Showing papers on "Subgroup analysis published in 2011"

A Systematic Review and Meta-Analysis on the Use of Preemptive Hemodynamic Intervention to Improve Postoperative Outcomes in Moderate and High-Risk Surgical Patients

Abstract: BACKGROUND: Complications from major surgery are undesirable, common, and potentially avoidable. The long-term consequences of short-term surgical complications have recently been recognized to have a profound influence on longevity and quality of life in survivors. In the past 30 years, there have been a number of studies conducted attempting to reduce surgical mortality and morbidity by deliberately and preemptively manipulating perioperative hemodynamics. Early studies had a high control-group mortality rate and were criticized for this as being unrepresentative of current practice and raised opposition to its implementation as routine care. We performed this review to update this body of literature and to examine the effect of changes in current practice and quality of care to see whether the conclusions from previous quantitative analyses of this field remain valid. METHODS: Randomized clinical trials evaluating the use of preemptive hemodynamic intervention to improve surgical outcome were identified using multiple methods. Electronic databases (MEDLINE, EMBASE, and the Cochrane Controlled Clinical Trials register) were screened for potential trials, reference lists of identified trials were examined, and additional sources were sought from experts and industry representatives. Identified studies that fulfilled the entry criteria were examined in full and subjected to quantifiable analysis, subgroup analysis, and sensitivity analysis where possible. RESULTS: There were 29 studies identified, 23 of which reported surgical complications. In total, the 29 trials involved 4805 patients with an overall mortality of 7.6%. The use of preemptive hemodynamic intervention significantly reduced mortality (pooled odds ratio [95% confidence interval] of 0.48 [0.33-0.78]; P = 0.0002) and surgical complications (odds ratio 0.43 [0.34-0.53]; P < 0.0001). Subgroup analysis showed significant reductions in mortality for studies using a pulmonary artery catheter, supranormal resuscitation targets, studies using cardiac index or oxygen delivery as goals, and the use of fluids and inotropes as opposed to fluids alone. By contrast, there was a significant reduction in morbidity for each of the 4 subgroups analyzed. CONCLUSION: The use of a preemptive strategy of hemodynamic monitoring and coupled therapy reduces surgical mortality and morbidity.

Subgroup identification from randomized clinical trial data

Abstract: We consider the problem of identifying a subgroup of patients who may have an enhanced treatment effect in a randomized clinical trial, and it is desirable that the subgroup be defined by a limited number of covariates. For this problem, the development of a standard, pre-determined strategy may help to avoid the well-known dangers of subgroup analysis. We present a method developed to find subgroups of enhanced treatment effect. This method, referred to as 'Virtual Twins', involves predicting response probabilities for treatment and control 'twins' for each subject. The difference in these probabilities is then used as the outcome in a classification or regression tree, which can potentially include any set of the covariates. We define a measure Q(Â) to be the difference between the treatment effect in estimated subgroup  and the marginal treatment effect. We present several methods developed to obtain an estimate of Q(Â), including estimation of Q(Â) using estimated probabilities in the original data, using estimated probabilities in newly simulated data, two cross-validation-based approaches, and a bootstrap-based bias-corrected approach. Results of a simulation study indicate that the Virtual Twins method noticeably outperforms logistic regression with forward selection when a true subgroup of enhanced treatment effect exists. Generally, large sample sizes or strong enhanced treatment effects are needed for subgroup estimation. As an illustration, we apply the proposed methods to data from a randomized clinical trial.

Ticagrelor Compared With Clopidogrel by Geographic Region in the Platelet Inhibition and Patient Outcomes (PLATO) Trial

Abstract: Background-In the Platelet Inhibition and Patient Outcomes (PLATO) trial, a prespecified subgroup analysis showed a significant interaction between treatment and region (P = 0.045), with less effec ...

Emotional distress in infertile women and failure of assisted reproductive technologies: meta-analysis of prospective psychosocial studies.

Abstract: Objective To examine whether pretreatment emotional distress in women is associated with achievement of pregnancy after a cycle of assisted reproductive technology. Design Meta-analysis of prospective psychosocial studies. Data sources PubMed, Medline, Embase, PsycINFO, PsychNET, ISI Web of Knowledge, and ISI Web of Science were searched for articles published from 1985 to March 2010 (inclusive). We also undertook a hand search of reference lists and contacted 29 authors. Eligible studies were prospective studies reporting a test of the association between pretreatment emotional distress (anxiety or depression) and pregnancy in women undergoing a single cycle of assisted reproductive technology. Review methods Two authors independently assessed the studies for eligibility and quality (using criteria adapted from the Newcastle-Ottawa quality scale) and extracted data. Authors contributed additional data not included in original publication. Results Fourteen studies with 3583 infertile women undergoing a cycle of fertility treatment were included in the meta-analysis. The effect size used was the standardised mean difference (adjusted for small sample size) in pretreatment anxiety or depression (priority on anxiety where both measured) between women who achieved a pregnancy (defined as a positive pregnancy test, positive fetal heart scan, or live birth) and those who did not. Pretreatment emotional distress was not associated with treatment outcome after a cycle of assisted reproductive technology (standardised mean difference −0.04, 95% confidence interval −0.11 to 0.03 (fixed effects model); heterogeneity I²=14%, P=0.30). Subgroup analyses according to previous experience of assisted reproductive technology, composition of the not pregnant group, and timing of the emotional assessment were not significant. The effect size did not vary according to study quality, but a significant subgroup analysis on timing of the pregnancy test, a contour enhanced funnel plot, and Egger’s test indicated the presence of moderate publication bias. Conclusions The findings of this meta-analysis should reassure women and doctors that emotional distress caused by fertility problems or other life events co-occurring with treatment will not compromise the chance of becoming pregnant.

Analysis of randomized comparative clinical trial data for personalized treatment selections

Abstract: Suppose that under the conventional randomized clinical trial setting, a new therapy is compared with a standard treatment. In this article, we propose a systematic, 2-stage estimation procedure for the subject-level treatment differences for future patient's disease management and treatment selections. To construct this procedure, we first utilize a parametric or semiparametric method to estimate individual-level treatment differences, and use these estimates to create an index scoring system for grouping patients. We then consistently estimate the average treatment difference for each subgroup of subjects via a nonparametric function estimation method. Furthermore, pointwise and simultaneous interval estimates are constructed to make inferences about such subgroup-specific treatment differences. The new proposal is illustrated with the data from a clinical trial for evaluating the efficacy and toxicity of a 3-drug combination versus a standard 2-drug combination for treating HIV-1-infected patients.

Risks for Stroke, Bleeding, and Death in Patients With Atrial Fibrillation Receiving Dabigatran or Warfarin in Relation to the CHADS2 Score: A Subgroup Analysis of the RE-LY Trial

Abstract: Whether CHADS2 scores are useful for predicting thromboembolic and bleeding complications in patients treated with anticoagulants for atrial fibrillation is not known. In this analysis of data from...

Thiazolidinediones and risk of heart failure in patients with or at high risk of type 2 diabetes mellitus: A meta-analysis and meta-regression analysis of placebo-controlled randomized clinical trials

Abstract: Recent meta-analyses of randomized clinical trials (RCTs) demonstrated a higher risk of heart failure (HF) with the use of thiazolidinediones (TZDs). However, this effect may have been diluted by including active controls. Also, it is uncertain whether the risk of HF is similar with rosiglitazone and pioglitazone. This study quantified the risks of HF with the use of TZDs in patients with or at high risk of developing type 2 diabetes mellitus (DM), and evaluated differential effects by type of TZD. Secondarily, we evaluated risks of peripheral edema. We performed a systematic review and meta-analysis of placebo-controlled RCTs evaluating the effect of rosiglitazone or pioglitazone on investigator-reported HF and edema. Articles published before 31 December 2009 were searched in MEDLINE, The Web of Science, and Scopus, and the data were extracted by three investigators. RCTs with ≥100 patients and ≥3 months of follow-up were included. We quantified the effect of TZDs as odds ratios (ORs) by using the Mantel-Haenzel and alternative models. We further evaluated the risk of serious/severe HF, and the effect of several trial characteristics on HF risk by subgroup analysis and meta-regression analysis. 29 trials (n = 20254) were evaluated. TZDs were significantly associated with HF (TZD 360/6807 [5.3%] vs placebo 234/6328 [3.7%], OR 1.59; 95% CI 1.34, 1.89; p<0.00001). The risk of HF was higher with rosiglitazone than with pioglitazone (2.73 [95% CI 1.46, 5.10] vs 1.51 [1.26, 1.81]; p = 0.06). TZDs were associated with a similar risk of serious/severe HF (OR 1.47; 95% CI 1.16, 1.87; p = 0.002). Use of TZDs was also associated with edema (OR 2.04; 95% CI 1.85, 2.26; p<0.00001). HF and edema risks were consistent using Peto and random effects models. Risks of HF were significantly high for the subgroups of trials including patients with or at high risk for type 2 DM, and for the subgroup of trials with ≥12 months of follow-up. Meta-regression analysis showed that trials with lower overall baseline risk had higher HF risks. In placebo-controlled trials of adult patients with or at high risk for type 2 DM, TZD therapy is significantly and consistently associated with a higher risk of HF. The risk of serious/severe HF is also increased with the use of TZDs. HF risks are similar to those of meta-analyses combining active- and placebo-controlled trials. The benefit/risk profile of TZDs should be considered when treating diabetic patients with or without prior HF.

Effects of augmented exercise therapy on outcome of gait and gait-related activities in the first 6 months after stroke: a meta-analysis

Abstract: Background and Purpose— The purpose of this study was to determine the effects of augmented exercise therapy on gait, gait-related activities, and (basic and extended) activities of daily living within the first 6 months poststroke. Methods— A systematic literature search in electronic databases from 1990 until October 2010 was performed. Randomized controlled trials were included in which the experimental group spent augmented time in lower-limb exercise therapy compared with the control group. Outcomes were gait, gait-related activities, and (extended) activities of daily living. Results from individual studies were pooled by calculating the summary effect sizes. Subgroup analyses were applied for a treatment contrast of ≥16 hours, timing poststroke, type of control intervention, and methodological quality. Results— Fourteen (N=725) of 4966 identified studies were included. Pooling resulted in small to moderate significant summary effect sizes in favor of augmented exercise therapy for walking ability, comfortable and maximum walking speed, and extended activities of daily living. No significant effects were found for basic activities of daily living. Subgroup analysis did not show a significant effect modification. Conclusions— Dose–response trials in stroke rehabilitation are heterogeneous. The present meta-analysis suggests that increased time spent on exercise of gait and gait-related activities in the first 6 months poststroke results in significant small to moderate effects in terms of walking ability, walking speed, and extended activities of daily living. High-quality dose–response exercise therapy trials are needed with identical treatment goals but incremental levels of intensity.

Pregnancy Outcome at Extremely Advanced Maternal Age

Abstract: Objective The purpose of this study was to evaluate pregnancy outcome in women at extremely advanced maternal age (≥45 years). Study Design We compared the condition of women aged ≥45 years (n = 177) in a 10:1 ratio (20-29, 30-39, and 40-44 years.). Subgroup analysis compared the condition of women aged 45-49 years with those women aged ≥50 years. Results The rates of gestational diabetes mellitus and hypertensive complications were higher for the study group, compared with the whole group (17.0% vs 5.6% and 19.7% vs 4.5%, respectively; P Conclusion Pregnancy at extreme advanced maternal age is associated with increased maternal and fetal risk.

Effects of exercise on quality of life in stroke survivors: a meta-analysis

Abstract: Background and Purpose—One of the major consequences after stroke is the deterioration in health-related quality of life (HRQOL). Three previous systematic reviews indicated that exercise has limited to no effect in improving HRQOL in stroke survivors. The objective of this meta-analysis was to update the evidence on exercise and HRQOL in stroke survivors with additional new information on randomized controlled trials that have been published since these 3 previous reviews. Methods—MEDLINE, Cumulated Index to Nursing and Allied Health Literature, EMBASE, and SportsDiscus databases were searched for randomized controlled trials reporting the effects of exercise on HRQOL in stroke survivors from 1950 to March 2010. The methodological quality of each study was appraised using the Physiotherapy Evidence Database scale. Standardized mean difference was used to compute effect size and subgroup analysis was conducted to test the consistency of results across the subgroups with different characteristics. Results—...

Bayesian models for subgroup analysis in clinical trials

Abstract: Background In a pharmaceutical drug development setting, possible interactions between the treatment and particular baseline clinical or demographic factors are often of interest However, the subgroup analysis required to investigate such associations remains controversial Concerns with classical hypothesis testing approaches to the problem include low power, multiple testing, and the possibility of data dredgingPurpose As an alternative to hypothesis testing, the use of shrinkage estimation techniques is investigated in the context of an exploratory post hoc subgroup analysis A range of models that have been suggested in the literature are reviewed Building on this, we explore a general modeling strategy, considering various options for shrinkage of effect estimates This is applied to a case-study, in which evidence was available from seven-phase II–III clinical trials examining a novel therapy, and also to two artificial datasets with the same structureMethods Emphasis is placed on hierarchical m

Prevention of atrial fibrillation with omega-3 fatty acids: a meta-analysis of randomised clinical trials

Abstract: Context Previous randomised controlled trials (RCT) regarding n-3 PUFA supplementation for atrial fibrillation (AF) prevention have yielded conflicting results. Objective A systematic review and meta-analysis of RCT was conducted to examine the role of n-3 PUFA in AF prevention. Data Sources MEDLINE, Web of Science and Cochrane clinical trials database were searched until November 2010. Study Selection Of 127 initially identified studies, 10 RCT with 1955 patients were finally analysed. Data Extraction Two blinded reviewers extracted data independently to a predefined form. Disagreements were resolved through discussion and consensus. Results n-3 PUFA had no significant effect on the prevention of AF (OR 0.81, 95% CI 0.57 to 1.15; p=0.24). There was significant heterogeneity among the studies (p=0.002, I 2 =65.0%). Subgroup analysis showed no significant beneficial effect of fish oils in any subset of population. Conclusions No significant effects of n-3 PUFA supplementation on AF prevention were observed in this meta-analysis. A large-scale trial with higher doses and longer follow-up might be required to rule out the possibility of any treatment benefit.

Does prolonged β-lactam infusions improve clinical outcomes compared to intermittent infusions? A meta-analysis and systematic review of randomized, controlled trials

Abstract: The emergence of multi-drug resistant Gram-negatives (MDRGNs) coupled with an alarming scarcity of new antibiotics has forced the optimization of the therapeutic potential of available antibiotics. To exploit the time above the minimum inhibitory concentration mechanism of β-lactams, prolonging their infusion may improve outcomes. The primary objective of this meta-analysis was to determine if prolonged β-lactam infusion resulted in decreased mortality and improved clinical cure compared to intermittent β-lactam infusion. Relevant studies were identified from searches of MEDLINE, EMBASE, and CENTRAL. Heterogeneity was assessed qualitatively, in addition to I2 and Chi-square statistics. Pooled relative risks (RR) and 95% confidence intervals (CI) were calculated using Mantel-Haenszel random-effects models. Fourteen randomized controlled trials (RCTs) were included. Prolonged infusion β-lactams were not associated with decreased mortality (n= 982; RR 0.92; 95% CI:0.61-1.37) or clinical cure (n = 1380; RR 1.00 95% CI:0.94-1.06) compared to intermittent infusions. Subgroup analysis for β-lactam subclasses and equivalent total daily β-lactam doses yielded similar results. Most studies had notable methodological flaws. No clinical advantage was observed for prolonged infusion β-lactams. The limited number of studies with MDRGNs precluded evaluation of prolonged infusion of β-lactams for this subgroup. A large, multicenter RCT with critically ill patients infected with MDRGNs is needed.

Understanding the complexity of homocysteine lowering with vitamins: the potential role of subgroup analyses.

Abstract: SINCE THE PUBLICATION OF SEVERAL RANDOMIZED TRIALS and a meta-analysis indicating that lowering homocysteine levels with B vitamins (to reduce the effects of homocysteine on the vascular endothelium) did not result in cardiovascular benefit, the use of vitamin therapy to lower homocysteine levels is widely regarded as ineffective. However, there has been renewed interest in the issue because an analysis of studies from the National Health and Nutrition Examination Survey and the Multi-Ethnic Study of Atherosclerosis showed that adding total homocysteine level to a Framingham risk score was associated with an approximately 20% net reclassification of intermediate-risk patients. A recent meta-analysis raised the question of whether population folate intake and polymorphisms of methylenetetrahydrofolate reductase may alter interpretation of these clinical trials; mendelian randomization analysis suggested that the polymorphisms might be important only among individuals with low folate status. A commentary about that article noted the hazards of the “spinal reflex” that leads to “automatic rejection of observational data when they appear to be discrepant from trials.” A similar spinal reflex, automatic rejection of subgroup analyses, is another hazard of interpretation of clinical trials. Subgroup analyses founded in biology may have the potential to importantly inform interpretation of clinical trial results, provided sufficient caution is exercised. Thoughtfully derived subgroups, especially those formed a priori and not derived post hoc from the same data set, can stimulate further work and reinterpretation of existing data. The question of whether B vitamin therapy to lower homocysteine levels may reduce the risk of stroke is becoming more complicated, and analyses that depended on grouping all patients together may have obscured important differences among patient (and perhaps population) subgroups. For instance, the main results of the Vitamin Intervention for Stroke Prevention (VISP) trial showed no effect of B vitamins (folic acid/pyridoxine/cyanocobalamin) on the risk of recurrent stroke, death, or myocardial infarction, whereas a subgroup analysis of the VISP trial showed benefit of B vitamins in a defined subset of the population. More recently, House et al reported that B vitamin therapy was shown to increase cardiovascular risk in patients with diabetic nephropathy. Hence, subgroup analyses have shown beneficial as well as adverse effects of B vitamin therapy. The VISP subgroup analysis excluded patients with B12 deficiency (because they were all receiving injections of cyanocobalamin, regardless of the treatment to which they were randomized), and patients with significant renal impairment (because it was thought they would not respond to vitamin therapy). There was a significant reduction of stroke or myocardial infarction with B vitamins in the remaining participants, and this finding was more pronounced when patients were stratified by baseline serum B12 level. The difference between patients who entered the study with a serum B12 level above the median (ie, they could absorb B12 reasonably well) and received high-dose vitamins and those who entered the study with a serum B12 level below the median and received low-dose vitamins was a 34% reduction of stroke, death, or myocardial infarction (P=.02). At the time, it seemed that the findings were explained mainly by exclusion of patients receiving vitamin B12 injections, and this seemed supported by the finding in the Heart Outcomes Prevention Evaluation 2 (HOPE-2) trial (the only large trial to use an adequate dose of B12 for elderly patients) that B vitamins significantly reduced the risk of stroke. In 2011, Hsu et al reported that in the VISP trial, a subgroup of patients with the GG phenotype of transcobalamin 2, a transport protein for vitamin B12, were responsive to high-dose vitamin therapy. Vitamin B12 may thus have a key role in stroke prevention interventions involving vitamin therapy used to lower homocysteine levels. Homocysteine increases thrombosis and is associated with a markedly increased risk of stroke in atrial fibrillation. The prevalence of atrial fibrillation increases steeply with age, as do metabolic B12 deficiency (not necessarily reflected in serum B12 levels, discussed below) and plasma total homocysteine levels. In the Framingham cohort, 1.5% of strokes at ages 50 through 59 years were attributable to atrial fibrillation, whereas by ages 80 through

Abstract 10956: Dabigatran Compared with Warfarin in Patients with Atrial Fibrillation and Symptomatic Heart Failure: A Subgroup Analysis of the RE-LY Trial

Abstract: We evaluated the effects of dabigatran compared with warfarin in the subgroup of patients with previous symptomatic heart failure (HF) in the RE‐LY trial.

Efficacy and safety of saxagliptin in older patients with type 2 diabetes mellitus.

Abstract: Objective:To assess the safety and efficacy of saxagliptin (5 mg once-daily) in older patients (≥65 years of age) with inadequately controlled type 2 diabetes.Research design and methods:In this retrospective subgroup analysis, data from five randomized, double-blind, placebo-controlled, multicenter, 24-week, phase 3 trials were included. The primary studies evaluated saxagliptin 5 mg once-daily (monotherapy or add-on) in patients aged 18–77 years with HbA1c ≥7.0% (four studies) or ≥7.5% (add-on to glyburide study) versus placebo.Main outcome measures:The primary efficacy endpoint of each study included in this pooled analysis was HbA1c change from baseline to week 24.Results:In the five-study pooled population, 279 (16.6%) patients were at least 65 years old; 142 received saxagliptin 5 mg once-daily and 137 received placebo. Treatment groups were well-balanced for baseline characteristics within each study. In older patients, the HbA1c adjusted mean change from a baseline of 8.1% was −0.73 ± 0.16...

Efficacy of tiotropium in COPD patients from Asia: A subgroup analysis from the UPLIFT trial

Abstract: Background and objective: Studies in respiratory diseases other than chronic obstructive pulmonary disease suggest potentially differing responses to medications among patients from different regions. We report a subgroup analysis of patients recruited to Asian centres from a previously reported 4-year COPD trial. Methods: Subgroup analysis from a randomized, double-blinded, placebo-controlled trial of tiotropium 18 µg daily in COPD. Primary end-point was rate of decline in FEV1. Secondary end-points included spirometry at individual time points, health-related quality of life (St George's Respiratory Questionnaire), exacerbations and mortality. Results: Of 5992 patients, 362 were from Asian centres (100 from Japan). Mean age 66 years, 95% men, 13% current smokers, BMI: 21 kg/m2; post-bronchodilator FEV1: 44% predicted; St George's Respiratory Questionnaire total score: 44 units. No treatment effect was observed for rate of decline in FEV1 although annual decline was less in Asian patients. Morning pre-bronchodilator FEV1 and forced vital capacity improved in Asian patients (P < 0.05). Tiotropium reduced number of exacerbations (rate ratio (95% confidence interval (CI)): 0.73 (0.57–0.94)). Hazard ratios (95%CI) for exacerbations and hospitalized exacerbations (tiotropium/control) were 0.81 (0.62–1.05) and 0.85 (0.61–1.19), respectively. St George's Respiratory Questionnaire total score improved by 1.5–6.1 units (P < 0.05 for months 18, 24, 30 and 36) with tiotropium. Fatal events occurred in 34 tiotropium (18.5%) and 42 control (23.6%) patients. Conclusions: In COPD patients from Asia, tiotropium improves lung function, improves health-related quality of life and reduces exacerbations over 4 years of treatment.

C-reactive protein as a predictor of mortality in critically ill patients: a meta-analysis and systematic review

Abstract: C-reactive protein is a marker of inflammatory response and has been widely investigated in cardiovascular and infectious diseases, especially to monitor therapeutic success. However, its role as a predictor of clinical outcome in critically ill patients remains uncertain and controversial. The objective of this study was to investigate the predictive value of C-reactive protein in critically ill patients. The databases of PubMed, the Cochrane clinical trial database and EMBASE (from inception to August 2010) were searched. Prospective non-randomised clinical studies comparing C-reactive protein concentrations between survivors and non-survivors were included. Pooled mean difference in C-reactive protein concentrations between survivors and non-survivors was calculated. Heterogeneity was analysed by I2. Sensitivity and subgroup analyses were conducted to explore the heterogeneity. Fourteen studies containing a total of 1969 patients were finally included in our analysis. The weighted mean difference in the C-reactive protein levels between survivors and non-survivors was 9.15 mg/l (95% confidence interval -6.50 to 24.81). The heterogeneity was large with I2 = 92%. Subsequent investigation of the heterogeneity with sensitivity analyses yielded no significant differences. The subgroup analysis showed that the weighted mean difference in early (within 48 hours) C-reactive protein levels between survivors and non-survivors was not significantly different, in contrast to the late (beyond 48 hours) C-reactive protein level. This was significantly greater in non-survivors with a weighted mean difference of 63.80 mg/l (95% confidence interval 35.67 to 91.93). Our systematic review shows that while the early C-reactive protein concentration is not a good predictor of survival in critically ill patients, the late C-reactive protein concentration may help to identify patients who are at risk of death.

A Bayesian subgroup analysis with a zero‐enriched Polya Urn scheme

Abstract: We introduce a new approach to inference for subgroups in clinical trials. We use Bayesian model selection, and a threshold on posterior model probabilities to identify subgroup effects for reporting. For each covariate of interest, we define a separate class of models, and use the posterior probability associated with each model and the threshold to determine the existence of a subgroup effect. As usual in Bayesian clinical trial design we compute frequentist operating characteristics, and achieve the desired error probabilities by choosing an appropriate threshold(s) for the posterior probabilities.

Vaccine therapy for metastatic melanoma: systematic review and meta-analysis of clinical trials.

Abstract: Clinical trials of melanoma vaccines have yielded inconclusive data on whether a positive melanoma-specific immune response predicts treatment benefit. The objective of this study was to evaluate the effect of different melanoma vaccine strategies and the association between immunologic response and survival. The authors conducted a systematic review and meta-analysis of phase II and III clinical trials of melanoma vaccine. Outcomes assessed included overall disease control, overall survival, and impact on immune response. For binary variables, proportions were reported for one-arm studies and risk ratios for controlled studies. For survival data, medians were reported for one-arm studies and hazard ratios for controlled studies. The existence and extent of heterogeneity between trials was evaluated using Cochran's Q statistic. A two-sided P value of less than 0.05 for meta-analysis results was considered statistically significant. Of 56 studies reporting data on 4375 patients, overall disease control was seen in 25.3% [95% confidence interval (CI): 20.7-30.5%] of patients. Subgroup analysis revealed that overall disease control for peptide vaccines plus interleukin-2 (IL-2) was improved compared with interleukin-2 alone (pooled risk ratio: 2.79, 95% CI: 1.62-4.80). Overall survival varied among six studies comparing vaccine with other treatments. Subgroup analysis revealed that tumor-specific immune response was associated with prolonged overall survival compared with the lack of response (pooled hazard ratio: 2.15, 95% CI: 1.88-2.44). Severe toxicity associated with vaccine treatment was uncommon. Overall, a melanoma-specific immune response predicted longer overall survival, although no evidence was found that vaccine therapy provides better overall disease control or overall survival compared with other treatments.

A method to estimate treatment efficacy among latent subgroups of a randomized clinical trial

Abstract: Subgroup analysis arises in clinical trials research when we wish to estimate a treatment effect on a specific subgroup of the population distinguished by baseline characteristics. Many trial designs induce latent subgroups such that subgroup membership is observable in one arm of the trial and unidentified in the other. This occurs, for example, in oncology trials when a biopsy or dissection is performed only on subjects randomized to active treatment. We discuss a general framework to estimate a biological treatment effect on the latent subgroup of interest when the survival outcome is right-censored and can be appropriately modelled as a parametric function of covariate effects. Our framework builds on the application of instrumental variables methods to all-or-none treatment noncompliance. We derive a computational method to estimate model parameters via the EM algorithm and provide guidance on its implementation in standard software packages. The research is illustrated through an analysis of a seminal melanoma trial that proposed a new standard of care for the disease and involved a biopsy that is available only on patients in the treatment arm.

Association of a vascular endothelial growth factor gene 936 C/T polymorphism with breast cancer risk: a meta-analysis

Abstract: Published studies on the association between the vascular endothelial growth factor (VEGF) gene 936 C/T polymorphism and breast cancer risk are inconclusive, and a meta-analysis is required to verify the association. Nine studies, including a total of 4,973 cases and 5,035 controls, were subjected to meta-analysis. When all eligible subjects were pooled for meta-analysis, the CT + TT genotypes were not associated with a significant decrease in breast cancer risk (odds ratio = 0.87; 95% confidence interval 0.75–1.02; P = 0.087). We also categorized by ethnicity (Caucasian, Asian, or mixed) for subgroup analysis, however, according to this subgroup analysis, we found no significant association between the CT and TT versus CC genotype with breast cancer risk reduction in any of the subgroups. We conclude that the VEGF gene 936 C/T polymorphism does not affect breast cancer risk.

RAD51 G135C polymorphism is associated with breast cancer susceptibility: a meta-analysis involving 22,399 subjects

Abstract: Several studies have investigated the associations between RAD51 G135C polymorphism and the susceptibility to breast cancer, but results have been inconclusive. In order to derive a more precise estimation of the relationship, a meta-analysis was performed. A total of 17 case control studies, including 12,153 cases and 10,245 controls, were selected. Overall, significant decreased risk was found for the additive model (OR = 0.995, 95% CI = 0.991–0.998) and dominant model (OR = 0.994, 95% CI = 0.991–0.998). In the subgroup analysis by ethnicity, statistically significantly decreased risk was found in Asians (additive model: OR = 0.977, 95% CI = 0.954–1.000 and dominant model: OR = 0.981, 95% CI = 0.963–1.000). In conclusion, this meta-analysis suggests that the RAD51 G135C polymorphism is a low-penetrant risk factor for developing breast cancer.

Population enrichment designs: case study of a large multinational trial.

Abstract: A method is proposed for modifying a group-sequential clinical trial by restricting future enrollment to a subgroup and possibly altering the sample size of the subgroup, based on an interim analysis of the data already obtained. The method provides strong control of type 1 error without requiring prespecification of the list of possible subgroups or of the decision rule for selecting among them. Nevertheless, for regulatory submissions it is recommended that the subgroups and decision rule be prespecified. The method is applied to a large cardiology trial in which the subgroups are prespecified and the decision rules for subgroup selection and sample size alteration are based on conditional power. It is shown by simulation that substantial gains in power can be attained if there is a subgroup by treatment interaction.