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Statistical methodologies in psychopharmacology: a review.

There has been a greatly increased interest in statistical methods in the psychiatric research and its applications over the past few decades, in parallel with advances in computers and statistical software. This review aims to describe the main topics related to statistical methods in psychopharmacology, namely nature of statistics in medicine, problems in data analysis, statistical modelling, developments in statistical technology, statistical reporting and meta-analysis.

Animals↗

An analysis of disease surveillance data that uses the geographic locations of the reporting units.

The primary purpose of a disease surveillance system is to provide data for the detection of changes in the incidence of the disease. Methods for the analysis of data from surveillance systems are reviewed. A new procedure is proposed for use when the system includes geographically dispersed reporting units, such as hospitals or administrative regions. The method is based on the cusum statistic, and combines information from different units according to their geographic relationships.

Data Interpretation, Statistical↗

PC program for simultaneously testing equality of means and variances for paired bivariate normal data.

A menu-driven PC program for simultaneously testing the equality of means and variances for paired bivariate normal data is described, illustrated and made available. While the corresponding tests for independent samples are well-known and widely implemented, in the paired situation only the test for no change in mean values (the paired t-test) has been similarly covered. Tests for no change in variability, while important, are less well-known and not implemented in most commercial statistical computing programs.

Analysis of Variance↗

What influences the choice of assessment methods in health technology assessments? Statistical analysis of international health technology assessments from 1989 to 2002.

OBJECTIVES: Health technology assessment (HTA) has been used as input in decision making worldwide for more than 25 years. However, no uniform definition of HTA or agreement on assessment methods exists, leaving open the question of what influences the choice of assessment methods in HTAs. The objective of this study is to analyze statistically a possible relationship between methods of assessment used in practical HTAs, type of assessed technology, type of assessors, and year of publication. METHODS: A sample of 433 HTAs published by eleven leading institutions or agencies in nine countries was reviewed and analyzed by multiple logistic regression. RESULTS: The study shows that outsourcing of HTA reports to external partners is associated with a higher likelihood of using assessment methods, such as meta-analysis, surveys, economic evaluations, and randomized controlled trials; and with a lower likelihood of using assessment methods, such as literature reviews and "other methods". The year of publication was statistically related to the inclusion of economic evaluations and shows a decreasing likelihood during the year span. The type of assessed technology was related to economic evaluations with a decreasing likelihood, to surveys, and to "other methods" with a decreasing likelihood when pharmaceuticals were the assessed type of technology. CONCLUSIONS: During the period from 1989 to 2002, no major developments in assessment methods used in practical HTAs were shown statistically in a sample of 433 HTAs worldwide. Outsourcing to external assessors has a statistically significant influence on choice of assessment methods.

Choice Behavior↗

Clinical and pharmacogenomic data mining: 1. Generalized theory of expected information and application to the development of tools.

New scientific problems, arising from the human genome project, are challenging the classical means of using statistics. Yet quantified knowledge in the form of rules and rule strengths based on real relationships in data, as opposed to expert opinion, is urgently required for researcher and physician decision support. The problem is that with many parameters, the space to be analyzed is highly dimensional. That is, the combinations of data to examine are subject to a combinatorial explosion as the number of possible events (entries, items, sub-records) (a),(b),(c),... per record (a,b,c,..) increases, and hence much of the space is sparsely populated. These combinatorial considerations are particularly problematic for identifying those associations called "Unicorn Events" which occur significantly less than expected to the extent that they are never seen to be counted. To cope with the combinatorial explosion, a novel numerical "book keeping" approach is taken to generate information terms relating to the combinatorial subsets of events (a,b,c,..), and, most importantly, the zeta (Zeta) function is employed. The incomplete Zeta function zeta(s,n) with s = 1, in which frequencies of occurrence such as n = n(a,b,c,...) determine the range of summation n, is argued to be the natural choice of information function. It emerges from Bayesian integration, taken over the distribution of possible values of information measures for sparse and ample data alike. Expected mutual information l(a;b;c) in nats (i.e., natural units analogous to bits but based on the natural logarithm), such as is available to the observer, is measured as e.g., the difference zeta(s,o(a,b,c..)) - zeta(s,e(a,b,c..)) where o(a,b,c,..) and e(a,b,c,..) are, or relate to, the observed and expected frequencies of occurrence, respectively. For real values of s > 1 the qualitative impact of strongly (positively or negatively) ranked data is preserved despite several numerical approximations. As real s increases, and the output of the information functions converge into three values +1, 0, and -1 nats representing a trinary logic system. For quantitative data, a useful ad hoc method, to report sigma-normalized covariations in an analogous manner to mutual information for significance comparison purposes, is demonstrated. Finally, the potential ability to make use of mutual information in a complex biomedical study, and to include Bayesian prior information derived from statistical, tabular, anecdotal, and expert opinion is briefly illustrated.

Clinical Trials as Topic↗

The agreement between two diagnostic methods in binary cases: a proposal.

This report can be considered as a resource in the analysis of agreement among raters, clinical tests, observers, judges or experts. The focus is on diagnostic methods. When the true results of diagnostic methods cannot be obtained, studying the agreement between them can reflect the difference between methods. Normal statistical procedures tackling this are not enough for deciding about the agreement from a clinical point of view. The clinical question is whether the new method agrees sufficiently with the old one. In binary cases, a solution for deciding about the agreement from a clinical viewpoint is introduced. The overall agreement is a duality and needs to be studied in two steps. In the first step, a condition for accepting the agreement is proposed: both methods need to have the same nosologic sensitivity and specificity. In the second step, another condition is proposed: the level of the agreement should be greater than a critical value, defined by the clinicians. When both steps show satisfactory results, the new method can replace the old one. The statistical procedures for testing both steps are presented.

Clinical Laboratory Techniques↗

Chapter 18: Statistical issues in the design and analysis of studies of human papillomavirus and cervical neoplasia.

Appropriately sophisticated statistical approaches are crucial for addressing the increasingly complex set of critical questions that follow from the recognition that human papillomavirus (HPV) is a necessary causal factor for cervical cancer. Cervical cancer researchers have defined the major stages of cervical carcinogenesis, with HPV infection as the necessary cause. Focus of etiologic studies is shifting from establishing causality to determining risk factors for HPV persistence and neoplastic progression using serially collected biomarkers. Prevention-oriented epidemiology and trials of new screening strategies and vaccines will rely on surrogate endpoints because we cannot let women develop cancer when it can be prevented. Future epidemiologic and prevention studies of HPV infection and cervical carcinogenesis will exploit subtle pathologic distinctions and will employ improved measurements of complex molecular biologic phenomena. The anticipated statistical issues are highlighted in this discussion.

Case-Control Studies↗

Spatial statistical methods in health.

The study of the geographical distribution of disease incidence and its relationship to potential risk factors (referred to here as "geographical epidemiology") has provided, and continues to provide, rich ground for the application and development of statistical methods and models. In recent years increasingly powerful and versatile statistical tools have been developed in this application area. This paper discusses the general classes of problem in geographical epidemiology and reviews the key statistical methods now being employed in each of the application areas identified. The paper does not attempt to exhaustively cover all possible methods and models, but extensive references are provided to further details and to additional approaches. The overall aim is to provide a picture of the "current state of the art" in the use of spatial statistical methods in epidemiological and public health research. Following the review of methods, the main software environments which are available to implement such methods are discussed. The paper concludes with some brief general reflections on the epidemiological and public health implications of the use of spatial statistical methods in health and on associated benefits and problems.

Cluster Analysis↗

Replication, variation and normalisation in microarray experiments.

INTRODUCTION: Microarray experiments often have complex designs that include sample pooling, biological and technical replication, sample pairing and dye-swapping. This article demonstrates how statistical modelling can illuminate issues in the design and analysis of microarray experiments, and this information can then be used to plan effective studies. METHODS: A very detailed statistical model for microarray data is introduced, to show the possible sources of variation that are present in even the simplest microarray experiments. Based on this model, the efficacy of common experimental designs, normalisation methodologies and analyses is determined. RESULTS: When the cost of the arrays is high compared with the cost of samples, sample pooling and spot replication are shown to be efficient variance reduction methods, whereas technical replication of whole arrays is demonstrated to be very inefficient. Dye-swap designs can use biological replicates rather than technical replicates to improve efficiency and simplify analysis. When the cost of samples is high and technical variation is a major portion of the error, technical replication can be cost effective. Normalisation by centreing on a small number of spots may reduce array effects, but can introduce considerable variation in the results. Centreing using the bulk of spots on the array is less variable. Similarly, normalisation methods based on regression methods can introduce variability. Except for normalisation methods based on spiking controls, all normalisation requires that most genes do not differentially express. Methods based on spatial location and/or intensity also require that the nondifferentially expressing genes are at random with respect to location and intensity. Spotting designs should be carefully done so that spot replicates are widely spaced on the array, and genes with similar expression patterns are not clustered. DISCUSSION: The tools for statistical design of experiments can be applied to microarray experiments to improve both efficiency and validity of the studies. Given the high cost of microarray experiments, the benefits of statistical input prior to running the experiment cannot be over-emphasised.

Algorithms↗

Understanding Rasch measurement: estimation methods for Rasch measures.

Rasch parameter estimation methods can be classified as non-interative and iterative. Non-iterative methods include the normal approximation algorithm (PROX) for complete dichotomous data. Iterative methods fall into 3 types. Datum-by-datum methods include Gaussian least-squares, minimum chi-square, and the pairwise (PAIR) method. Marginal methods without distributional assumptions include conditional maximum-likelihood estimation (CMLE), joint maximum-likelihood estimation (JMLE) and log-linear approaches. Marginal methods with distributional assumptions include marginal maximum-likelihood estimation (MMLE) and the normal approximation algorithm (PROX) for missing data. Estimates from all methods are characterized by standard errors and quality-control fit statistics. Standard errors can be local (defined relative to the measure of a particular item) or general (defined relative to the abstract origin of the scale). They can also be ideal (as though the data fit the model) or inflated by the misfit to the model present in the data. Five computer programs, implementing different estimation methods, produce statistically equivalent estimates. Nevertheless, comparing estimates from different programs requires care.

Algorithms↗

[An observational study requires careful consideration by the reader].

The observational study has its merits when randomized controlled studies are impossible to perform. This review discusses its merits and weaknesses for a reader of such studies. The reader has to consider the internal and external validity of the study and its role in the establishment of causal relationships and estimations of risks. The reader is recommended to primarily evaluate the quality of study design, confounding and measurement bias, rather than to try to understand if an advanced statistical analysis is correct. The possibilities of misleading results are discussed.

Bias↗

Using Six Sigma to make a difference in health care quality.

For years, the health care industry has borrowed ideas and initiatives from other industries to promote and enhance quality. The most recent idea to capture the interest of many in the health care field has been Six Sigma, which has been used and refined during the past two decades by top corporations. This issue looks at how five organizations are using the Six Sigma management process--with its reliance on data, statistical analysis, and change--to enhance quality.

Benchmarking↗

Trends in waiting time to date and total time waited: are the sources compatible?

Department of Health Waiting List returns routinely measure the number of patients waiting for elective NHS admitted patient care on a given day, grouped by long they have been waiting to date. The trend in the average waiting time estimated from this istribution is different from the trend in the average total time waited by patients admitted over a period of time, calculated from Hospital Episodes Statistics. This article investigates whether the results from the two sources are consistent.

Data Interpretation, Statistical↗

The relationship of the intensity of lens opacity with physical activity.

OBJECTIVE: To study the character and the intensity of lens opacity and the visual acuity in cataract patients and controls and to determine the association of these indices with the subjects' physical activity. MATERIAL AND METHODS: The lens opacity in 110 eyes of patients (n=110) aged 60.3+/-0.4 (mean+/-SEM) years admitted to the Clinic of Eye Diseases of Kaunas University of Medicine Hospital for cataract surgery and the lens opacity of 100 eyes of controls (n=50) aged 59.8+/-0.4 (mean+/-SEM) (p>0.05) years hospitalized in the Clinic of Skin and Venereal Diseases was evaluated according to the Lens Opacity Classification System, version III. Visual acuity was investigated using the Snellen chart. Physical activity in metabolic equivalent minutes per week (MET-minutes/week) was evaluated according to the International Physical Activity Questionnaire. RESULTS: The means of the intensity of lens opacity of patients with cataract were significantly higher, and the means of visual acuity and physical activity were significantly lower, compared to controls (p<0.01-0.001). For less active patients (<5900 MET-minutes/week) with the right eye examined, the odds ratio of cataract was by 7.00 (95% confidence interval 2.93-16.74, p<0.001) and for those with the left eye studied by 4.43 (95% confidence interval 1.97-9.98, p<0.001) times higher, compared to physically active (>5900 MET-minutes/week) patients. Physical activity was inversely correlated (r=-0.452, p<0.05) with the lens opacity in the cortex in physically active (>5900 MET-minutes/week) subjects with cataract who underwent the examination of the left eye. CONCLUSION: The intensity of lens opacity and cataract are statistically significantly related to physical activity.

Cataract↗

Sub clinical infection and the relative risk of developing leprosy: a statistical approach.

Subclinical infection in contacts of leprosy patients was identified by FLA-ABS test and Serum Antibody Competition Test (SACT). The risk of developing leprosy and the confidence intervals were worked out. The importance of expressing the risk ratio and confidence interval of the tests is brought out. This method is a useful adjunct to the routine statistical methods in epidemiological studies.

Antibodies, Monoclonal↗

Reading research critically: statistical significance.

Statistical significance pertains to the probability that a finding of difference between two groups in a study has occurred by chance. Unfortunately, statistical significance often is confused with significance. This article discusses the meaning of statistical significance, how it differs from significance, and when it can be misleading.

Data Interpretation, Statistical↗

[Evaluating correctly the validity of a rating scale: the numerous pitfalls to avoid].

The validity is the most important quality of a rating scale, but unfortunately it is very badly evaluated in practice. The different facets of the concept: content, criterion, construct, face validity are thoroughly studied. Each facet is accurately defined and the experimental and statistical methods used are explained in detail. Finally practical recommendations are given.

Bias↗