COMPARING PER-PROTOCOL EFFECT ESTIMATES FOR RANDOMIZED CLINICAL TRIALS IN POPULATION HEALTH: A REANALYSIS OF THE FEEDING AMERICA INTERVENTION TRIAL FOR HEALTH FOR DIABETES MELLITUS.
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SUBMITTER: Li CX
PROVIDER: S-EPMC10691192 | biostudies-literature | 2023 Nov
REPOSITORIES: biostudies-literature
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COMPARING PER-PROTOCOL EFFECT ESTIMATES FOR RANDOMIZED CLINICAL TRIALS IN POPULATION HEALTH: A REANALYSIS OF THE FEEDING AMERICA INTERVENTION TRIAL FOR HEALTH FOR DIABETES MELLITUS.
Li Catherine X CX Cole Stephen R SR Seligman Hilary K HK Berkowitz Seth A SA
American journal of epidemiology 20231101 12
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Project description:Background To understand when results from observational studies and randomized trials are comparable, we performed an observational emulation of a target trial designed to ask similar questions as the VALIDATE (Bivalirudin Versus Heparin in ST-Segment and Non-ST-Segment Elevation Myocardial Infarction in Patients on Modern Antiplatelet Therapy) randomized trial. The VALIDATE trial compared the effect of bivalirudin and heparin during percutaneous coronary intervention on the risk of death, myocardial infarction, and bleeding across Sweden. Methods and Results We specified the protocol of a target trial similar to the VALIDATE trial, then emulated the target trial in the period before the VALIDATE trial took place using data from the SWEDEHEART (Swedish Web System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies) registry-the same registry in which the trial was undertaken. The target trial emulation and the VALIDATE trial both estimated little or no effect of bivalirudin versus heparin on the risk of death or myocardial infarction by 180 days (target trial emulation risk ratio for death, 1.21 [95% CI, 0.88 - 1.54]; VALIDATE trial hazard ratio for death, 1.05 [95% CI, 0.78 - 1.41]). The observational data, however, could not capture less severe cases of bleeding, resulting in an inability to define a bleeding outcome like the trial, and could not accurately estimate the comparative risk of death by 14 days, which may be the result of intractable confounding early in follow-up or the inability to precisely emulate the trial's eligibility criteria. Conclusions Using real-world data to emulate a target trial can deliver accurate effect estimates. Yet, even with rich observational data, it is not always possible to estimate the short-term effect of interventions or the effect on outcomes for which data are not routinely collected.
| S-EPMC8483524 | biostudies-literature
Project description:Effect estimates from randomized trials and observational studies might not be directly comparable because of differences in study design, other than randomization, and in data analysis. We propose a 3-step procedure to facilitate meaningful comparisons of effect estimates from randomized trials and observational studies: 1) harmonization of the study protocols (eligibility criteria, treatment strategies, outcome, start and end of follow-up, causal contrast) so that the studies target the same causal effect, 2) harmonization of the data analysis to estimate the causal effect, and 3) sensitivity analyses to investigate the impact of discrepancies that could not be accounted for in the harmonization process. To illustrate our approach, we compared estimates of the effect of immediate with deferred initiation of antiretroviral therapy in individuals positive for the human immunodeficiency virus from the Strategic Timing of Antiretroviral Therapy (START) randomized trial and the observational HIV-CAUSAL Collaboration.
| S-EPMC6670045 | biostudies-literature
Project description:BackgroundIn many randomized controlled trials, patients and doctors are more interested in the per-protocol effect than in the intention-to-treat effect. However, valid estimation of the per-protocol effect generally requires adjustment for prognostic factors associated with adherence. These adherence adjustments have been strongly questioned in the clinical trials community, especially after 1980 when the Coronary Drug Project team found that adherers to placebo had lower 5-year mortality than non-adherers to placebo.MethodsWe replicated the original Coronary Drug Project findings from 1980 and re-analyzed the Coronary Drug Project data using technical and conceptual developments that have become established since 1980. Specifically, we used logistic models for binary outcomes, decoupled the definition of adherence from loss to follow-up, and adjusted for pre-randomization covariates via standardization and for post-randomization covariates via inverse probability weighting.ResultsThe original Coronary Drug Project analysis reported a difference in 5-year mortality between adherers and non-adherers in the placebo arm of 9.4 percentage points. Using modern approaches, we found that this difference was reduced to 2.5 (95% confidence interval: -2.1 to 7.0).ConclusionValid estimation of per-protocol effects may be possible in randomized clinical trials when analysts use appropriate methods to adjust for post-randomization variables.
| S-EPMC4942353 | biostudies-literature
Project description:Electronic health record (EHR) systems provide an opportunity to use a novel data source for population health surveillance. Validation studies that compare prevalence estimates from EHRs and surveys most often use difference testing, which can, because of large sample sizes, lead to detection of significant differences that are not meaningful. We explored a novel application of the two one-sided t test (TOST) to assess the equivalence of prevalence estimates in 2 population-based surveys to inform margin selection for validating EHR-based surveillance prevalence estimates derived from large samples.We compared prevalence estimates of health indicators in the 2013 Community Health Survey (CHS) and the 2013-2014 New York City Health and Nutrition Examination Survey (NYC HANES) by using TOST, a 2-tailed t test, and other goodness-of-fit measures.A ±5 percentage-point equivalence margin for a TOST performed well for most health indicators. For health indicators with a prevalence estimate of less than 10% (extreme obesity [CHS, 3.5%; NYC HANES, 5.1%] and serious psychological distress [CHS, 5.2%; NYC HANES, 4.8%]), a ±2.5 percentage-point margin was more consistent with other goodness-of-fit measures than the larger percentage-point margins.A TOST with a ±5 percentage-point margin was useful in establishing equivalence, but a ±2.5 percentage-point margin may be appropriate for health indicators with a prevalence estimate of less than 10%. Equivalence testing can guide future efforts to validate EHR data.
| S-EPMC5467464 | biostudies-other
Project description:BackgroundIn recent years the "noninferiority" trial has emerged as the new standard design for HIV drug development among antiretroviral patients often with a primary endpoint based on the difference in success rates between the two treatment groups. Different statistical methods have been introduced to provide confidence intervals for that difference. The main objective is to investigate whether the choice of the statistical method changes the conclusion of the trials.MethodsWe presented 11 trials published in 2010 using a difference in proportions as the primary endpoint. In these trials, 5 different statistical methods have been used to estimate such confidence intervals. The five methods are described and applied to data from the 11 trials. The noninferiority of the new treatment is not demonstrated if the prespecified noninferiority margin it includes in the confidence interval of the treatment difference.ResultsResults indicated that confidence intervals can be quite different according to the method used. In many situations, however, conclusions of the trials are not altered because point estimates of the treatment difference were too far from the prespecified noninferiority margins. Nevertheless, in few trials the use of different statistical methods led to different conclusions. In particular the use of "exact" methods can be very confusing.ConclusionStatistical methods used to estimate confidence intervals in noninferiority trials have a strong impact on the conclusion of such trials.
| S-EPMC3168436 | biostudies-literature
Project description:Background: We examined the similarities and differences between studies using two common metrics used in cost-effectiveness analyses (CEAs): cost per quality-adjusted life year (QALY) gained and cost per disability-adjusted life year (DALY) averted. Methods: We used the Tufts Medical Center CEA Registry, which contains English-language cost-per-QALY gained studies, and the Global Cost-Effectiveness Analysis (GHCEA) Registry, which contains cost-per-DALY averted studies. We examined study characteristics, including intervention type, sponsor, country, and primary disease, and also compared the number of published CEAs to disease burden for major diseases and conditions across geographic regions. Results: We identified 6,438 cost-per-QALY and 543 cost-per-DALY studies published through 2016 and observed rapid growth for both literatures. Cost-per-QALY studies most often examined pharmaceuticals and interventions in high-income countries. Cost-per-DALY studies predominantly focused on infectious disease interventions and interventions in low and lower-middle income countries. We found that while diseases imposing a larger burden tend to receive more attention in the cost-effectiveness analysis literature, the number of publications for some diseases and conditions deviates from this pattern, suggesting "under-studied" conditions (e.g., neonatal disorders) and "over-studied" conditions (e.g., HIV and TB). Conclusions: The CEA literature has grown rapidly, with applications to diverse interventions and diseases. The publication of fewer studies than expected for some diseases given their imposed burden suggests funding opportunities for future cost-effectiveness research.
| S-EPMC5801595 | biostudies-literature
Project description:BackgroundCluster randomized trials (CRTs) and individually randomized trials (IRTs) are often pooled together in meta-analyses (MAs) of randomized trials. However, the potential systematic differences in intervention effect estimates between these two trial types has never been investigated. Therefore, we conducted a meta-epidemiological study comparing intervention effect estimates between CRTs and IRTs.MethodsAll Cochrane MAs including at least one CRT and one IRT, published between 1 January 2010 and 31 December 2014, were included. For each MA, we estimated a ratio of odds ratios (ROR) for binary outcomes or a difference of standardized differences (DSMD) for continuous outcomes, where less than 1 (or 0, respectively) indicated a greater intervention effect estimate with CRTs.ResultsAmong 1301 screened reviews, we selected 121 MAs, of which 76 had a binary outcome and 45 had a continuous outcome. For binary outcomes, intervention effect estimates did not differ between CRTs and IRTs [ROR 1.00, 95% confidence interval (0.93 to 1.08)]. Subgroup and adjusted analyses led to consistent results. For continuous outcomes, the DSMD was 0.13 (0.06 to 0.19). It was lower for MAs with a pharmacological intervention [-0.03, (-0.12 to 0.07)], an objective outcome [0.05, (-0.08 to 0.17)] or after adjusting for trial size [0.06, (-0.01 to 0.15)].ConclusionFor binary outcomes, CRTs and IRTs can safely be pooled in MAs because of an absence of systematic differences between effect estimates. For continuous outcomes, the results were less clear although accounting for trial sample sizes led to a non-significant difference. More research is needed for continuous outcomes and, meanwhile, MAs should be completed with subgroup analyses (CRTs vs IRTs).
| S-EPMC6469309 | biostudies-literature
Project description:BackgroundThe problem of childhood undernutrition in low-income countries persists despite long-standing efforts by local governmental and international development agencies. In order to address this problem, the Peruvian Ministry of Health has focused on improving access to primary healthcare and providing maternal and child health monitoring and education. Current maternal-child health policies in Peru introduce recommendations that are in some respect distinct from those of Indigenous highland communities. This paper analyses the similarities and differences between public health and mothers' infant feeding recommendations. Furthermore, it analyses persistence and change in those recommendations among women who were mothers before and after the introduction of current public health policies.MethodsSemi-structured interviews were conducted with 18 older mothers, 15 currently breastfeeding mothers, and 15 public health staff in highland rural communities of Peru. During data analysis, thematic codes and text passages were used in an iterative analytic process to document emerging themes.ResultsThe results highlight the existence of a traditional corpus of beliefs surrounding infant feeding and care that is consistent with Andean ethnomedical beliefs. This is illustrated by mother's accounts referring to the importance of maintaining a dietary balance of fluids and semi-fluids and of maintaining harmony with the elements in the natural environment. Mothers also incorporate aspects of public health recommendations that they find useful including initiating breastfeeding immediately after birth and exclusive breastfeeding up until 6 months. There are also tensions between the two systems including differences in the conceptualization of breastfeeding and infant food, the imposition of public health care services by coercive means, and negative stereotyping of rural Andean diets and mothers.ConclusionsIdentifying similarities and differences between distinct systems may provide useful input for effective intercultural health policies. Sources of tension should be carefully assessed with the aim of improving public health policies. Such efforts should apply a process of cultural humility engaging health care professionals in exchange and conversations with patients and communities acknowledging the assumptions and beliefs that are embedded in their own understanding. This process should also recognize and value the knowledge and practices of Andean mothers and their role as primary caretakers.
| S-EPMC6245876 | biostudies-literature
Project description:ImportanceThree similar phase 3 randomized clinical trials have investigated PD-1/PD-L1 (programmed cell death 1 protein/programmed cell death 1 ligand 1) inhibitors in combination with platinum-based chemotherapy vs chemotherapy alone as first-line treatment for advanced urothelial carcinoma (IMvigor130, atezolizumab; KEYNOTE-361, pembrolizumab; and CheckMate901, nivolumab). Only CheckMate901 reported overall survival (OS) benefit for the combination. The reason for these inconsistent results is unclear.ObjectiveTo explore whether differential censoring-that is, censoring imbalance between the study groups-is a possible explanation for these inconsistent findings.Design, setting, and participantsThis comparative effectiveness study involved a censoring analysis of data from IMvigor130, KEYNOTE-361, and CheckMate901, which enrolled patients between 2016 and 2022. Participants included patients in these 3 trials.ExposureParticipation in 1 of the 3 trials.Main outcomes and measuresThe primary outcomes were censoring rates adjusted for treatment effects. Censoring rates were calculated from the Kaplan-Meier (KM) curves. When excess censoring in the control group of open-label trials was found, the hypothesis was that better-performing patients might be dropping out to seek alternative treatments; a sensitivity analysis was conducted in which their survival was assumed to be similar to that of the longest surviving patients in the control group. Treatment effects of the censoring-adjusted KM curves were calculated using the 2-sided log-rank test.ResultsThe 3 trials involved a total of 2162 patients (1640 male [76%]; age range, 65-69 years) Analysis of progression-free survival (PFS) curves demonstrated no differential censoring in IMvigor130, but there was more than 30% excess censoring in the chemotherapy-only groups in KEYNOTE-361 and CheckMate901 trials. After sensitivity analysis, the PFS benefit was no longer significant in either study (KEYNOTE-361, adjusted hazard ratio [HR], 1.13 [95% CI, 0.95-1.35]; CheckMate901, adjusted HR, 1.17 [0.96-1.44]). Analysis of OS curves demonstrated no differential censoring in IMvigor130 or KEYNOTE-361, but there was more censoring in the chemotherapy-only group in CheckMate901. After sensitivity analysis, the OS benefit of adding nivolumab to chemotherapy was lost (before adjustment, HR, 0.77 [95% CI, 0.63-0.95]; P = .01; adjusted HR, 0.95 [95% CI, 0.77-1.17]; P = .64).Conclusions and relevanceIn this comparative effectiveness study, differential censoring explained the inconsistent results reported in the evaluated trials. The term perceived-inferiority censoring is suggested to describe a phenomenon wherein better-performing patients are aware of their treatment and drop out to pursue alternative therapeutic options; it is possible that this occurred in the open-label KEYNOTE-361 and CheckMate901 trials. Such censoring confounds randomization and interpretation of clinical trials, since a larger experimental group is compared with a selected group of controls with poorer prognosis.
| S-EPMC11755191 | biostudies-literature
Project description:A growing field of research aims to characterise the contribution of anthropogenic emissions to the likelihood of extreme weather and climate events. These analyses can be sensitive to the shapes of the tails of simulated distributions. If tails are found to be unrealistically short or long, the anthropogenic signal emerges more or less clearly, respectively, from the noise of possible weather. Here we compare the chance of daily land-surface precipitation and near-surface temperature extremes generated by three Atmospheric Global Climate Models typically used for event attribution, with distributions from six reanalysis products. The likelihoods of extremes are compared for area-averages over grid cell and regional sized spatial domains. Results suggest a bias favouring overly strong attribution estimates for hot and cold events over many regions of Africa and Australia, and a bias favouring overly weak attribution estimates over regions of North America and Asia. For rainfall, results are more sensitive to geographic location. Although the three models show similar results over many regions, they do disagree over others. Equally, results highlight the discrepancy amongst reanalyses products. This emphasises the importance of using multiple reanalysis and/or observation products, as well as multiple models in event attribution studies.
| S-EPMC5351813 | biostudies-literature