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Finding the truth: a guide to interpreting HIV clinical trials.

The complex social, epidemiologic, and pathologic aspects of HIV disease, the variation in the nature of the disease from person to person, and the constantly changing roster of available treatments create intense and often contradictory concerns. Clinical trials are rarely interested only in the study patients, but are designed to enable us to make inferences about a general HIV-infected population. To do this most effectively, we must confirm the internal and external validity of the study. Statistics enable us to generalize from a particular study to the broader population, but the statistical problems arising from AIDS clinical trials are unique and complex.

Bias↗

Statistical issues in tumor marker studies.

CONTEXT: Inferences from tumor marker studies are complicated by a variety of statistical concerns, which can make proper interpretation of results difficult. This article focuses on important issues that should be addressed when designing, conducting, and analyzing tumor marker studies. OBJECTIVE: To highlight the importance of considering statistical significance, risk ratios, statistical power, reproducibility, multiple testing, confirmatory studies, and missing data in the design of marker studies used for prognosis. RESULTS: Suggestions are provided for more effectively conducting marker studies. These include more careful attention to adequacy of the number of subjects for a marker study and improved documentation and standardization of assay methods. The importance of complete reporting of study results and description of the statistical analysis methods used is also emphasized. CONCLUSION: Cooperation among clinicians, laboratory scientists, and statisticians will be required to conduct statistically sound tumor marker studies and to facilitate prioritizing markers for new and confirmatory studies in an environment of limited patient and specimen resources.

Biomarkers, Tumor↗

A sequential approach to testing with the rodent bone marrow micronucleus assay--obviation of the need for statistical analyses of data.

The 'sequential' protocol we use for the conduct of mouse bone marrow micronucleus assays is described. The most important criterion for activity in the assay is the reproducibility of any induced effects. The frequencies of micronucleated polychromatic erythrocytes among 239 male CBA control mice are displayed and discussed. Our decision to avoid statistical analysis when assessing mouse bone marrow micronucleus data is explained.

Animals↗

Interpreting statistics in the urological literature.

PURPOSE: Knowledge of statistical terminology and the ability to critically interpret research findings are critical skills in the practice of evidence based medicine. MATERIALS AND METHODS: We provide a series of nontechnical explanations of basic statistical concepts commonly encountered in the urological literature. In addition, we provide examples of common statistical pitfalls to increase awareness of limitations to consider when applying research findings to practice. RESULTS: Statistical goals encountered in the urological literature can be broadly categorized as summarizing outcome variables, comparing 2 or more groups, measuring association among variables or predicting 1 variable from another. Errors frequently include the use of an inappropriate test for the data type of interest or using statistical testing in a manner that increases the likelihood of false-positive results. Such errors pose a threat to the validity of research findings and they may undermine study conclusions. CONCLUSIONS: Editors and reviewers alike should strive for high standards of statistical analysis and reporting, and promote the publication of high quality evidence in the urological literature. The understanding of basic statistical concepts and the principles of the hypothesis testing framework is essential to the critical appraisal process and, therefore, important to all urologists. Statistical literacy should be fostered through educational materials and courses in the urological community.

Data Interpretation, Statistical↗

VAMPIRE microarray suite: a web-based platform for the interpretation of gene expression data.

Microarrays are invaluable high-throughput tools used to snapshot the gene expression profiles of cells and tissues. Among the most basic and fundamental questions asked of microarray data is whether individual genes are significantly activated or repressed by a particular stimulus. We have previously presented two Bayesian statistical methods for this level of analysis, collectively known as variance-modeled posterior inference with regional exponentials (VAMPIRE). These methods each require a sophisticated modeling step followed by integration of a posterior probability density. We present here a publicly available, web-based platform that allows users to easily load data, associate related samples and identify differentially expressed features using the VAMPIRE statistical framework. In addition, this suite of tools seamlessly integrates a novel gene annotation tool, known as GOby, which identifies statistically overrepresented gene groups. Unlike other tools in this genre, GOby can localize enrichment while respecting the hierarchical structure of annotation systems like Gene Ontology (GO). By identifying statistically significant enrichment of GO terms, Kyoto Encyclopedia of Genes and Genomes pathways, and TRANSFAC transcription factor binding sites, users can gain substantial insight into the physiological significance of sets of differentially expressed genes. The VAMPIRE microarray suite can be accessed at http://genome.ucsd.edu/microarray.

Bayes Theorem↗

Statistical modeling of sequencing errors in SAGE libraries.

MOTIVATION: Sequencing errors may bias the gene expression measurements made by Serial Analysis of Gene Expression (SAGE). They may introduce non-existent tags at low abundance and decrease the real abundance of other tags. These effects are increased in the longer tags generated in LongSAGE libraries. Current sequencing technology generates quite accurate estimates of sequencing error rates. Here we make use of the sequence neighborhood of SAGE tags and error estimates from the base-calling software to correct for such errors. RESULTS: We introduce a statistical model for the propagation of sequencing errors in SAGE and suggest an Expectation-Maximization (EM) algorithm to correct for them given observed sequences in a library and base-calling error estimates. We tested our method using simulated and experimental SAGE libraries. When comparing SAGE libraries, we found that sequencing errors can introduce considerable bias. High abundance tags may be falsely called as significantly differentially expressed, especially when comparing libraries with different levels of sequencing errors and/or of different size. Truly, differentially expressed tags have decreased significance as 'true'-tag counts are generally underestimated. This may alter if tags near the threshold of differential expression are called significant. Moreover, the number of different transcripts present in a library is overestimated as false tags are introduced at low abundance. Our correction method adjusts the tag counts to be closer to the true counts and is able to partly correct for biases introduced by sequencing errors. AVAILABILITY: An implementation using R is distributed as an R package. An online version is available at http://tagcalling.mbgproject.org

Algorithms↗

Can the famous really postpone death?

David P. Phillips has reported evidence that famous people are often able to postpone their deaths until after a birthday. A reexamination of Phillips' data shows some aspects of his analysis to be questionable, including the lumping together of deaths that occur during the birthmonth, which does not distinguish deaths that occurred before the birthday from those that occurred afterward. A reanalysis of his data shows that there were actually a relatively large number of deaths in the month preceding and the months following the birthday. One explanation is that the anxiety associated with this milestone and the excesses associated with its celebration are sometimes fatal. Another explanation is that Phillips' results were a fluke created by a selective use of data.

Anxiety↗

Object-oriented data handler for sequence analysis software development.

We report an object-oriented data handler and supplementary tools for the development of molecular genetics application software for various sequence analyses. Our data handler has a flexible and expandable format that supports the most common data types for molecular genetic software. New data types can be constructed in an object-oriented manner from the basic units. The data handler includes an object library, a format-converting program and a viewer that can visualize simultaneously the data contained in several files to construct a general picture from separate data. This software has been implemented on an IBM PC-compatible personal computer.

Atrial Natriuretic Factor↗

Rules for collection of clinical data: the eight Rs.

Many reports in medical journals give advice on statistical analysis of data collected in clinical studies. The terms used are statistical, and clinicians often ponder how their data stand up to these analyses. Eight simple, easy to remember words are suggested that will help clinicians both to interpret their own data and to assess the accuracy of presented or published data.

Data Collection↗

Effects of an endothelin receptor antagonist in rats with cyclosporine-induced hypertension.

Cyclosporine, a potent immunosuppressant, is associated with the development of hypertension and nephrotoxicity. We have previously shown that endothelin release from the arteries is increased in rats with cyclosporine-induced hypertension. We conducted the present study to determine whether the specific endothelin type A (ETA) receptor antagonist FR 139317 prevents cyclosporine-induced hypertension and whether cyclosporine increases ETA receptor mRNA in blood vessels. Cyclosporine (25 mg/kg per day) given for 4 weeks increased blood pressure from 98 +/- 12 to 156 +/- 14 mm Hg; this increase was blunted by coadministration of 10 mg/kg per day FR 139317 (ie, blood pressure was 138 +/- 14 mm Hg) in Wistar-Kyoto rats. Cyclosporine induced greater vasoconstrictor responses to norepinephrine and angiotensin II in isolated mesenteric arteries. FR 139317 normalized the vasoconstrictor responses to angiotensin II and norepinephrine. Cyclosporine (25 mg/kg per day) given for 4 weeks increased ETA receptor mRNA expression in the rat aorta and mesenteric artery (170% and 176%, respectively). Little change was observed in ETB receptor mRNA. These results indicate that cyclosporine may increase blood pressure by increasing not only endothelin production but also ETA receptor in the vasculature. The specific ETA receptor antagonist FR 139317 may prevent the hypertension induced by cyclosporine.

Angiotensin II↗

Detailed protein sequence alignment based on Spectral Similarity Score (SSS).

BACKGROUND: The chemical property and biological function of a protein is a direct consequence of its primary structure. Several algorithms have been developed which determine alignment and similarity of primary protein sequences. However, character based similarity cannot provide insight into the structural aspects of a protein. We present a method based on spectral similarity to compare subsequences of amino acids that behave similarly but are not aligned well by considering amino acids as mere characters. This approach finds a similarity score between sequences based on any given attribute, like hydrophobicity of amino acids, on the basis of spectral information after partial conversion to the frequency domain. RESULTS: Distance matrices of various branches of the human kinome, that is the full complement of human kinases, were developed that matched the phylogenetic tree of the human kinome establishing the efficacy of the global alignment of the algorithm. PKCd and PKCe kinases share close biological properties and structural similarities but do not give high scores with character based alignments. Detailed comparison established close similarities between subsequences that do not have any significant character identity. We compared their known 3D structures to establish that the algorithm is able to pick subsequences that are not considered similar by character based matching algorithms but share structural similarities. Similarly many subsequences with low character identity were picked between xyna-theau and xyna-clotm F/10 xylanases. Comparison of 3D structures of the subsequences confirmed the claim of similarity in structure. CONCLUSION: An algorithm is developed which is inspired by successful application of spectral similarity applied to music sequences. The method captures subsequences that do not align by traditional character based alignment tools but give rise to similar secondary and tertiary structures. The Spectral Similarity Score (SSS) is an extension to the conventional similarity methods and results indicate that it holds a strong potential for analysis of various biological sequences and structural variations in proteins.

Algorithms↗

Matched case-control data analysis with selection bias.

Case-control studies offer a rapid and efficient way to evaluate hypotheses. On the other hand, proper selection of the controls is challenging, and the potential for selection bias is a major weakness. Valid inferences about parameters of interest cannot be drawn if selection bias exists. Furthermore, the selection bias is difficult to evaluate. Even in situations where selection bias can be estimated, few methods are available. In the matched case-control Northern Manhattan Stroke Study (NOMASS), stroke-free controls are sampled in two stages. First, a telephone survey ascertains demographic and exposure status from a large random sample. Then, in an in-person interview, detailed information is collected for the selected controls to be used in a matched case-control study. The telephone survey data provides information about the selection probability and the potential selection bias. In this article, we propose bias-corrected estimators in a case-control study using a joint estimating equation approach. The proposed bias-corrected estimate and its standard error can be easily obtained by standard statistical software.

Bias↗

Complex sampling designs and statistical issues in secondary analysis.

Conducting secondary analysis using large national survey data sets to answer pressing research questions is gaining acceptance in the nursing science community. There are, however, challenges confronted by researchers who wish to apply secondary analysis to large data sets due to the incorporation of complex sampling designs. This article presents sampling design issues inherent in many large national surveys and explains the rationale for applying sample and variance estimation weights when conducting statistical analyses. In addition, the rationale for using statistical software packages capable of analyzing data derived from complex sampling designs is described. Examples of differences in statistical outcomes with and without weights using Stata and SPSS are provided using data from the Medical Expenditure Panel Survey (MEPS). Based on the example analyses, the implications of the statistical outcome differences for study findings are discussed.

Data Collection↗

Q-factor analysis as a tool for phylogenetic studies of morphometric data.

The statistical procedure of Q-factor analysis was applied with the aim to detect complex morphological characters, which clearly separate taxonomic groups. Since Q-factor analysis, unlike cluster analysis, does not prescribe a hierarchical grouping, the results can be interpreted phylogenetically using an outgroup comparison. The essential steps of the approach are demonstrated by an empirical study on the phylogeny of Callitrichinae. Except for some complications concerning the determination of the number of relevant factors and factor rotation, the procedure proved to be a suitable instrument for phylogenetic research.

Animals↗

Interpretation of bone densitometry studies.

Dual-energy x-ray absorptiometry (DXA) is widely used for identifying patients with osteoporosis, making decisions about the commencement of preventive therapy, and following up response to treatment. It is important that radiologists and nuclear medicine physicians issuing clinical reports present clear interpretations that aid the primary care physician in making decisions affecting treatment. This review discusses the principles behind the interpretation of bone mineral density (BMD) studies. After a World Health Organization report published in 1994, osteoporosis is often diagnosed on the basis of the patient's T-score value (difference of BMD from young adult mean normalized to the population SD). T-scores are a measure of current fracture risk. There are problems relating to the use of T-scores in the elderly, and we argue that decisions about treatment are generally best made on the basis of the Z-score value (difference of BMD from age-matched mean normalized to the population SD) because this measures the patient's fracture risk relative to his or her peers. Recent studies confirm that the posteroanterior (PA) projection lumbar spine scan is still the optimum measurement site for monitoring response to treatment. A BMD change of 4.5% is required to register a statistically significant change.

Absorptiometry, Photon↗