundBRCA1 and BRCA2 pathogenic variants (PVs) are associated with prostate cancer (PCa) risk, but a wide range of relative risks (RRs) has been reported.MethodsWe systematically searched PubMed, Embase, MEDLINE and Cochrane Library in June 2021 for studies that estimated PCa RRs for male BRCA1/2 carriers, with no time or language restrictions. The literature search identified 27 studies (BRCA1: n = 20, BRCA2: n = 21).ResultsThe heterogeneity between the published estimates was high (BRCA1: I2 = 30%, BRCA2: I2 = 83%); this could partly be explained by selection for age, family history or aggressive disease, and study-level differences in ethnicity composition, use of historical controls, and location of PVs within BRCA2. The pooled RRs were 2.08 (95% CI 1.38–3.12) for Ashkenazi Jewish BRCA2 carriers, 4.35 (95% CI 3.50–5.41) for non-Ashkenazi European ancestry BRCA2 carriers, and 1.18 (95% CI 0.95–1.47) for BRCA1 carriers. At ages <65 years, the RRs were 7.14 (95% CI 5.33–9.56) for non-Ashkenazi European ancestry BRCA2 and 1.78 (95% CI 1.09–2.91) for BRCA1 carriers.ConclusionsThese PCa risk estimates will assist in guiding clinical management. The study-level subgroup analyses indicate that risks may be modified by age and ethnicity, and for BRCA2 carriers by PV location within the gene, which may guide future risk-estimation studies.

A Structural Equation Modeling Approach to Meta-analytic Mediation Analysis Using Individual Participant Data: Testing Protective Behavioral Strategies as a Mediator of Brief Motivational Intervention Effects on Alcohol-Related Problems

This paper introduces a meta-analytic mediation analysis approach for individual participant data (IPD) from multiple studies. Mediation analysis evaluates whether the effectiveness of an intervention on health outcomes occurs because of change in a key behavior targeted by the intervention. However, individual trials are often statistically underpowered to test mediation hypotheses. Existing approaches for evaluating mediation in the meta-analytic context are limited by their reliance on aggregate data; thus, findings may be confounded with study-level differences unrelated to the pathway of interest. To overcome the limitations of existing meta-analytic mediation approaches, we used a one-stage estimation approach using structural equation modeling (SEM) to combine IPD from multiple studies for mediation analysis. This approach (1) accounts for the clustering of participants within studies, (2) accommodates missing data via multiple imputation, and (3) allows valid inferences about the indirect (i.e., mediated) effects via bootstrapped confidence intervals. We used data (N = 3691 from 10 studies) from Project INTEGRATE (Mun et al. Psychology of Addictive Behaviors, 29, 34–48, 2015) to illustrate the SEM approach to meta-analytic mediation analysis by testing whether improvements in the use of protective behavioral strategies mediate the effectiveness of brief motivational interventions for alcohol-related problems among college students. To facilitate the application of the methodology, we provide annotated computer code in R and data for replication. At a substantive level, stand-alone personalized feedback interventions reduced alcohol-related problems via greater use of protective behavioral strategies; however, the net-mediated effect across strategies was small in size, on average.

A Systematic Review and Network Meta-analysis of Novel Androgen Receptor Inhibitors in Non-metastatic Castration-resistant Prostate Cancer.

Among men with high-risk non-metastatic castrate-resistant prostate cancer (nmCRPC), we used network meta-analysis to compare non-steroidal anti-androgens (NSAAs) and stratified class-level meta-analysis to identify subgroups with particular benefit from NSAAs with androgen deprivation therapy versus androgen deprivation therapy alone. We performed a systematic review of phase III parallel-group randomized controlled trials in adult men with nmCRPC. Primary outcome was metastasis-free survival (MFS). Secondary outcomes included overall survival (OS), prostate-specific antigen (PSA) progression-free survival (PFS), and rates of grade 3 to 4 adverse events (AEs). We assessed class-level effects using random effects models; effect modification owing to subgroup effects using random-effects models to pool study-level differences; and comparative outcomes between agents using fixed-effect network models in a Bayesian framework. Three randomized controlled trials were identified. Pooled MFS, PSA-PFS, and OS were significantly greater with NSAA versus placebo (hazard ratio [HR], 0.32; 95% confidence interval [CI], 0.25-0.41; HR, 0.08; 95% CI, 0.05-0.13; and HR, 0.74; 95% CI, 0.61-0.90, respectively). Subgroup analysis demonstrated a greater benefit with NSAAs in men with Eastern Cooperative Oncology Group performance status 0 (HR, 0.30; 95% CI, 0.24-0.38) versus 1 (HR, 0.45; 95% CI, 0.36-0.56; P= .005), but no difference owing to PSA doubling time (P= .43) or use of osteoclast targeting therapy (P= .77). Bayesian analysis showed apalutamide and enzalutamide had a 56% and 44% likelihood of maximizing MFS, respectively, with subgroup analysis demonstrating these agents were preferred regardless of PSA doubling time and performance status. There was a 44%, 41%, and 15% likelihood that apalutamide, darolutamide and enzalutamide offered the greatest OS benefit, respectively. Grade 3 to 4 AEs were more common with NSAAs (odds ratio [OR], 1.47; 95% CI, 1.27-1.71) and there was a 61% chance that darolutamide was preferred. NSAAs improve survival in high-risk nmCRPC. Apalutamide and enzalutamide may result in improved oncologic outcomes. Darolutamide may result in fewer AEs. Phase IV data are needed to validate these findings.

Association between PD-L1 status and immune checkpoint inhibitor response in advanced malignancies: a systematic review and meta-analysis of overall survival data.

Targeting the programmed death ligand 1 (PD-L1) pathway has become standard for many advanced malignancies. Whether PD-L1 expression predicts response is unclear. We assessed the association between PD-L1 expression and immunotherapy response using stratified meta-analysis. We performed a systematic review of randomized clinical trials published prior to October 2018 comparing overall survival (OS) in patients with advanced solid organ malignancies treated with immunotherapy or standard treatment. Pooled hazard ratios were calculated among patients with high and low PD-L1 levels independently. Differences between the two estimates were assessed using meta-analysis of study-level differences. Our primary analysis assessed a 1% threshold while secondary analyses utilized 5, 10 and 50%. 14 eligible trials reporting on 8887 patients were included. While there was a significant OS benefit for immunotherapy compared with standard treatment for all patients, the magnitude of benefit was significantly larger among those with high PD-L1 expression (P=0.006). This finding persisted regardless of threshold used and across subgroup analyses according to PD-L1 assay type, tumor histology, line of therapy, type of inhibitor and study methodology. PD-L1 levels have important predictive value in determining the response to immunotherapy. However, patients with low PD-L1 levels also experience improved survival with immunotherapy compared with standard treatment.

Association of Patient Sex With Efficacy of Immune Checkpoint Inhibitors and Overall Survival in Advanced Cancers

Sex-associated differences in immune response are known, but a meta-analysis suggested men, compared with women, derive greater value from immunotherapy for advanced solid-organ malignant neoplasms. However, methodologic concerns and subsequent trials have placed these results in doubt. To perform an updated, comprehensive meta-analysis that assesses the efficacy of immunotherapy in advanced cancers according to patient sex. A systematic review of studies (n = 23) indexed in MEDLINE (PubMed), Embase, and Scopus from inception of these databases to October 2, 2018, was conducted. Randomized clinical trials that compared immunotherapy with standard of care in the treatment of advanced solid-organ malignant neoplasms were included if overall survival was reported as an outcome and if data stratified by patient sex were available. Observational studies, editorials, commentaries, review articles, non-peer-reviewed publications, studies that compared various immunotherapy regimens, studies that reported other measures of oncologic response, and studies that reported subgroup analyses for 1 sex only were excluded. Overall survival, with a test for heterogeneity between women and men, to assess the null hypothesis that no difference in the survival advantage of immunotherapy exists by patient sex. This meta-analysis included 23 randomized clinical trials that reported on 9322 men (67.9%) and 4399 women (32.1%); the age of most patients was in the 70s. An overall survival benefit of immunotherapy was found for both men (hazard ratio [HR], 0.75; 95% CI, 0.69-0.81; P < .001) and women (HR, 0.77; 95% CI, 0.67-0.88; P = .002). Random-effects meta-analysis of study-level differences in response to immunotherapy demonstrated no statistically significant difference between the sexes (I2 = 38%; P = .60). Subgroup analyses according to disease site, line of therapy, class of immunotherapy, study methodology, and representation of women recapitulated these findings. Stratified analyses demonstrated no statistically significant association of patient sex with the efficacy of immunotherapy in the treatment of advanced cancers using overall survival as the outcome.

Evaluating the addition of bevacizumab (Bev) to endocrine therapy as first-line treatment for hormone-receptor positive (HR+)/HER2-negative advanced breast cancer (ABC): Pooled-analysis from the LEA (GEICAM/2006-11_GBG51) and CALGB 40503 (Alliance) trials.

1012 Background: Data from randomized trials comparing ET v ET-Bev in 1st line HR+/HER2- ABC pts showed controversial results. We performed a pooled-analysis of two randomized trials (LEA and CALGB 40503) to refine the Bev value in this patient population. Methods: We analysed 749 ABC pts with ET (letrozole-673, tamoxifen-39, fulvestrant 250mg-37) +/- Bev. Primary objective was to compare progression-free survival (PFS). Secondary endpoints were: safety; other efficacy (overall response rate [ORR], clinical benefit rate [CBR] and overall survival [OS]) in all pts; and efficacy in de novo pts and by previous endocrine-sensitivity (-/+ 24 months [mo] without recurrence under ET in adjuvant setting). Multivariable Cox models were fitted for PFS adjusted by study co-variables and controlled for study level differences. Results: Median age was 61 years (yr) (range: 25-87); 40% had de novo ABC and 60% recurrent disease (with disease free interval of ≤ 1 yr in 5%, 1-2 yr in 7% and &gt; 2 yr in 88%); 82% of recurrent pts had previous ET sensitivity. Median PFS was 14.3 mo in the ET arm v 19 mo in the ET+Bev arm (HR 0.77; 95% CI 0.66-0.91; p&lt;0.01). ORR and CBR with ET v ET+Bev were 40 v 61% (p&lt;0.01) and 64 v 77% (p&lt;0.01). OS did not differ between arms (HR 0.96; 95% CI 0.77-1.18; p=0.68). PFS for de novo ABC pts was 14.6 and 19.3 mo in the ET and ET+Bev arms (HR 0.82; 95% CI 0.63-1.06; p=0.13). PFS differed between arms for previous sensitive pts (HR 0.68; 95% CI 0.53-0.89; p=0.004) but not for ET-resistant pts (HR 0.73; 95% CI 0.4-1.3; p=0.29). Grade 3-5 hypertension (2.2 v 20.1%), proteinuria (0 v 9.3%), cardiovascular events (0.5 v 4.2%) and liver events (0 v 2.9%) were significantly higher in the ET+Bev arm (all p&lt;0.01). Multivariable analyses showed age (p&lt;0.01), PgR status (p&lt;0.01), type of prior ET (p&lt;0.01) and treatment arm (p&lt;0.01) to be associated with PFS. Conclusions: The addition of Bev to ET increased PFS but not OS. Analyses to define subgroups with prolonged benefit from ET alone or ET-Bev are ongoing. Support: U10CA180821, U10CA180882, Breast Cancer Research Foundation, Genentech, Roche. Clinical trial information: NCT00545077 / NCT00601900.

Baseline Depression Severity as Moderator of Depression Outcomes Between Cognitive Behavioral Therapy vs Pharmacotherapy: An Individual Patient Data Meta-analysis.

Current guidelines recommend treating severe depression with pharmacotherapy. Randomized clinical trials as well as traditional meta-analyses have considerable limitations in testing for moderators of treatment outcomes. To conduct a systematic literature search, collect primary data from trials, and analyze baseline depression severity as a moderator of treatment outcomes between cognitive behavioral therapy (CBT) and antidepressant medication (ADM). A total of 14 902 abstracts were examined from a comprehensive literature search in PubMed, PsycINFO, EMBASE, and Cochrane Registry of Controlled Trials from 1966 to January 1, 2014. Randomized clinical trials in which CBT and ADM were compared in patients with a DSM-defined depressive disorder were included. Study authors were asked to provide primary data from their trial. Primary data from 16 of 24 identified trials (67%), with 1700 outpatients (794 from the CBT condition and 906 from the ADM condition), were included. Missing data were imputed with multiple imputation methods. Mixed-effects models adjusting for study-level differences were used to examine baseline depression severity as a moderator of treatment outcomes. Seventeen-item Hamilton Rating Scale for Depression (HAM-D) and Beck Depression Inventory (BDI). There was a main effect of ADM over CBT on the HAM-D (β = -0.88; P = .03) and a nonsignificant trend on the BDI (β = -1.14; P = .08, statistical test for trend), but no significant differences in response (odds ratio [OR], 1.24; P = .12) or remission (OR, 1.18; P = .22). Mixed-effects models using the HAM-D indicated that baseline depression severity does not moderate reductions in depressive symptoms between CBT and ADM at outcome (β = 0.00; P = .96). Similar results were seen using the BDI. Baseline depression severity also did not moderate the likelihood of response (OR, 0.99; P = .77) or remission (OR, 1.00; P = .93) between CBT and ADM. Baseline depression severity did not moderate differences between CBT and ADM on the HAM-D or BDI or in response or remission. This finding cannot be extrapolated to other psychotherapies, to individual ADMs, or to inpatients. However, it offers new and substantial evidence that is of relevance to researchers, physicians and therapists, and patients.

Why Students Share Misinformation on Social Media: Motivation, Gender, and Study-level Differences

The increasing use of social media for information sharing has elevated the need for information literacy (IL) education to prepare students to be effective information creators and communicators. One concern is that students sometimes indiscriminately forward misinformation. Understanding the reasons behind misinformation sharing would help the development of IL intervention strategies. Guided by the Uses and Gratifications approach and rumor research, undergraduate and graduate students in Singapore were surveyed on why they share misinformation on social media. Gender and study-level differences were investigated. Over 60% of respondents had shared misinformation. The top reasons were related to the information's perceived characteristics, as well as self-expression and socializing. Accuracy and authoritativeness did not rank highly. Women had a higher prevalence of sharing and intention to share misinformation. Undergraduate and graduate students differed in their reasons for sharing misinformation. The former share (and intend to share) more misinformation than the latter, but the difference was not statistically significant. Because many of the reasons cited were social in nature, IL training should address the social motivations propelling such behavior. Social media systems may also develop features that encourage users to flag debunked postings and allow a correction to be displayed alongside the misinformation.

Apolipoprotein E ε4 Prevalence in Alzheimer’s Disease Patients Varies across Global Populations: A Systematic Literature Review and Meta-Analysis

Background: The Ε4 allele of apolipoprotein E (APOE) is associated with Alzheimer’s disease (AD). However, attributable risk due to APOE4 varies by region and by race/ethnicity. Methods: A literature review and meta-analysis were conducted to estimate the prevalence of APOE4 by geographic area among AD patients. Results: Although estimates varied significantly by study design and case definition, AD patients recruited in Asian and southern European/Mediterranean communities seemed to have significantly lower E4 carrier status estimates (37 and 43%) than those recruited in North America (58%) or northern Europe (64%; all: p < 0.05). Conclusions: APOE4 genotype frequency varies among AD patients in regional patterns similar to that of the general population. Study level differences may also contribute to the heterogeneity of published estimates of APOE4 in AD cases.

Expectation States Theory and Research

Over the past 50 years, the expectation states research program has generated a set of interrelated theories to explain the relation between performance expectations and social influence. Yet while the relationship between performance expectations and social influence is now axiomatic, the reported effects do differ in magnitude, sometimes widely. The authors present results from the first formal meta-analysis of expectation states research on social influence. Their findings indicate that theoretically unimportant study-level differences alter expectation states and the baseline propensity to accept or reject social influence. Data from 26 separate experiments reveal that protocol variations, including the use of video and computer technology, sample size, and the number of trials, have important but previously unrecognized effects. The authors close by discussing the more general implications of their research for future investigators.