Simultaneous comparison of multiple treatments: combining direct and indirect evidence.
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ABSTRACT:
SUBMITTER: Caldwell DM
PROVIDER: S-EPMC1255806 | biostudies-literature | 2005 Oct
REPOSITORIES: biostudies-literature
Publications
Simultaneous comparison of multiple treatments: combining direct and indirect evidence.
Caldwell Deborah M DM Ades A E AE Higgins J P T JP
BMJ (Clinical research ed.) 20051001 7521
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Project description:In recent years, new treatments have been studied for relapsed-refractory multiple myeloma (RRMM), including two CAR-T products and a variety of non-CAR-T agents. Since direct comparisons between these innovative treatments are not available, indirect comparisons can be of interest. Reconstruction of individual patient data from Kaplan-Meier graphs (e.g., according to the Shiny method) has been the subject of numerous reports that have fully validated their performance. In the present systematic review, we evaluated six treatments proposed for RRMM, including two CAR-T products (ciltacabtagene autoleucel and idecabtagene vicleucel) and four treatments not based on a CAR-T (melflufen plus dexamethasone, isatuximab plus dexamethasone, selinexor, and belantamab). The endpoint was overall survival (OS). Our results showed statistically significant differences in OS across these treatments. In particular, ciltacabtagene autoleucel showed better OS than idecabtagene vicleucel. As regards non-CAR-T treatments, the ranking in OS was headed by isatuximab plus dexamethasone, followed by belantamab, selinexor, and melflufen plus dexamethasone. In conclusion, while the Shiny method has confirmed its validity in reconstructing individual patient data, our indirect comparisons have offered some original clues to interpret the results of OS published in these studies.
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Project description:Treatment for metastatic renal cell cancer (mRCC) has advanced dramatically with understanding of the pathogenesis of the disease. New treatment options may provide improved progression-free survival (PFS). We aimed to determine the relative effectiveness of new therapies in this field.We conducted comprehensive searches of 11 electronic databases from inception to April 2008. We included randomized trials (RCTs) that evaluated bevacizumab, sorafenib, and sunitinib. Two reviewers independently extracted data, in duplicate. Our primary outcome was investigator-assessed PFS. We performed random-effects meta-analysis with a mixed treatment comparison analysis.We included 3 bevacizumab (2 of bevacizumab plus interferon-a [IFN-a]), 2 sorafenib, 1 sunitinib, and 1 temsirolimus trials (total n = 3,957). All interventions offer advantages for PFS. Using indirect comparisons with interferon-alpha as the common comparator, we found that sunitinib was superior to both sorafenib (HR 0.58, 95% CI, 0.38-0.86, P = < 0.001) and bevacizumab + IFN-a (HR 0.75, 95% CI, 0.60-0.93, P = 0.001). Sorafenib was not statistically different from bevacizumab +IFN-a in this same indirect comparison analysis (HR 0.77, 95% CI, 0.52-1.13, P = 0.23). Using placebo as the similar comparator, we were unable to display a significant difference between sorafenib and bevacizumab alone (HR 0.81, 95% CI, 0.58-1.12, P = 0.23). Temsirolimus provided significant PFS in patients with poor prognosis (HR 0.69, 95% CI, 0.57-0.85).New interventions for mRCC offer a favourable PFS for mRCC compared to interferon-alpha and placebo.
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Project description:The transcriptional regulator CprK controls the expression of the reductive dehalogenase CprA in organohalide-respiring bacteria. Desulfitobacterium hafniense CprA catalyses the reductive dechlorination of the terminal electron acceptor o-chlorophenol acetic acid, generating the phenol acetic acid product. It has been shown that CprK has ability to distinguish between the chlorinated CprA substrate and the de-halogenated end product, with an estimated an estimated 10(4)-fold difference in affinity. Using a green fluorescent protein GFPUV-based transcriptional reporter system, we establish that CprK can sense o-chlorophenol acetic acid at the nanomolar level, whereas phenol acetic acid leads to transcriptional activation only when approaching micromolar levels. A structure-activity relationship study, using a range of o-chlorophenol acetic-acid-related compounds and key CprK mutants, combined with pKa calculations on the effector binding site, suggests that the sensitive detection of chlorination is achieved through a combination of direct and indirect readout mechanisms. Both the physical presence of the bulky chloride substituent as well as the accompanying electronic effects lowering the inherent phenol pKa are required for high affinity. Indeed, transcriptional activation by CprK appears strictly dependent on establishing a phenolate-K133 salt bridge interaction, rather than on the presence of a halogen atom per se. As K133 is strictly conserved within the CprK family, our data suggest that physiological function and future applications in biosensing are probably restricted to phenolic compounds.
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Project description:Formal theoretical models propose that cooperative networks can be maintained when individuals condition behavior on social standing. Here, we empirically examine the predictions of such models of positive and negative indirect reciprocity using a suite of network-structured economic games in four rural Colombian communities (Nind = 496 individuals, Nobs = 53,876 ratings/transfers). We observe that, at a dyadic-level, individuals have a strong tendency to exploit and punish others in bad standing (e.g., those perceived as selfish), and allocate resources to those in good standing (e.g., those perceived as generous). These dyadic findings scale to a more generalized, community level, where reputations for being generous are associated with receipt of allocations, and reputations for being selfish are associated with receipt of punishment. These empirical results illustrate the roles that both positive and negative reciprocity, and costly punishment, play in sustaining community-wide cooperation networks.
| S-EPMC11332088 | biostudies-literature
Project description:BackgroundFor nonmetastatic castration-resistant prostate cancer (nmCRPC), 3 drugs under patent protection-apalutamide, enzalutamide, and darolutamide-were approved based on randomized, placebo-controlled trials; 1 drug with generic availability, abiraterone acetate, showed efficacy in a single-arm trial and is commonly prescribed. Lacking head-to-head trials, the optimal treatment for nmCRPC is unknown, despite widely varied treatment costs. We compared the efficacy and safety of nmCRPC treatments.MethodsWe searched bibliographic databases, regulatory documents, and trial registries for nmCRPC trials. We included published results and, when available, original data. We performed matching-adjusted indirect comparison and network meta-analysis and compared treatments regarding metastasis-free survival, overall survival, and serious adverse events.ResultsWe analyzed 5 trials with 4360 participants. Compared with placebo, abiraterone acetate engendered the lowest hazard of metastasis and death (hazard ratio [HR] = 0.22, 95% credible interval [CrI] = 0.12-0.41), followed by apalutamide (HR = 0.28, 95% CrI = 0.23-0.34), enzalutamide (HR = 0.30, 95% CrI = 0.25-0.36), and darolutamide (HR = 0.41, 95% CrI = 0.34-0.49); darolutamide led to the lowest hazard of death (HR = 0.69, 95% CrI = 0.53-0.90), followed by enzalutamide (HR = 0.73, 95% CrI = 0.61-0.87) and apalutamide (HR = 0.75, 95% CrI = 0.59-0.95); darolutamide resulted in the lowest odds of serious adverse events (odds ratio [OR] = 1.32, 95% CrI = 1.02-1.70), followed by enzalutamide (OR =1.43, 95% CrI = 1.08-1.89), apalutamide (OR = 1.58, 95% CrI = 1.23-2.03), and abiraterone acetate (OR = 1.94, 95% CrI = 1.17-3.22).ConclusionsFor nmCRPC, darolutamide offered optimal efficacy and safety among approved drugs, and abiraterone acetate may offer comparable metastasis-free survival benefit with cost savings from generic availability. Future research is needed to more fully examine the benefit of abiraterone acetate.
| S-EPMC8826526 | biostudies-literature
Project description:BackgroundSensitive, rapid, and accessible diagnostics continue to be critical to track the COVID-19 pandemic caused by the SARS-CoV-2 virus. RT-qPCR is the gold standard test, and comparison of methodologies and reagents, utilizing patient samples, is important to establish reliable diagnostic pipelines.MethodsHere, we assessed indirect methods that require RNA extraction with direct RT-qPCR on patient samples. Four different RNA extraction kits (Qiagen, Invitrogen, BGI and Norgen Biotek) were compared. For detection, we assessed two recently developed Taqman-based modules (BGI and Norgen Biotek), a SYBR green-based approach (NEB Luna Universal One-Step Kit) with published and newly-developed primers, and clinical results (Seegene STARMag RNA extraction system and Allplex 2019-nCoV RT-qPCR assay). We also tested and optimized direct, extraction-free detection using these RT-qPCR systems and performed a cost analysis of the different methods evaluated here.ResultsMost RNA isolation procedures performed similarly, and while all RT-qPCR modules effectively detected purified viral RNA, the BGI system provided overall superior performance (lower detection limit, lower Ct values and higher sensitivity), generating comparable results to original clinical diagnostic data, and identifying samples ranging from 65 copies to 2.1 × 105 copies of viral genome/μl. However, the BGI detection system is more expensive than other options tested here. With direct RT-qPCR, simply adding an RNase inhibitor greatly improved detection, without the need for any other treatments (e.g. lysis buffers or boiling). The best direct methods detected ~ 10 fold less virus than indirect methods, but this simplified approach reduced sample handling, as well as assay time and cost.ConclusionsWith extracted RNA, the BGI RT-qPCR detection system exhibited superior performance over the Norgen system, matching initial clinical diagnosis with the Seegene Allplex assay. The BGI system was also suitable for direct, extraction-free analysis, providing 78.4% sensitivity. The Norgen system, however, still accurately detected samples with a clinical Ct < 33 from extracted RNA, provided significant cost savings, and was superior to SYBR green assays that exhibited reduced specificity.
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Project description:BACKGROUND:The observation that females mate multiply when males provide nothing but sperm - which sexual selection theory suggests is unlikely to be limiting - continues to puzzle evolutionary biologists. Here we test the hypothesis that multiple mating is prevalent under such circumstances because it enhances female fitness. We do this by allowing female Trinidadian guppies to mate with either a single male or with multiple males, and then tracking the consequences of these matings across two generations. RESULTS:Overall, multiply mated females produced 67% more F2 grand-offspring than singly mated females. These offspring, however, did not grow or mature faster, nor were they larger at birth, than F2 grand-offspring of singly mated females. Our results, however, show that multiple mating yields benefits to females in the form of an increase in the production of F1. The higher fecundity among multiply mated mothers was driven by greater production of sons but not daughters. However, contrary to expectation, individually, the offspring of multiply mated females do not grow at different rates than offspring of singly mated females, nor do any indirect fitness benefits or costs accrue to second-generation offspring. CONCLUSIONS:The study provides strong evidence that multiple mating is advantageous to females, even when males contribute only sperm. This benefit is achieved through an increase in fecundity in the first generation, rather than through other fitness correlates such as size at birth, growth rate, time to sexual maturation and survival. Considered alongside previous work that female guppies can choose to mate with multiple partners, our results provide compelling evidence that direct fitness benefits underpin these mating decisions.
| S-EPMC3499236 | biostudies-literature
Project description:No head-to-head trials have compared the efficacy of tisagenlecleucel vs historical treatments for adults with relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL). This study indirectly compared the overall survival (OS) and overall response rate (ORR) associated with tisagenlecleucel, using data from the JULIET study (Study of Efficacy and Safety of CTL019 in Adult DLBCL Patients; #NCT02445248), vs historical treatments assessed in the CORAL (Collaborative Trial in Relapsed Aggressive Lymphoma) study follow-up population. To assess treatment effects in the treated (full analysis set [FAS]) and enrolled (intention-to-treat [ITT]) study populations, the JULIET FAS vs the CORAL follow-up FAS and JULIET ITT vs CORAL follow-up ITT populations were separately compared. Propensity score weighting using standardized mortality ratio weight (SMRW) and fine stratification weight (FSW) was used to compare OS and ORR, adjusting for baseline confounders. The results indicated that tisagenlecleucel was associated with a lower hazard of death among the FAS (adjusted hazard ratio [95% confidence interval], both FSW and SMRW, 0.44 [0.32, 0.59]) and ITT populations (FSW, 0.60 [0.44, 0.77]; SMRW, 0.57 [0.44, 0.73]; all, P < .001). Median OS was 12.48 months (JULIET) vs 4.34 to 4.40 months (CORAL) for the FAS, and 8.25 (JULIET) months vs 4.04 to 4.86 (CORAL) months for the ITT populations. Tisagenlecleucel was associated with a significantly higher ORR compared with historical treatments among the FAS (adjusted response rate difference [95% confidence interval], both FSW and SMRW, 36% [22%, 0.48%]; P < .001) and among the ITT populations after SMRW adjustment (11% [0%, 22%]; P = .043). This analysis supports that improved response and OS are achieved in patients with r/r DLBCL treated with tisagenlecleucel compared with those treated with alternative historical treatments.
| S-EPMC9043930 | biostudies-literature
Project description:Background and Objectives: Acute Respiratory Distress Syndrome (ARDS) is a heterogeneous syndrome that encompasses lung injury from a direct pulmonary or indirect systemic insult. Studies have shown that direct and indirect ARDS differ in their pathophysiologic process. In this study, we aimed to compare the different clinical characteristics and predictors of 28-day mortality between direct and indirect ARDS. Materials and Methods: The data of 1291 ARDS patients from September 2012 to December 2021 at the Second Affiliated Hospital of Chongqing Medical University were reviewed. We enrolled 451 ARDS patients in our study through inclusion and exclusion criteria. According to the risk factors, each patient was divided into direct (n = 239) or indirect (n = 212) ARDS groups. The primary outcome was 28-day mortality. Results: The patients with direct ARDS were more likely to be older (p < 0.001) and male (p = 0.009) and have more comorbidity (p < 0.05) and higher 28-day mortality (p < 0.001) than those with indirect ARDS. Age and multiple organ dysfunction syndrome (MODS) were predictors of 28-day mortality in the direct ARDS group, while age, MODS, creatinine, prothrombin time (PT), and oxygenation index (OI) were independent predictors of 28-day mortality in the indirect ARDS group. Creatinine, PT, and OI have interactions with ARDS types (all p < 0.01). Conclusions: The patients with direct ARDS were more likely to be older and male and have worse conditions and prognoses than those with indirect ARDS. Creatinine, PT, and OI were predictors of 28-day mortality only in the indirect ARDS group. The differences between direct and indirect ARDS suggest the need for different management strategies of ARDS.
| S-EPMC9697068 | biostudies-literature