Chihiro Hirotsu

A contribution to genome-wide association studies: search for susceptibility loci for schizophrenia using DNA microsatellite markers on chromosomes 19, 20, 21 and 22.

&NA; As an initial step for genome‐wide association studies, we sought an association between schizophrenia and 34 microsatellite markers on chromosomes 19, 20, 21 and 22 by a case‐control design. The samples examined for an association were 168 schizophrenic patients and 146 control subjects in the Japanese population. The allele distribution of the 34 loci differed significantly between Japanese and French populations. Significant deviation from the Hardy‐Weinberg equilibrium was observed at D19S209 and D21S1256 in the control subjects. Case‐control comparisons of the initial screening revealed a significant difference in allele frequency at D20S95 and a trend of difference at D20S118. To confirm these possible associations, additional samples consisting of 110 schizophrenic patients and 116 control subjects were examined, and an association between D20S95 and schizophrenia was confirmed (corrected P value after Bonferroni correction, 0.00035). D20S95 is located close to the gene (CHGB) encoding chromogranin B. These findings suggest that CHGB could be an important candidate gene involved in the development of schizophrenia.

An approach to defining the pattern of interaction effects in a two-way layout

SummaryA method is given to classify rows and columns into subgroups so that additivity holds within each of the subtables made of the grouped rows or the grouped columns. The least squares estimators of the cell means are easily obtained for the resulting linear model together with their variances. An estimator of the error varianceσ2 is given when there is only one observation per cell. A treatment of an ordered table is also given.

Simultaneous confidence intervals based on one-sided max t test

Simultaneous lower bounds (SLB) for the isotonic contrasts in normal means are obtained. In particular a SLB for the range is given. These SLBs are obtained from the one-sided max t test. It is then generalized to obtain simultaneous upper bounds for the responses at lower levels. Under the assumption of the convexity of the response curve at lower levels the upper bounds are further improved. The method compares very well with other available methods numerically as well as in real examples.

Changepoint Analysis as a Method for Isotonic Inference

Concavity and sigmoidicity hypotheses are developed as a natural extension of the simple ordered hypothesis in normal means. Those hypotheses give reasonable shape constraints for obtaining a smooth response curve in the non-parametric input-output analysis. The slope change and inflection point models are introduced correspondingly as the corners of the polyhedral cones defined by those isotonic hypotheses. Then a maximal contrast type test is derived systematically as the likelihood ratio test for each of those changepoint hypotheses. The test is also justified for the original isotonic hypothesis by a complete class lemma. The component variables of the resulting test statistic have second or third order Markov property which, together with an appropriate non- linear transformation, leads to an exact and very efficient algorithm for the probability calculation. Some considerations on the power of the test are given showing this to be a very promising way of approaching to the isotonic inference.

Beyond analysis of variance techniques : Some applications in clinical trials

Clinical trials often have special features that require other methods of analysis besides the usual analysis of variance techniques. For example, data are usually not normally distributed and frequently are in the form of rank data or ordered categorical data. The cumulative chi-squared statistic and its maximal component are proposed as nonparametric tests for analyzing such data. They offer not only robustness of validity but also that of efficiency. These two statistics are useful generally for modelling and analyzing data in situations where there is an ordering in the parameters. The cumulative chi-squared statistic is applied to the profile analysis of repeated measures that require taking the natural ordering along the time axis into account. The maximal component statistic is applied to a dose finding experiment where a particular multiple comparison procedure is required for ordered parameters corresponding to dose levels. Other problems addressed in the paper include various kinds of multiplicity problems and the proving equivalence of a test drug to the standard which require a quite different approach from the usual significance tests.

Clustering rows and/or columns of a two-way contingency table and a related distribution theory

The row-wise multiple comparison procedure proposed in Hirotsu [Hirotsu, C., 1977. Multiple comparisons and clustering rows in a contingency table. Quality 7, 27-33 (in Japanese); Hirotsu, C., 1983. Defining the pattern of association in two-way contingency tables. Biometrika 70, 579-589] has been verified to be useful for clustering rows and/or columns of a contingency table in several applications. Although the method improved the preceding work there was still a gap between the squared distance between the two clusters of rows and the largest root of a Wishart matrix as a reference statistic for evaluating the significance of the clustering. In this paper we extend the squared distance to a generalized squared distance among any number of rows or clusters of rows and dissolves the loss of power in the process of the clustering procedure. If there is a natural ordering in columns we define an order sensitive squared distance and then the reference distribution becomes that of the largest root of a non-orthogonal Wishart matrix, which is very difficult to handle. We therefore propose a very nice @g^2-approximation which improves the usual normal approximation in Anderson [Anderson, T.W., 2003. An Introduction to Multivariate Statistical Analysis. 3rd ed. Wiley Intersciences, New York] and also the first @g^2-approximation introduced in Hirotsu [Hirotsu, C., 1991. An approach to comparing treatments based on repeated measures. Biometrika 75, 583-594]. A two-way table reported by Guttman [Guttman, L., 1971. Measurement as structural theory. Psychometrika 36, 329-347] and analyzed by Greenacre [Greenacre, M.J., 1988. Clustering the rows and columns of a contingency table. Journal of Classification 5, 39-51] is reanalyzed and a very nice interpretation of the data has been obtained.

Impact of the ICH E9 Guideline Statistical Principles for Clinical Trials on the Conduct of Clinical Trials in Japan

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.

Estimating the Dose-Response Pattern by the Maximal Contrast Type Test Approach

In a phase II clinical trial it is simultaneously required to prove a drug is truly effective by showing a monotone dose-response relationship and also to obtain information on the recommended dose for the ordinary clinical treatments. Then the multiple comparisons of the interested dose-response patterns are more preferable than an overall testing of the null hypothesis or a fitting of a particular parametric model. In this article the maximal accumulated t statistic (max acc. t-test) proposed for the monotone hypothesis testing is compared with other maximal contrast type tests and shown to be useful also for estimating the dose-response pattern. It is even remarkable that the effect of adding other monotone contrasts to the basic contrasts of max acc. t is so small. The simultaneous lower bounds obtained by the inversion of max acc. t is also shown to be useful for this purpose and has some advantage in giving the lower confidence bound for the mean difference of the estimated optimal dose against the basic dose level. In particular a new formula is obtained in this article for extending the basic lower bounds of max acc. t to all the monotone contrasts by the unique and positive linear combination.

A class of estimable contrasts in an age-period-cohort model

A class of estimable contrasts is defined for cohort effects in an age-period-cohort model. It is useful for detecting a systematic change in cohort effects without suffering from a short term deviation. This together with the follow-up analysis of residuals will give a good insight into the data. Numerical examples are given to illustrate how the method applies.

A unifying approach to the shape and change-point hypotheses in the discrete univariate exponential family

A unifying approach to the shape and change-point hypotheses is extended generally to a discrete univariate exponential family. The maximal contrast type tests are newly proposed for the convexity and sigmoidicity hypotheses based on the complete class lemma of tests for the restricted alternatives. Those tests are also efficient score tests for the slope change-point and inflection point models, respectively. For each of those tests the successive component statistics are the doubly- and triply-accumulated statistics. They have nice Markov properties for the exact and efficient recursion formulae for calculating the p -value. Further the sum of squares of the component statistics are developed as the cumulative chi-squared statistics for the directional goodness-of-fit tests of the dose-response model. Therefore the interesting applications will be in monitoring of spontaneous reporting of the adverse drug events and the directional goodness-of-fit tests.