Cochran-armitage test versus logistic regression in the analysis of genetic association studies

Objective: The Cochran-Armitage trend test based on the linear regression model has become a standard procedure for association testing in case-control studies. In contrast, the logistic regression model is generally used for estimating effect sizes. The aim of this paper is to propose an approach that allows for association testing and parameter estimation by means of the same statistic. Methods/Results: The trend test is recommendable as a test of no association between genotype and risk of disease. It is a two-sample test for differences between cases and controls with respect to the average number of risk alleles occurring in the genotype of an individual. We argue that this difference is not of primary interest in genetic association studies. It should be replaced with the disease odds ratio, which can be assessed under both cohort sampling and case-control sampling. Conclusion: The Cochran-Armitage trend test should be replaced by the Wald statistic from a logistic regression model for hypothesis testing and estimation in genetic association studies. Copyright (C) 2011 S. Karger AG, Base

Results of a randomized trial of treatment modalities in patients with low or early-intermediate risk prostate cancer (PREFERE trial)

Purpose The optimal treatment for patients with low to early-intermediate risk prostate cancer (PCa) remains to be defned. The randomized PREFERE trial (DRKS00004405) aimed to assess noninferiority of active surveillance (AS), externalbeam radiotherapy (EBRT), or brachytherapy by permanent seed implantation (PSI) vs. radical prostatectomy (RP) for these patients. Methods PREFERE was planned to enroll 7600 patients. The primary endpoint was disease specifc survival. Patients with PCa stage≤cT2a, cN0/X, M0, PSA ≤10 ng/ml and Gleason-Score≤3+4 at reference pathology were eligible. Patients were allowed to exclude one or two of the four modalities, which yielded eleven combinations for randomization. Sixty-nine German study centers were engaged in PREFERE. Results Of 2251 patients prescreened between 2012 and 2016, 459 agreed to participate in PREFERE. Due to this poor accrual, the trial was stopped. In 345 patients reference pathology confrmed inclusion criteria. Sixty-nine men were assigned to RP, 53 to EBRT, 93 to PSI, and 130 to AS. Forty patients changed treatment shortly after randomization, 21 to AS. Fortyeight AS patients with follow-up received radical treatment. Median follow-up was 19 months. Five patients died, none due to PCa; 8 had biochemical progression after radical therapy. Treatment-related acute grade 3 toxicity was reported in 3 RP patients and 2 PSI patients. Conclusions In this prematurely closed trial, we observed an unexpected high rate of termination of AS and an increased toxicity related to PSI. Patients hesitated to be randomized in a multi-arm trial. The optimal treatment of low and earlyintermediate risk PCa remains unclear

Termination rates and histological reclassification of active surveillance patients with low- and early intermediate-risk prostate cancer : results of the PREFERE trial

Purpose Active surveillance (AS) strategies for patients with low- and early intermediate-risk prostate cancer are still not consistently defined. Within a controlled randomized trial, active surveillance was compared to other treatment options for patients with prostate cancer. Aim of this analysis was to report on termination rates of patients treated with AS including different grade groups. Methods A randomized trial comparing radical prostatectomy, active surveillance, external beam radiotherapy and brachytherapy was performed from 2013 to 2016 and included 345 patients with low- and early intermediate-risk prostate cancer (ISUP grade groups 1 and 2). The trial was prematurely stopped due to slow accrual. A total of 130 patients were treated with active surveillance. Among them, 42 patients were diagnosed with intermediate-risk PCA. Reference pathology and AS quality control were performed throughout. Results After a median follow-up time of 18.8 months, 73 out of the 130 patients (56%) terminated active surveillance. Of these, 56 (77%) patients were histologically reclassified at the time of rebiopsy, including 35% and 60% of the grade group 1 and 2 patients, respectively. No patients who underwent radical prostatectomy at the time of reclassification had radical prostatectomy specimens ≥ grade group 3. Conclusion In this prospectively analyzed subcohort of patients with AS and conventional staging within a randomized trial, the 2-year histological reclassification rates were higher than those previously reported. Active surveillance may not be based on conventional staging alone, and patients with grade group 2 cancers may be recommended for active surveillance in carefully controlled trials only

Testing Statistical Hypotheses of Equivalence and Noninferiority

While continuing to focus on methods of testing for two-sided equivalence, "Testing Statistical Hypotheses of Equivalence and Noninferiority, Second Edition" gives much more attention to noninferiority testing. It covers a spectrum of equivalence testing problems of both types, ranging from a one-sample problem with normally distributed observations of fixed known variance to problems involving several dependent or independent samples and multivariate data. Along with expanding the material on noninferiority problems, this edition includes new chapters on equivalence tests for multi

Testing for goodness rather than lack of fit of an X-chromosomal SNP to the Hardy-Weinberg model.

The problem of checking the genotype distribution obtained for some diallelic marker for compatibility with the Hardy-Weinberg equilibrium (HWE) condition arises also for loci on the X chromosome. The possible genotypes depend on the sex of the individual in this case: for females, the genotype distribution is trinomial, as in the case of an autosomal locus, whereas a binomial proportion is observed for males. Like in genetic association studies with autosomal SNPs, interest is typically in establishing approximate compatibility of the observed genotype frequencies with HWE. This requires to replace traditional methods tailored for detecting lack of fit to the model with an equivalence testing procedure to be derived by treating approximate compatibility with the model as the alternative hypothesis. The test constructed here is based on an upper confidence bound and a simple to interpret combined measure of distance between true and HWE conforming genotype distributions in female and male subjects. A particular focus of the paper is on the derivation of the asymptotic distribution of the test statistic under null alternatives which is not of the usual Gaussian form. A closed sample size formula is also provided and shown to behave satisfactorily in terms of the approximation error

Investigating Hardy-Weinberg equilibrium in case-control or cohort studies or meta-analysis.

peer reviewedYu et al. (Breast Cancer Res Treat 117:675-677, 2009) recently stated that testing for deviation from Hardy-Weinberg equilibrium (HWE) is necessary to identify systematic genotyping errors in case-control studies. They criticized a meta-analytic study for the deviation from HWE in the case group of one study. The aim of this article is twofold. First, we derive recommendations on how to test for deviations from HWE in different study designs. Second, we develop a meta-analytic framework for assessing compatibility with HWE or measuring deviation from HWE. The authors sketch the possible reasons behind deviation from HWE and provide guidelines for proper investigation of HWE deviations in different study designs. The authors argue that the standard HWE chi(2) lack of fit test is logically flawed and provide a logically unflawed approach for measuring deviation from HWE using confidence intervals. The proposed method is applicable to meta-analyses of both case-control or cohort association studies. The proposed approach is illustrated using the meta-analysis criticized by Yu et al. Heterogeneity between studies can be assessed. The critique of Yu et al. to the article of Frank et al. (Breast Cancer Res Treat 111:139-144, 2008) can be refuted. Even more, validity of HWE can be proven for the pooled control sample. The authors advocate the use of a confidence interval-based approach to assess HWE. The latter should only be investigated in control populations. In multicenter studies or meta-analysis, deviation from HWE should be analyzed using a meta-analytic approach

Equivalence Testing With Particle Size Distribution Data: Methods and Applications in the Development of Inhalative Drugs

<p>Key criteria of the quality of inhalative drugs are assessed in experiments generating so-called particle size distributions as data. Many experiments of that kind are carried out to demonstrate that necessary modifications to whatever part of the manufacturing process do not substantially change basic characteristics of an inhalable drug product. The equivalence testing procedures we derive for that purpose rely on different models accommodating the specific structure of such data and on different ways of specifying the region of nonrelevant differences. For each hypotheses formulation, three different tests are derived (two parametric and one asymptotically distribution-free procedures) and compared in terms of level and power. The results support the conclusion that the asymptotically distribution-free procedure exhibits surprisingly favorable properties. Supplementary materials for this article are available online.</p

Stratification of medulloblastoma on the basis of histopathological grading

Medulloblastoma (WHO grade IV) is an embryonal tumour of the cerebellum and the most common malignant central nervous system tumour in children. Despite significant advances in treatment, 5-year survival rates are still less than 70%, suggesting the presence of subgroups with different response to radio/chemotherapy. In the present study, we re-evaluated a series of 347 medulloblastomas from the SIOP II clinical trial of the International Society of Paediatric Oncology to identify features predictive of clinical outcome. Relapse free survival for medulloblastomas with severe anaplasia [5-year rate: S(60)=49.5%], was significantly shorter than for tumours with moderate or mild anaplasia S(60)=65.4%; P=0.001). The difference between both groups was even larger when the presence or absence of extensive apoptosis was included (46.5 vs. 66.7%; P=0.0216). Other histological features including nodularity, necrosis, vascular proliferation and the presence of beta-catenin mutations (7% of cases) were not predictive for relapse free survival. These findings indicate that degree of anaplasia is the most significant histologic feature predictive of the survival of medulloblastoma patients