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Results for “statistical inference”

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PubMed2026

DNA Methylation, SERPING1 Expression, and Immune-related Traits in Osteoporosis: A Mendelian Randomization Study And Supportive Ex Vivo Evidence.

INTRODUCTION: Osteoporosis (OP) is a major public health burden; however, the role of SERPIN family proteins remains incompletely understood. This study aimed to investigate genetically inferred associations between SERPINs and OP and to explore potential regulatory relationships. METHODS: Genome-wide association study (GWAS) summary statistics were used to perform two-sample Mendelian randomization (MR) and summary-data-based Mendelian randomization (SMR) analyses. Primary MR estimates were derived using inverse-variance-weighted (IVW), MR-Egger, weighted median, simple mode, and weighted mode methods. Cancellous bone tissue from the greater trochanter of the femur was collected from three patients with OP and three non-osteoporotic controls. qPCR and WB were used to analyze the whole bone homogenate, IHC was used to detect decalcified bone sections, and mediation analysis was used to explore potential regulatory associations. RESULTS: Among the proteins of the SERPIN family, only SERPING1 had an obvious positive correlation with the risk of osteoporosis (OR = 1.06, P = 0.0012). qPCR, WB, and IHC analyses demonstrated increased SERPING1 mRNA and protein expression in bone tissue from OP patients. Mediation analyses suggested that cg15918732 DNA methylation may serve as an upstream regulatory factor for SERPING1 expression. In addition, the downstream associations also consist of the alteration of immune cell conditions, like the decrease in the quantity of natural killer cells and T cells, and the rise in the level of mononuclear cells, and so forth. DISCUSSION: These findings provide genetic evidence for the possible role of SERPING1 in OP, which may be achieved through epigenetic regulation and immune pathways. Due to the corresponding characteristics of genetic inference and the small sample size, these results are hypothetical and generative. CONCLUSION: This study shows that DNA methylation of cg15918732 may be associated with SERPING1 expression in osteoporosis and immune-related traits. These findings provide new insights into potential epigenetic and immunological pathways in osteoporosis, which may contribute to future mechanistic and translational research.

Humans↗

PubMed2005

Combining multiple comparisons and modeling techniques in dose-response studies.

The analysis of data from dose-response studies has long been divided according to two major strategies: multiple comparison procedures and model-based approaches. Model-based approaches assume a functional relationship between the response and the dose, taken as a quantitative factor, according to a prespecified parametric model. The fitted model is then used to estimate an adequate dose to achieve a desired response but the validity of its conclusions will highly depend on the correct choice of the a priori unknown dose-response model. Multiple comparison procedures regard the dose as a qualitative factor and make very few, if any, assumptions about the underlying dose-response model. The primary goal is often to identify the minimum effective dose that is statistically significant and produces a relevant biological effect. One approach is to evaluate the significance of contrasts between different dose levels, while preserving the family-wise error rate. Such procedures are relatively robust but inference is confined to the selection of the target dose among the dose levels under investigation. We describe a unified strategy to the analysis of data from dose-response studies which combines multiple comparison and modeling techniques. We assume the existence of several candidate parametric models and use multiple comparison techniques to choose the one most likely to represent the true underlying dose-response curve, while preserving the family-wise error rate. The selected model is then used to provide inference on adequate doses.

Clinical Trials, Phase II as Topic↗

PubMed1997

Bayesian statistical analyses for presence of single genes affecting meat quality traits in a crossed pig population.

Presence of single genes affecting meat quality traits was investigated in F2 individuals of a cross between Chinese Meishan and Western pig lines using phenotypic measurements on 11 traits. A Bayesian approach was used for inference about a mixed model of inheritance, postulating effects of polygenic background genes, action of a biallelic autosomal single gene and various nongenetic effects. Cooking loss, drip loss, two pH measurements, intramuscular fat, shearforce and back-fat thickness were traits found to be likely influenced by a single gene. In all cases, a recessive allele was found, which likely originates from the Meishan breed and is absent in the Western founder lines. By studying associations between genotypes assigned-to individuals based on phenotypic measurements for various traits, it was concluded that cooking loss, two pH measurements and possibly backfat thickness are influenced by one gene, and that a second gene influences intramuscular fat and possibly shearforce and drip loss. Statistical findings were supported by demonstrating marked differences in variances of families of fathers inferred as carriers and those inferred as noncarriers. It is concluded that further molecular genetic research effort to map single genes affecting these traits based on the same experimental data has a high probability of success.

Animals↗

PubMed2005

Approximate Bayesian inference reveals evidence for a recent, severe bottleneck in a Netherlands population of Drosophila melanogaster.

Genome-wide nucleotide variation in non-African populations of Drosophila melanogaster is a subset of variation found in East sub-Saharan African populations, suggesting a bottleneck in the history of the former. We implement an approximate Bayesian approach to infer the timing, duration, and severity of this putative bottleneck and ask whether this inferred model is sufficient to account for patterns of variability observed at 115 loci scattered across the X chromosome. We estimate a recent bottleneck 0.006N(e) generations ago, somewhat further in the past than suggested by biogeographical evidence. Using various proposed statistical tests, we find that this bottleneck model is able to predict the majority of observed features of diversity and linkage disequilibrium in the data. Thus, while precise estimates of bottleneck parameters (like inferences of selection) are sensitive to model assumptions, our results imply that it may be unnecessary to invoke frequent selective sweeps associated with the dispersal of D. melanogaster from Africa to explain patterns of variability in non-African populations.

Animals↗

PubMed1992

The Lancet's statistical review process: areas for improvement by authors.

The Lancet now incorporates statistical review of submitted papers which remain candidates for publication after conventional review. We summarise here criticisms noted by the statistical reviewers for 191 such papers received between November, 1990, and June, 1991. Only 54% of papers were deemed acceptable or acceptable after revision; the others were either recommended for rejection (14%) or for more substantial revision and re-review (32%). Descriptions of methods and of results were found inadequate in about half of the papers; about one-quarter of papers had inadequate abstracts and conclusions. Major errors of inference were made in 48 papers and went hand in hand with major criticisms of analysis or design in those papers. The natural focus of statistical review is whether conclusions drawn are justified by study design and statistical analysis. In this, there is room for improvement by authors.

Bias↗

PubMed1996

Statistical properties of the variation at linked microsatellite loci: implications for the history of human Y chromosomes.

It has recently been suggested that observed levels of variation at microsatellite loci can be used to infer patterns of selection in genomes and to assess demographic history. In order to evaluate the feasibility of these suggestions it is necessary to know something about how levels of variation at microsatellite loci are expected to fluctuate due simply to stochasticity in the processes of mutation and inheritance (genetic sampling). Here we use recently derived properties of the stepwise mutation model to place confidence intervals around the variance in repeat score that is expected at mutation-drift equilibrium and outline a statistical test for whether an observed value differs significantly from expectation. We also develop confidence intervals for the time course of the buildup of variation following a complete elimination of variation, such as might be caused by a selective sweep or an extreme population bottleneck. We apply these methods to the variation observed at human Y-specific microsatellites. Although a number of authors have suggested the possibility of a very recent sweep, our analyses suggest that a sweep or extreme bottleneck is unlikely to have occurred anytime during the last approximately 74,000 years. To generate this result we use a recently estimated mutation rate for microsatellite loci of 5.6 x 10(-4) along with the variation observed at autosomal microsatellite loci to estimate the human effective population size. This estimate is 18,000, implying an effective number of 4,500 Y chromosomes. One important general conclusion to emerge from this study is that in order to reject mutation-drift equilibrium at a set of linked microsatellite loci it is necessary to have an unreasonably large number of loci unless the observed variance is far below that expected at mutation-drift equilibrium.

Biological Evolution↗

PubMed2001

Short-term estradiol replacement in postmenopausal women selectively mutes somatostatin's dose-dependent inhibition of fasting growth hormone secretion.

How estradiol stimulates pulsatile GH secretion in the human is not well understood. Here, we test the clinical hypothesis that estradiol stimulates GH secretion, in part, by opposing somatostatin's inhibition of GH release. To this end, 13 estrogen-withdrawn postmenopausal women received placebo or 1 mg micronized estradiol-17beta orally, twice daily for 14 days, in a prospectively randomized, patient-blinded, within-subject cross-over design. For each intervention, the dose-dependent suppressive actions of somatostatin were evaluated by infusing 0 (saline), 3, 10, 30, 100, or 300 microg/1.73 m(2).h somatostatin-14 continuously, iv, for 3 h, on separate mornings, in the fasting state, 48 h apart. Blood was sampled at 10-min intervals for 2 h before, for 3 h concurrently with, and for 1 h after each infusion. Serum GH concentrations were quantitated in an ultrasensitive chemiluminescence-based assay (detection threshold, 0.005 microg/L). In the estrogen-deficient milieu, constant iv somatostatin infusions inhibited steady-state serum GH concentrations (valley mean during the last 60 min of the infusion interval) in a dose-dependent manner (P < 10(-4) interventional effect). Maximally effective doses of somatostatin reduced the latter by 89 +/- 6.1% (mean +/- SEM) below the subject-specific preinfusion baseline. Estrogen administration increased the serum estradiol concentration from 12 +/- 1 to 245 +/- 35 pg/mL [42 +/- 4 to 920 +/- 110 pmol/L] (P < 10(-4)); decreased serum concentrations of LH (P = 0.018), FSH (P < 10(-4)), and insulin-like growth factor-I (P = 0.003); and elevated the fasting (6-h mean) serum GH concentration from 0.41 +/- 0.07 to 0.87 +/- 0.27 (P = 0.011). Estradiol supplementation did not alter somatostatin's maximal suppression of GH by 89 +/- 4.7% (P < 10(-4) below subject-specific preinfusion baseline), thus signifying unchanging somatostatin efficacy. In contrast, estradiol replacement significantly elevated the half-maximally inhibitory dose of infused somatostatin by 13.5-fold, from 0.43 (0.38-0.48, 95% group statistical confidence intervals) (placebo) to 6.0 (5.2-7.0) (estradiol) microg/1.73 m(2)/h (P < 10(-4)), denoting muting of somatostatin's inhibitory potency. The latter inference was confirmed by a concomitant 4-fold decrease in the exponential steepness of the somatostatin inhibitory dose-response function; viz., mean 1.42 (1.49 to 1.33) (placebo) vs. 0.34 (0.62 to 0.26) (estradiol) slope units (P < 10(-4)). The foregoing effects were specific, because estrogen did not alter somatostatin's dose-dependent enhancement (P < 10(-4)) of the orderliness of GH release patterns, as quantitated via the approximate entropy regularity statistic. In summary, short-term replacement of estradiol to midfollicular phase levels in postmenopausal women selectively reduces the potency, but not the efficacy, of somatostatin's dose-dependent inhibition of GH release. Estrogen supplementation does not modify somatostatin's reciprocal enhancement of the quantifiable orderliness (approximate entropy) of the GH secretory process. Accordingly, we postulate that estradiol can facilitate pulsatile GH secretion, in part, by opposing the repressive actions of somatostatin.

Cross-Over Studies↗

PubMed2006

Multivariate voxel-based morphometry successfully differentiates schizophrenia patients from healthy controls.

Currently available laboratory procedures might provide additional information to psychiatric diagnostic systems for more valid classifications of mental disorders. To identify the correlative pattern of gray matter distribution that best discriminates schizophrenia patients from healthy subjects, we applied discriminant function analysis techniques using the multivariate linear model and the voxel-based morphometry. The first analysis was conducted to obtain a statistical model that classified 30 male healthy subjects and 30 male schizophrenia patients diagnosed according to current operational criteria. The second analysis was performed to prospectively validate the statistical model by successfully classifying a new cohort that consisted of 16 male healthy subjects and 16 male schizophrenia patients. Inferences about the structural relevance of the gray matter distribution could be made if the individual profile of pattern expression could be linked to the specific diagnosis of each subject. The result was that 90% of the subjects were correctly classified by the eigenimage, and the Jackknife approach revealed well above chance accuracy. The pattern of the eigenimage was characterized by positive loadings indicating gray matter decline in the patients in the lateral and medial prefrontal regions, insula, lateral temporal regions, medial temporal structures, and thalamus as well as the negative loadings reflecting gray matter increase in the patients in the putamen and cerebellum. When the eigenimage derived from the original cohort was applied to classify data from the second cohort, it correctly assigned more than 80% of the healthy subjects and schizophrenia patients. These findings suggest that the characteristic distribution of gray matter changes may be of diagnostic value for schizophrenia.

Adult↗

PubMed2002

The ethics of consulting for the tobacco industry.

This article describes how and why I became involved in consulting for the tobacco industry. I briefly discuss the four relatively distinct statistical topics that were the primary focus of my work, all of which have been central to my published academic research for over three decades: missing data; causal inference; adjustment for covariates in observational studies; and meta-analysis. To me, it is entirely appropriate to present the application of this academic work in a legal setting.

Consultants↗

PubMed2003

Coding DNA sequences: statistical distributions.

The base distributions in coding DNA sequences (CDS) are investigated. We explore the scaling properties of the 4-dimensional directed random walk and compare them with that for the DNA sequences. Inference from these observation are, however, contradicted by alternate analysis using factorial moments. To resolve this conflict we look directly at the nucleotide base distributions. In all the cases the base distributions change from gaussian to non-gaussian as the scale size is increased. The CDS, therefore, have nucleotide distributions different from the random.

Animals↗

PubMed1986

Verbal and non-verbal behaviour of doctors while conveying distressing information.

This study was an attempt to gather information on doctors' verbal and non-verbal hand- and speech-related behaviours during interactions involving the conveyance of distressing information. Similarities and differences in verbal/non-verbal communication were identified and described between doctors rated high, medium or low in communication skills. Gender differences were also explored. Statistically significant differences were found among doctors rated high in communication skills on the use of 'Information/advice' and 'Emotional probes'. Differences were also found on the frequency of speech disruptions and hand behaviour patterns. Doctors rated high were less anxious during the interactions as inferred from their hand- and speech-related behaviours. Gender differences on verbal behaviours indicate that 'Emotional probing' and 'Reflection of feelings' were exhibited more frequently by females. On the other hand, no statistically significant differences were found in non-verbal hand- and speech-related behaviours.

Female↗

PubMed1999

Spatial genetic structure of delphinium nuttallianum populations: inferences about gene flow

The spatial genetic structure of a plant population provides a potential record of past gene flow and mating. We used hierarchical F-statistics and spatial autocorrelation to characterize spatial genetic differentiation of allozymes in adult Delphinium nuttallianum plants within and among six natural populations separated from one another by up to 3 km. Previous direct estimates suggested that gene flow is highly localized, averaging << 10 m. Earlier studies of seed-set, pollen-tube growth and progeny fitness suggested that partial reproductive isolation exists between plants growing too close together (<3 m) and too far apart (>100 m). Thus we anticipated substantial genetic differentiation on scales of a few to hundreds of metres. However, we detected little differentiation among the six populations, among replicate study plots within populations, or among subsections of study plots, except at the smallest scale of cm to m. These results suggest that relatively rare long-distance pollen movement has gone undetected and that postpollination selection may further modify genetic structure during the life cycle. Lack of differentiation is not at odds with the observation of partial reproductive isolation, because some loci may respond to spatial variation in selection without this response being evident at marker loci.

Journal Article↗

PubMed1998

Much ado about two: reconsidering retransformation and the two-part model in health econometrics.

In health economics applications involving outcomes (y) and covariates (x), it is often the case that the central inferential problems of interest involve E[y/x] and its associated partial effects or elasticities. Many such outcomes have two fundamental statistical properties: y > or = 0; and the outcome y = 0 is observed with sufficient frequency that the zeros cannot be ignored econometrically. This paper (1) describes circumstances where the standard two-part model with homoskedastic retransformation will fail to provide consistent inferences about important policy parameters; and (2) demonstrates some alternative approaches that are likely to prove helpful in applications.

Data Interpretation, Statistical↗

PubMed2000

Association mapping in structured populations.

The use, in association studies, of the forthcoming dense genomewide collection of single-nucleotide polymorphisms (SNPs) has been heralded as a potential breakthrough in the study of the genetic basis of common complex disorders. A serious problem with association mapping is that population structure can lead to spurious associations between a candidate marker and a phenotype. One common solution has been to abandon case-control studies in favor of family-based tests of association, such as the transmission/disequilibrium test (TDT), but this comes at a considerable cost in the need to collect DNA from close relatives of affected individuals. In this article we describe a novel, statistically valid, method for case-control association studies in structured populations. Our method uses a set of unlinked genetic markers to infer details of population structure, and to estimate the ancestry of sampled individuals, before using this information to test for associations within subpopulations. It provides power comparable with the TDT in many settings and may substantially outperform it if there are conflicting associations in different subpopulations.

Alleles↗

PubMed2001

Development of inferential measurements using neural networks.

In many industrial processes, the most desirable variables to control are measured infrequently off-line in a quality control laboratory. In these situations, use of advanced control or optimization techniques requires use of inferred measurements generated from correlations. For well-understood processes, the structure of the correlation as well as the choice of inputs may be known a priori. However, many industrial processes are too complex and the appropriate form of the correlation and choice of input measurements are not obvious. Here, process knowledge, operating experience, and statistical methods play an important role in development of correlations. This paper describes a systematic approach to the development of nonlinear correlations for inferential measurements using neural networks. A three-step procedure is proposed. The first step consists of data collection and preprocessing. Next, the process variables are subjected to simple statistical analyses to identify a subset of measurements to be used in the inferential scheme. The third step involves generation of the inferential scheme. We demonstrate the methodology by inferring the ASTM 95% endpoint of a petroleum product using data from a domestic US refinery.

Algorithms↗

PubMed2001

Heart rate variability does not tap putative efficacy of Thought Field Therapy.

Callahan (2001) has offered a series of case reports in an effort to validate the rationale and methods of Thought Field Therapy (TFT). These case reports employ subjective ratings, that is, the Subjective Units of Distress (SUD) rating scale as well as a gross measure of heart rate variability (HRV). My criticisms center around (a) inappropriately strong inferences given exclusive reliance on case reports, a potentially biased sample, and lack of appropriate controls; (b) misinterpretation of statistical artifact as systematic effect; (c) lack of systematic evaluation of HRV changes; and (d) erroneous interpretation of HRV. Callahan's article provides no evidence for the efficacy of TFT nor does it provide evidence for the credibility of TFT's rationale.

Heart Rate↗

PubMed1990

Moderation of morbidity following tonsillectomy and adenoidectomy: a study of awareness under anesthesia.

Sixty-seven children between the ages 3 and 10, undergoing tonsillectomy and adenoidectomy, were randomly assigned to one of 3 groups. Therapeutic suggestions recited in English (n = 31), French (n = 19), or continuous white noise (n = 18) were repetitively administered by means of earphones in a double blind design. Randomization to the English condition was associated with a more favorable outcome with respect to all parameters evaluated by physicians and nurses. However, statistical significance could not be demonstrated. Should this observed favorable outcome be legitimate, cortical interpretation of language context was inferred as recovery was not influenced by randomization into the French or white noise conditions. Preoperative behavior, as defined by preoperative upset and cooperation scores, may be predictive of postoperative convalescence. The favorable outcome imparted by the English condition appeared most significant with respect to those patients at highest risk for poor convalescence i.e. poor status preoperative patients.

Adenoidectomy↗

PubMed2026

Immune cell-specific genetic architecture of Alzheimer's disease revealed by multi-omics analysis for therapeutic target discovery and prioritization.

Alzheimer's disease (AD) is a multifactorial neurodegenerative condition in which accumulating genetic and molecular evidence implicates dysregulation of peripheral immune processes in disease pathogenesis. Nevertheless, the contribution of distinct peripheral immune cell subsets and associated gene regulatory landscapes to AD risk remains incompletely defined. To address this gap, we integrated single-cell expression quantitative trait loci (sc‑eQTL) data from the OneK1K cohort with AD GWAS summary statistics. We systematically interrogated immune cell-specific genes for their contributions to AD risk by integrating genetic causal inference with Bayesian colocalization analyses, and identified 24 eGenes that passed both the MR significance threshold (P < 0.05) and the criterion for strong shared genetic signals (PP.H4 > 0.8). Notable candidates included GATS, HLA-DOB, HLA-DQA1, PM20D1, and others, with each gene demonstrating a cell-type-specific association restricted to its corresponding immune cell type, such as monocytes, CD8 + T cells, or B cells. Independent peripheral blood single-cell transcriptomic data further supported disease-associated shifts in cell-type-specific expression patterns in AD. Phenome-wide association studies (PheWAS) indicated limited associations with off-target traits, indicating a favorable safety profile for therapeutic intervention, with the exceptions of B4GALNT3, PM20D1, and CNN2. Integration of immune gene targets with pharmacological databases yielded three candidate compound, including NSC321521 (targeting HLA-DQA1), phenoxybenzamine (targeting GSTP1), and rimexolone (targeting BIN1). Among these compounds, Predicted blood-brain barrier permeability was observed only for phenoxybenzamine and rimexolone, with docking studies indicating stable interactions, such as those between NSC321521 and HLA-DQA1, phenoxybenzamine and GSTP1, and rimexolone and BIN1. This integrative approach highlights key immune‑cell‑specific genes involved in AD and proposes repurposable drugs with central nervous system potential, paving the way for more targeted immunomodulatory strategies in AD.

Humans↗