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PubMed1999

Inferring causality from relational data and designs: historical and contemporary lessons for research and clinical practice.

My address to you today is born of frustration with the growing claims, evident in the research literature and in clinical reports that happen to cross my desk, of causation made on the basis of correlational data. I recall, as a sophomore in college, being taught early in my first experimental psychology course, "you cannot infer causality from correlation." This point was made adamant in my first face-to-face critique of an experimental psychology research paper by Dr. Robert T. Brown, who pointed out, in lowering my grade, that I had inferred organic causes to behavior patterns in gerbils based solely on correlational data. This caution was reiterated in my statistics courses until it must have been indelibly stamped upon my then still somewhat plastic brain.

Analysis of Variance↗

PubMed2000

Recombinational and mutational hotspots within the human lipoprotein lipase gene.

Here an analysis is presented of the roles of recombination and mutation in shaping previously determined haplotype variation in 9.7 kb of genomic DNA sequence from the human lipoprotein lipase gene (LPL), scored in 71 individuals from three populations: 24 African Americans, 24 Finns, and 23 non-Hispanic whites. Recombination and gene-conversion events inferred from data on 88 haplotypes that were defined by 69 variable sites were tested. The analysis revealed 29 statistically significant recombination events and one gene-conversion event. The recombination events were concentrated in a 1.9-kb region, near the middle of the segment, that contains a microsatellite and a pair of tandem and complementary mononucleotide runs; both the microsatellite and the runs show length variation. An analysis of site variation revealed that 9.6% of the nucleotides at CpG sites were variable, as were 3% of the nucleotides found in mononucleotide runs of >/=5 nucleotides, 3% of the nucleotides found </=3 bp from certain putative polymerase alpha-arrest sites, and 0. 5% of the remaining nucleotides. This nonhomogeneous distribution of variation suggests that multiple mutational hits at certain sites are common, an observation that challenges the fundamental assumption of the infinite-sites-mutation model. The nonrandom patterns of recombination and mutation suggest that randomly chosen single-nucleotide polymorphisms may not be optimal for disequilibrium mapping of this gene. Overall, these results indicate that both recombinational and mutational hotspots have played significant roles in shaping the haplotype variation at the LPL locus.

Black People↗

PubMed2003

Healthy life expectancy: comparison of OECD countries in 2001.

OBJECTIVES: To compare average levels of population health for Australia and other OECD countries in 2001. METHODS: Healthy life expectancies (HALE) for OECD countries for 2001 are based on analysis of mortality data for OECD countries, country-specific estimates of health state prevalences for 135 causes from the Global Burden of Disease 2000 study, and an analysis of 34 health surveys in 28 OECD countries, using novel methods to improve the comparability of self-report data. RESULTS: HALE at birth ranges from a low of 59.8 years for Turkey to a high of 73.6 years in Japan in 2001. Australia ranks fourth among OECD countries at 71.6 years with a 95% uncertainty interval of 70.9 to 72.8 years, ahead of New Zealand in 13th place at 70.3 years. The equivalent 'lost' healthy years at birth range from around 10 years in OECD countries with lowest life expectancies to around eight years in those with high life expectancies at birth. There is a statistically significant association between higher levels of health expenditure and higher healthy life expectancy across OECD countries, although causal inferences require more sophisticated analyses of the health system and non-health system determinants of levels of health. CONCLUSIONS: The new methods used in the WHO Multi-Country Household Survey Study have increased the comparability of self-report data across OECD countries, a major step forward in the use of self-reported data on health. Building on this experience, WHO is developing improved health status measurement techniques for a World Health Survey to be carried out in 2002/03.

Aged↗

PubMed1983

Classification and diagnosis of depression.

There is no general consensus how to classify and diagnose depressive disorders. The main reason is disagreement regarding etiology. This is reflected in the several theoretical models of depression which has been proposed. On the other hand, a reliable way of characterizing groups of patients that can be used by both clinicians and researchers, is necessary both for communication and progress of research. Facing this situation, the inclusion of etiological theories in classification of depression obviously would be an obstacle to the use of such a classification system by clinicians of various theoretical orientation at current. Thus, a classification system which describes the clinical features of the mental disorders comprehensively and at the lowest order of inference necessary to identify the disorder in a reliable way is needed. The third edition of the Diagnostic and Statistical Manual of Mental Disorder (DSM-III) represents such a classification system. By providing operational diagnostic criteria for each diagnosis, DSM-III represents a major achievement of classification in clinical psychiatry and research. This paper will present the classification of depression and the problem of differential diagnosis as outlined in DSM-III. Further, the validity of the DSM-III classification of depression will be discussed with reference to some recent research findings on biopsychosocial and treatment aspects of depressive disorders.

Adjustment Disorders↗

PubMed2004

Practical introduction to record linkage for injury research.

The frequency of early fatality and the transient nature of emergency medical care mean that a single database will rarely suffice for population based injury research. Linking records from multiple data sources is therefore a promising method for injury surveillance or trauma system evaluation. The purpose of this article is to review the historical development of record linkage, provide a basic mathematical foundation, discuss some practical issues, and consider some ethical concerns. Clerical or computer assisted deterministic record linkage methods may suffice for some applications, but probabilistic methods are particularly useful for larger studies. The probabilistic method attempts to simulate human reasoning by comparing each of several elements from the two records. The basic mathematical specifications are derived algebraically from fundamental concepts of probability, although the theory can be extended to include more advanced mathematics. Probabilistic, deterministic, and clerical techniques may be combined in different ways depending upon the goal of the record linkage project. If a population parameter is being estimated for a purely statistical study, a completely probabilistic approach may be most efficient; for other applications, where the purpose is to make inferences about specific individuals based upon their data contained in two or more files, the need for a high positive predictive value would favor a deterministic method or a probabilistic method with careful clerical review. Whatever techniques are used, researchers must realize that the combination of data sources entails additional ethical obligations beyond the use of each source alone.

Databases, Factual↗

PubMed2004

Calculating the statistical significance of changes in pathway activity from gene expression data.

We present a statistical approach to scoring changes in activity of metabolic pathways from gene expression data. The method identifies the biologically relevant pathways with corresponding statistical significance. Based on gene expression data alone, only local structures of genetic networks can be recovered. Instead of inferring such a network, we propose a hypothesis-based approach. We use given knowledge about biological networks to improve sensitivity and interpretability of findings from microarray experiments. Recently introduced methods test if members of predefined gene sets are enriched in a list of top-ranked genes in a microarray study. We improve this approach by defining scores that depend on all members of the gene set and that also take pairwise co-regulation of these genes into account. We calculate the significance of co-regulation of gene sets with a nonparametric permutation test. On two data sets the method is validated and its biological relevance is discussed. It turns out that useful measures for co-regulation of genes in a pathway can be identified adaptively. We refine our method in two aspects specific to pathways. First, to overcome the ambiguity of enzyme-to-gene mappings for a fixed pathway, we introduce algorithms for selecting the best fitting gene for a specific enzyme in a specific condition. In selected cases, functional assignment of genes to pathways is feasible. Second, the sensitivity of detecting relevant pathways is improved by integrating information about pathway topology. The distance of two enzymes is measured by the number of reactions needed to connect them, and enzyme pairs with a smaller distance receive a higher weight in the score calculation.

Journal Article↗

PubMed1992

A consumer's guide to subgroup analyses.

The extent to which a clinician should believe and act on the results of subgroup analyses of data from randomized trials or meta-analyses is controversial. Guidelines are provided in this paper for making these decisions. The strength of inference regarding a proposed difference in treatment effect among subgroups is dependent on the magnitude of the difference, the statistical significance of the difference, whether the hypothesis preceded or followed the analysis, whether the subgroup analysis was one of a small number of hypotheses tested, whether the difference was suggested by comparisons within or between studies, the consistency of the difference, and the existence of indirect evidence that supports the difference. Application of these guidelines will assist clinicians in making decisions regarding whether to base a treatment decision on overall results or on the results of a subgroup analysis.

Causality↗

PubMed2002

Is microsatellite mutational asymmetry detectable in allele frequency distributions?

We explore the mutational processes giving rise to microsatellite diversity by analysing allele lengths in 6045 human microsatellite markers drawn from the CEPH panel. Assuming a general mutation-drift process generating this diversity, the bias of the mutation distribution cannot be directly estimated from such data. However, inferences can still be made about the degree and sign of the asymmetry of the mutation distribution. We consider statistics based on moments of the observed length distribution, and derive their relevant analytical properties, showing that they have a high sampling variance. We conclude that moment estimators applied to allele length frequencies within the CEPH database could not be used to reject a null hypothesis of no bias even if bias was present. However, an order parameter does provide evidence of asymmetrically biased mutation: there is an unambiguous preponderance of alleles in which the shortest locus is the most frequent. It will be important to further characterize the sampling properties of such order parameters to estimate the magnitude of any mutation bias and the sensitivity of this estimation to the mutation model assumed.

Computer Simulation↗

PubMed1991

A comparison of exact, mid-P, and score tests for matched case-control studies.

A recently developed algorithm for generating the distribution of sufficient statistics for conditional logistic models can be put to a twofold use. First, it provides an avenue for performing inference for matched case-control studies that does not rely on the assumption of a large sample size. Second, joint distributions generated by this algorithm can be used to make comparisons of various inferential procedures that are free from Monte Carlo sampling errors. In this paper, these two features of the algorithm are utilized to compare small-sample properties of the exact, mid-P value, and score tests for a conditional logistic model with two unmatched binary covariates. Both uniparametric and multiparametric tests, performed at a nominal significance level of .05, were studied. It was found that the actual significance levels of the mid-P test tend to be closer to the nominal level when compared with those of the other two tests.

Algorithms↗

PubMed1990

[Changes in the level of immunoglobulins and other serum proteins in hepatic echinococcosis].

The humoral immunity and the protein-synthesizing function of the liver of 35 patients with liver echinococcosis were studied. No humoral immunity deficit was found. Statistically significant abnormalities in a number of proteins were reduced, with evidence of reduced protein-synthesizing liver function. Inferences are made on the anesthesia, resuscitation and operative interventions, in connection with the results of the study.

Adolescent↗

PubMed1987

Numbers and dispersion of repopulating hematopoietic cell clones in radiation chimeras as functions of injected cell dose.

Lethally irradiated mice were repopulated with low (10(5)), medium (10(6)) or high (10(7)) doses of congenic bone marrow cells. Marrow donors were heterozygous for the X-chromosome-encoded allozyme marker phosphoglycerate kinase (PGK-1). A second allozyme marker, phosphoglucose isomerase (GPI-1), distinguished between donor and radioresistant host cells. Use of these markers allowed the numbers and dispersion of repopulating hematopoietic clones to be estimated by binomial statistics. The number of major repopulating clones was related to the injected cell dose in a linear fashion, the inferred frequency of clonogenic cells in donor bone marrow being about 1:40,000. In high-dose recipients, the clones grew locally, with little or no dispersion between bones. Low-dose recipients, in contrast, carried widely dispersed clones; these tended to become reduced in number with increasing time after repopulation. Most of the (few) bone marrow clones present in low-dose recipients were also present in the thymus. In contrast, only about 10% of bone marrow clones in high-dose recipients were substantially represented in the thymus at any one time--about 16 clones in each lobe.

Animals↗

PubMed1995

Have sperm counts been reduced 50 percent in 50 years? A statistical model revisited.

OBJECTIVE: To reanalyze data that were used in a linear model to predict that mean sperm counts have been reduced globally by approximately 50% in the last 50 years. DESIGN: The mean sperm counts and their temporal distribution were reanalyzed via several different statistical models (quadratic, spline fit, and stairstep). CONCLUSION: There are several reasons why a published linear regression model is inappropriate to infer a 50% reduction in mean sperm counts in the last 50 years. These include [1] the potential selection biases that may have occurred with the 61 assembled studies such that they are not representative of their underlying populations; [2] the likely variability in collection methods, in particular, the lack of adherence to a minimum prescribed abstinence period, as has been stated for the largest study, which contained 29.7% of all the subjects included in the analysis; [3] the paucity of data in the first 30 years of the 50-year trend analysis; [4] the fact that if the last 20 years of data are examined, which contains 78.7% of all the studies and 88.1% of the total number of subjects, there is no decrease in sperm counts, in fact, sperm counts were observed to have increased; [5] the conflicting data from a large individual laboratory, which was not prone to the collection variability that likely occurred between the 61 studies, that did not suggest a decline in mean sperm count or seminal volume during a comparable time period, even though this laboratory published the data that were largely responsible for the high historical values in the linear model; and, most importantly, [6] the variety of other mathematical models that perform statistically better at describing the recent data than the linear model and thus offer substantially different hypotheses. The data are only robust during the last 20 years of the analysis, in which all the models, except the linear model, suggest constant or slightly increasing sperm counts.

Female↗

PubMed2025

Towards improved fine-mapping of candidate causal variants.

Fine-mapping in genome-wide association studies aims to identify potentially causal genetic variants among a set of candidate variants that are often highly correlated with each other owing to linkage disequilibrium. A variety of statistical approaches are used in fine-mapping, almost all of which are based on a multiple regression framework to model the relationship between genotype and phenotype, while accommodating specific assumptions about the distribution of variant effect sizes and using different inference algorithms. Owing to their modelling flexibility and the ease of making inferential statements, these approaches are predominantly Bayesian in nature. Recently, these approaches have been improved by refining modelling assumptions, integrating additional information, accommodating summary statistics, and developing scalable computational algorithms that improve computation efficiency and fine-mapping resolution.

Humans↗

PubMed2026

PyEvoMotion: a Python tool for population-based time-course analysis of genome evolution.

SUMMARY: We present PyEvoMotion, an open-source Python tool for inferring molecular clock models with time-dependent Gaussian noise from high-throughput genomic datasets. PyEvoMotion features a command-line interface and a modular architecture, allowing seamless integration into larger bioinformatic pipelines. The tool supports customizable filtering, temporal discretization definition, and mutation classification, making it adaptable to diverse research needs. While traditional phylogenetic methods may encounter computational challenges with large datasets, PyEvoMotion can process thousands to millions of sequences to compute statistical parameters associated with a stochastic differential equation model, thereby weighting the genetic variation within the population. Using viral genomic data, we demonstrate its capability to infer evolutionary rates and detect non-Brownian evolutionary motions with subdiffusive behavior. PyEvoMotion shows potential to provide overlooked insights into genome evolution in different contexts. AVAILABILITY AND IMPLEMENTATION: The open source software is available on GitHub at https://github.com/luksgrin/PyEvoMotion and on SourceForge at https://sourceforge.net/projects/pyevomotion.

Software↗

PubMed2004