Proper metrics for clinical trials: transformations and other procedures to remove non-normality effects

A simulation study was performed to study the effects of non-normality and to examine procedures to ameliorate possible loss of power when data are incorrectly assumed to be normally distributed. It was found that only distributions with high asymmetry or heavy tails seriously affect the t-test. The Box-Cox likelihood ratio test appears to have some advantages over the others, but this must be offset by the greater complexity in making the results understandable to non-statisticians. The variability in outcomes with the different procedures demonstrates the importance of specifying such procedures a priori.     

A new test for supplier-inducement and application to the Canadian market for dental care

The hypothesis that dentists do not induce demand for their services is tested using reduced form estimates of the price elasticity of demand. If demand is autonomous, shifts in supply for whatever reason should generate equivalent estimates provided access costs change proportionately with shifts in supply. If demand inducement is present demand can appear to be very elastic, or very inelastic, depending on what is causing the shift in supply. Each of three applications of this test, conducted in the context of jointly estimated fee and quantity equations using annual Canadian data for 1956-1989, rejects the no inducement hypothesis.     

A preference-based measure for test performance with an application to prenatal diagnostics

Clinical epidemiology generally uses the receiver operating characteristic curve to summarize the accuracy of a diagnostic test and to compare the relative performance of different tests. This paper extends this concept to include the utility gains and losses of true and false test outcomes over the range of a priori risk. A utility index is developed first in situations where test accuracy is exogenously given, second where the test cutpoint can be chosen by the clinician according to the patient's a priori risk and preferences. By integrating over the a priori risk range, we derive an overall measure for a test's performance weighted by utility gains and losses. An example in prenatal diagnostics finally illustrates the clinical uses of the novel approach. Integrating patients' preference into clinical decision making will lead to different cutpoints and different assessments of test performance compared to unweighted policies.     

A Welch-type test for homogeneity of contrasts under heteroscedasticity with application to meta-analysis

A common problem that arises in the meta-analysis of several studies, each with independent treatment and control groups, is to test for the homogeneity of effect sizes without the assumptions of equal variances of the treatment and the control groups and of equal variances among the separate studies. A commonly used test statistic, frequently denoted as Q, is the weighted sum of squares of the differences of the individual effect sizes from the mean effect size, with weights inversely proportional to the variances of the effect sizes. The primary contributions of this article are the presentation of improved and very accurate approximations to the distributions of the Q statistic when the effect size is a linear contrast such as the difference between the treatment and control means. Our improved approximation to the distribution of Q under the null hypothesis is based on a multiple of an F-distribution; its use yields a substantial reduction in the type I error rate of the homogeneity test. Our improved approximation to the distribution of Q under an alternative hypothesis is based on a shift of a chi-square distribution; its use allows for much greater accuracy in the computation of the power of the homogeneity test. These two improved approximate distributions are developed using the Welch methodology of approximating the moments of Q by the use of multivariate Taylor expansions. The quality of these approximations is studied by simulation. A secondary contribution of this article is a study of how best to combine the variances of the treatment and control groups (needed for the calculation of weights in the Q statistic). Our conclusion, based on simulations, is that use of pooled variances can result in substantially erroneous conclusions.     

A test for differential ascertainment in case-control studies with application to child maltreatment

We propose a method to test for the presence of differential ascertainment in case-control studies, when data are collected by multiple sources. We show that, when differential ascertainment is present, the use of only the observed cases leads to severe bias in the computation of the odds ratio. We can alleviate the effect of such bias using the estimates that our method of testing for differential ascertainment naturally provides. We apply it to a dataset obtained from the National Violent Death Reporting System, with the goal of checking for the presence of differential ascertainment by race in the count of deaths caused by child maltreatment.     

Travel medicine consultation: An opportunity to improve coverage for routine vaccinations

BackgroundTravelers may be responsible for the spread of vaccine-preventable diseases upon return. Travel physicians and family physicians may play a role in checking and updating vaccinations before traveling. Our aim was to evaluate the vaccine coverage for mandatory and recommended vaccination in travelers attending a travel medicine clinic (TMC).MethodsVaccine coverage was measured using the current French immunization schedule as reference for correct immunization, in travelers providing a vaccination certificate during the TMC visit (university hospital of Saint-Étienne), between August 1, 2013 and July 31, 2014.ResultsIn total, 2336 travelers came to the TMC during the study period. Among the 2019 study participants, only 1216 (60.3%) provided a vaccination certificate. Travelers who provided a vaccination certificate were significantly younger than travelers who did not (mean age: 34.8 ± 17.8 vs. 46 ± 18.4 years, P < 0.005) and were less likely to be Hajj pilgrims. Vaccine coverage against Tetanus, Diphtheria, and Poliomyelitis (Td/IPV vaccine) was 91.8%, 78.6% against Measles, Mumps, and Rubella (MMR), and 59.4% against Viral Hepatitis B (HBV). BCG vaccine coverage was 71.9%. Older travelers were less likely to be correctly vaccinated, except against HBV as vaccinated travelers were significantly older than unvaccinated travelers.ConclusionObtaining information about immunization in travelers is difficult. Coverage for routine vaccines should be improved in this population. Travel medicine consultations could be the opportunity to vaccinate against MMR, HBV, and Td/IPV.     

Occupational medicine: a proposed systematic approach and model algorithm for the physician

Lack of adequate training in occupational medicine for medical students has resulted in physicians who are ill prepared to evaluate workers potentially or actually exposed to an ever-expanding list of hazardous occupational agents. A systematic approach is presented for the physician in his contact with workers exposed or potentially exposed to hazardous industrial agents. The algorithm includes consideration of the worker, his environment, and the hazardous agent(s). Useful references are cited, basic considerations of the occupational medicine approach to patient contacts are discussed, and pitfalls and limitations the physician may encounter are presented.     

An EM algorithm for nonparametric estimation of the cumulative incidence function from repeated imperfect test results

In screening and surveillance studies, event times are interval censored. Besides, screening tests are imperfect so that the interval at which an event takes place may be uncertain. We describe an expectation–maximization algorithm to find the nonparametric maximum likelihood estimator of the cumulative incidence function of an event based on screening test data. Our algorithm has a closed‐form solution for the combined expectation and maximization step and is computationally undemanding. A simulation study indicated that the bias of the estimator tends to zero for large sample size, and its mean squared error is in general lower than the mean squared error of the estimator that assumes the screening test is perfect. We apply the algorithm to follow‐up data from women treated for cervical precancer. Copyright © 2017 John Wiley & Sons, Ltd.     

New multivariate test for linkage,with application to pleiotropy: fuzzy Haseman-Elston

We propose a new method of linkage analysis based on using the grade of membership scores resulting from fuzzy clustering procedures to define new dependent variables for the various Haseman-Elston approaches. For a single continuous trait with low heritability, the aim was to identify subgroups such that the grade of membership scores to these subgroups would provide more information for linkage than the original trait. For a multivariate trait, the goal was to provide a means of data reduction and data mining. Simulation studies using continuous traits with relatively low heritability (H=0.1, 0.2, and 0.3) showed that the new approach does not enhance power for a single trait. However, for a multivariate continuous trait (with three components), it is more powerful than the principal component method and more powerful than the joint linkage test proposed by Mangin et al. ([1998] Biometrics 54:88-99) when there is pleiotropy.     

A sequential design for psychophysical experiments: An application to estimating timing of sensory events

An experimental subject sequentially receives different levels of a stimulus, and data are recorded on response or non-response to the stimulus. To ensure that the subject cannot predict the next stimulus level based on previous stimulus levels, a randomized design, based on a generalized Pólya urn model, is used to allocate the stimulus levels. The goal of the experiment is to elicit information efficiently about the relationship between stimulus level and response (either for an individual subject or a group of independent subjects), by estimating quantiles of the stimulus–response curve. Our design allocates stimulus levels unimodally and symmetrically around the unknown median of the stimulus–response curve. We discuss estimation under a broad family of distributions and also fully discuss design issues and options. This design was used for an experiment in neurophysiology in humans to estimate the timing of onset of kinesthetic stimuli. Such psychophysical studies can increase our understanding of normal and pathological function. We present data from that experiment. © 1997 John Wiley & Sons Ltd.     

A robust mean and variance test with application to high-dimensional phenotypes

European Journal of Epidemiology - Most studies of continuous health-related outcomes examine differences in mean levels (location) of the outcome by exposure. However, identifying effects on the...     

A robust goodness-of-fit test statistic with application to ordinal regression models

We propose a goodness-of-fit test statistic for linear regression with heterogeneous variance, which is asymptotically chi-square if the given model is correct. The test statistic is computed as a quadratic form of observed minus predicted responses. We apply the method to a linear regression for an ordinal categorical response, the wheezing status of a child (no wheeze, wheeze with cold, wheeze apart from cold) as a function of maternal smoking and city of residence.     

Estimation of k for the poly-k test with application to animal carcinogenicity studies

This paper extends the survival-adjusted Cochran-Armitage test in order to achieve improved robustness to a variety of tumour onset distributions. The Cochran-Armitage test is routinely applied for detecting a linear trend in the incidence of a tumour of interest across dose groups. To improve the robustness to the effects of differential mortality across groups, Bailer and Portier introduced the poly-3 test by a survival adjustment using a fractional weighting scheme for subjects not at full risk of tumour development. The performance of the poly-3 test depends on how closely it represents the correct specification of the time-at-risk weight in the data. Bailer and Portier further suggested that this test can be improved by using a general k reflecting the shape of the tumour onset distribution. In this paper, we propose a method to estimate k by equating the empirical lifetime tumour incidence rate obtained from the data based on the fractional weighting scheme to a separately estimated cumulative lifetime tumour incidence rate. This poly-k test with the statistically estimated k appears to perform better than the poly-3 test which is conducted without prior knowledge of the tumour onset distribution. Our simulation shows that the proposed method improves the robustness to various tumour onset distributions in addition to the robustness to the effects of mortality achieved by the poly-3 test. Large sample properties are shown via simulations to illustrate the consistency of the proposed method. The proposed methods are applied to analyse two real data sets. One is to find a dose-related linear trend on animal carcinogenicity, and the other is to test an effect of calorie restriction on experimental animals.     

Marker-dependent hazard estimation: An application to AIDS

The acquired immunodeficiency syndrome (AIDS) results from infection with the human immunodeficiency virus (HIV). The time of infection is generally unknown since transmission usually occurs during the course of repeated sexual contacts or needle sharing. Brookmeyer and Gail describe the biases that may arise in survival analyses using the recruitment time rather than the unknown infection time as the origin in prevalent cohorts of HIV-infected individuals. We apply a non-parametric hazard estimator, introduced by Nielsen, that assumes the hazard of an AIDS diagnosis depends upon the unknown time of infection solely through the value of possibly multidimensional markers of HIV-disease progression such as CD4⁺ T lymphocyte cell counts. Essentially, we estimate the hazard for a specific marker value y by dividing the number of occurrences among subjects with marker measurements in a neighbourhood of y by the total risk time in that neighbourhood. We present this estimator, which relies upon kernel estimator techniques to produce a smooth estimate, within a counting process framework. We apply this method to marker data from the San Francisco Men's Health Study.     

老年性痴呆治疗药物的临床应用（综述）

目的:评价老年痴呆病治疗的药物及临床疗效.方法:以老年痴呆的病理、生理变化为依据,采用乙酰胆碱酯酶 (ACh E) 抑制剂、神经细胞活化剂、神经细胞营养剂,进行临床疗效观察.结果: ACh E抑制剂是目前研究最多、应用最广泛的 一类药物.结论:继续寻找疗效高而副作用小、适合病人长期服用的药物已成为当务之急.