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Genome-wide association studies have reported an association between the A-allele of rs1006737 within CACNA1C and affective disorders and schizophrenia. The aim of the present study was to investigate the relationship between rs1006737 and established and potential endophenotypes for these disorders in a population-based cohort of 3793 subjects, using an analytical method designed to assess a previously reported sex-specific effect of CACNA1C . The investigated endophenotypes included personality traits and resilience factors. At 10-year follow-up, subjects were screened for depressive symptoms. All subjects were genotyped for rs1006737. The direction of the effect and mode of inheritance of rs1006737 differed between the sexes. In men, the A-allele was associated with higher emotional lability and lower resilience, that is, lower sense of coherence ( P =0.021), lower perceived social support ( P =0.018), lower dispositional optimism ( P =0.032) and more depressive symptoms at follow-up ( P =0.007). In women, the A-allele was associated with lower emotional lability and stronger resilience, that is, higher sense of coherence ( P =0.00028), higher perceived social support ( P =0.010), lower neuroticism ( P =0.022) and fewer depressive symptoms at follow-up ( P =0.035). After conservative Bonferroni correction for 32 tests, results only remained significant for sense of coherence in women ( P =0.009). These results suggest that CACNA1C is involved in the genetic architecture of endophenotypes for affective disorders and schizophrenia, and that it shows a distinct sex-specific effect. Comprehensive phenotype characterization in case–control samples and the general population, as well as an adequate modeling of sex-specific genetic effects, may be warranted to elucidate the pathogenetic mechanisms conferred by robustly identified susceptibility genes.

As part of a long-term safety study the bisphosphonate ibandronate was investigated for its effects on bone quality in lumbar vertebrae in rats. Bone area, bone density and mechanical properties were assessed by peripheral quantitative computed tomography (pQCT), dual-energy X-ray absorptiometry (DXA) and compression tests. Female and male groups of Wistar rats received either vehicle or 3, 7 or 15 mg/kg per day of ibandronate over 104 weeks orally by gavage. Compared with the control group, bone mineral density, compressive strength and stiffness were significantly higher in ibandronate-treated animals, whereas no changes occurred in strain or modulus of elasticity. The increase in vertebral body stress was significant in some of the ibandronate-treated groups. The changes in mechanical properties appear to be due mainly to an increase in bone mass. A highly significant correlation was found between bone mineral density measured either by DXA (r = 0.86) or pQCT (r = 0.85) and maximal strength in vertebral bodies (p < 0.0001 each). In conclusion, we demonstrated that lifelong administration of doses of ibandronate far in excess of any therapeutically intended dose not only increases bone mass and apparent density, but also maintains or even slightly improves bone quality. Bone mineral density measured either by pQCT or DXA can be used as a predictor for ultimate strength in rat lumbar vertebral bodies after treatment with ibandronate.

Objective: In this study, we present a simultaneous inference procedure as a unified analysis framework for genetic association studies. Methods: The method is based on the formulation of multiple marginal models that reflect different modes of inheritance. The basic advantage of this methodology is that no explicit formulation of the correlation between the test statistics is required. Moreover, the genotype scores are considered as a quantitative explanatory variable, i.e., regression models are used. Results: The proposed approach covers a wide variety of endpoints (binary, count, quantitative, and time-to-event data). In addition, multiple endpoints of different types can be assessed simultaneously. This allows the detection of pleiotropic effects while taking the mode of inheritance into account. Moreover, multiple loci can be assessed simultaneously. Conclusion: The flexibility of the proposed approach is demonstrated while analyzing a variety of data examples.

The crossover is considered to be the design of choice for bioequivalence studies and regulatory authorities currently require evidence of average bioequivalence which is a special case of population bioequivalence. To assess average bioequivalence, the double t-test can be performed without Welch's approximation.

Using three well-designed experimental studies as illustration, we demonstrate that the biostatistical design and analysis of long-term animal studies simulating human osteoporosis should be analogous to the design and analysis of randomized clinical trials. This principal is in accordance with the recommendations from the International Conference on Harmonisation guidelines concerning statistical principles in clinical trials (1). An important element of biostatistical study design is sample size. The three studies that are described herein used an a-priori sample size estimation for the one-way layout that included controls and several treatment and dose groups. In these k-sample designs, with at least one control group, both the multiple comparison procedure and trend tests within procedures for identification of the minimal-effective dose are recommended. Although p-values in pharmacology are quite common, confidence intervals should be used according to their interpretation for both statistical significance and clinical relevance. The use of one-sided confidence intervals for both the difference and the ratio to control for proving either superiority or at least noninferiority is demonstrated by real data examples. Relevant and relatively straightforward software is available for biostatistical analysis and can also be used to aid design. In summary, referring to published, well-designed experimental studies can help to assist with ensuring the quality of future investigations.

The aquatic warbler, Acrocephalus paludicola, is one of a few species in which nestlings from a single nest can be sired by up to four different fathers. Data from a DNA fingerprinting study suggest that there is a trend: the larger the number of fathers in a brood the larger is the number of nestlings. However, the number of young within a single nest cannot be smaller than the number of fathers. This restriction causes an inherent trend and, consequently, can lead to a false-positive trend test result. For this nonstandard situation, we propose a trend test that differentiates between the inherent trend and a \"real\" trend, that is, a larger brood size through multiple paternity. Using DNA fingerprinting data, we performed a randomization test using the proposed new trend test statistic and obtained a significant result (P = 0.047). This indicates that a larger number of fathers per brood is associated with a larger brood size. In addition, we consider an umbrella alternative, that is, a downturn in effect may occur after the optimal number of fathers per brood is exceeded. An appropriate test for this alternative also leads to a significance (P = 0.011).

This article evaluates the impact of the ICH E9 guideline Statistical Principles for Clinical Trials on the conduct of clinical trials in Japan. In particular, the following Japanese practices in the conduct of clinical trials are discussed in detail from the ethical, statistical, and logical viewpoints: 1. Conducting only one phase 3 multicenter trial with many centers and few subjects per center; 2. Seeking to show noninferiority to an active control rather than superiority to placebo; and 3. Choosing a global assessment variable with a subjective component as the primary endpoint. The influence of public health insurance and the potential number of patients in Japan on various aspects of a trial are discussed. Problems requiring further research are mentioned and points requiring clarification are highlighted.

The comparison of increasing doses of a treatment to a negative control is frequently part of toxicological studies. For normally distributed data Williams (1971, 1972) introduced a maximum likelihood test under total order restriction. But until now there seems to have been no solution for the arbitrary unbalanced case. According to the idea proposed by Robertson et al. (1988) we will apply in this article the basic concept of Williams on the class of multiple contrast tests for the general unbalanced parametric set-up. Simulation results for size and power and two examples for estimating the minimal toxic dose (MTD) are given.[PUBLICATION ABSTRACT]

The objective of mutagenicity assays in regulatory toxicology is the decision on non-mutagenicity or mutagenicity. An inherent problem of statistical tests is the possibility of false decisions, i.e., a mutagenic substance will be falsely labeled as non-mutagenic or a non-mutagenic substance will be falsely labeled as mutagenic. These probabilities of false negative (consumer's risk=type II error) and/or false positive decision (producer's risk=type I error) can be limited by using suitable testing procedures as well as a design including an appropriate positive control. Using the proof of hazard concept the well-known many-to-one procedures with total order restriction for increasing effect differences are used, while using the proof of safety concept procedures on equivalence with total order restriction are discussed. Both approaches are demonstrated on a real data example.[PUBLICATION ABSTRACT]

In most real data situations in the one-way design both the underlying distribution and the shape of the dose-response curve are a priori unknown. The power of a trend test strongly depends on both. However, tests which are routinely used to analyze toxicological assays must be robust. We use nonparametric tests with different scores--powerful for different distributions--and different contrasts--powerful for different shapes--and use the maximum of all test statistics as a new test statistic. Simulation results indicate that this maximum test, which is a nonparametric multiple contrast test, stabilizes the power for various shapes and distributions. The investigated tests are applied to the data of a toxicological assay.[PUBLICATION ABSTRACT]