Search PubMed⌕ Search

Biomedical subjects

B Devlin

Publications and source records attributed to B Devlin.

At least 55 records · Page 3Linked to original sources
PubMed1997

Binning clones by hybridization with complex probes: statistical refinement of an inner product mapping method.

Molecular methods that use long-range information to solve genomics problems (i.e., top-down strategies) efficiently have become increasingly prominent in the genomics literature. One such method, an implementation of inner product mapping (IPM), uses noisy, long-range radiation hybrid (RH)/YAC overlap data and relatively noise-free RH/STS overlap data to localize clones to specific chromosomal regions. Because the molecular data are rarely noise-free, statistical models tailored to the top-down molecular methods make the methods far more effective. We develop two statistical models for IPM (or any other top-down strategy of similar form), a parametric logit model and a nonparametric order-restricted model, and show how these models can be implemented within a hierarchical Bayes framework. Using these models, we refine the chromosome 11 map reported in M. Perlin et al. (1995, Genomics 28: 315-327). Our analyses improve the IPM map, both in terms of successful localization of clones and in terms of the confidence with which they are localized.

Chromosome Mapping↗
PubMed1997

A controlled family history study of childhood-onset depressive disorder.

BACKGROUND: We studied the family psychiatric history of 125 youths with childhood-onset depressive disorder (a portion of whom developed bipolar disorder) and 55 psychiatric controls with nonaffective disorder. METHODS: Probands were classified according to prospectively observed clinical course in childhood. Family psychiatric history was determined by interviewers blind to probands' diagnosis, with mothers typically informing about themselves and about remaining first- and a all second-degree adult relatives. RESULTS: Families of affectively ill juveniles had 5-fold greater odds of lifetime depressive disorder and 2-fold greater odds of recurrent unipolar depressive disorder than did families of psychiatric controls. The higher risk of depression was most evident in first-degree and female relatives. Mothers of affectively ill youths were younger at onset of depression than were mothers of controls. Alcoholism and substance use disorders were more prevalent in relatives of affectively ill probands than in controls and cosegregated with familial depression. However, other covariates were more important at predicting patterns of familial depression. Familial illness patterns also varied somewhat with proband characteristics. CONCLUSIONS: Child probands with affective disorder identify families enriched with affective disorder (even compared with families of psychiatric controls), suggesting that juvenile- and adult-onset forms of this condition share the same diathesis. Rates of affective illness in the families of depressed youngsters also are notably higher than population-based estimates. The findings therefore indicate that very-early-onset affective disorder is familial and that pedigrees ascertained through affectively ill children are good candidates for family and genetic studies.

Adolescent↗
PubMed1996

Disequilibrium mapping: composite likelihood for pairwise disequilibrium.

The pattern of linkage disequilibrium between a disease locus and a set of marker loci has been shown to be a useful tool for geneticists searching for disease genes. Several methods have been advanced to utilize the pairwise disequilibrium between the disease locus and each of a set of marker loci. However, none of the methods take into account the information from all pairs simultaneously while also modeling the variability in the disequilibrium values due to the evolutionary dynamics of the population. We propose a Composite Likelihood (CL) model that has these features when the physical distances between the marker loci are known or can be approximated. In this instance, and assuming that there is a single disease mutation, the CL model depends on only three parameters, the recombination fraction between the disease locus and an arbitrary marker locus, theta, the age of the mutation, and a variance parameter. When the CL is maximized over a grid of theta, it provides a graph that can direct the search for the disease locus. We also show how the CL model can be generalized to account for multiple disease mutations. Evolutionary simulations demonstrate the power of the analyses, as well as their potential weaknesses. Finally, we analyze the data from two mapped diseases, cystic fibrosis and diastrophic dysplasia, finding that the CL method performs well in both cases.

Computer Simulation↗
PubMed1995

A comparison of linkage disequilibrium measures for fine-scale mapping.

Linkage mapping generally localizes disease genes to 1- to 2-cM regions of chromosomes. In theory, further refinement of location can be achieved by population-based studies of linkage disequilibrium between disease locus alleles and alleles at adjacent markers. One approach to localization, dubbed simple disequilibrium mapping, is to determine the relative location of the disease locus by plotting disequilibrium values against marker locations. We investigate the simple mapping properties of five disequilibrium measures, the correlation coefficient delta, Lewontin's D', the robust formulation of the population attributable risk delta, Yule's Q, and Kaplan and Weir's proportional difference d under the assumption of initial complete disequilibrium between disease and marker loci. The studies indicate that delta is a superior measure for fine mapping because it is directly related to the recombination fraction between the disease and the marker loci, and it is invariant when disease haplotypes are sampled at a rate higher than their population frequencies, as in a case-control study. D' yields results comparable to those of delta in many realistic settings. Of the remaining three measures, Q, delta, and d, Q yields the best results. From simulations of short-term evolution, all measures show some sensitivity to marker allele frequencies; however, as predicted by analytic results, Q, delta, and d exhibit the greatest sensitivity to variation in marker allele frequencies across loci.

Alleles↗
PubMed1995

Seasonal abundance of Lutzomyia longipalpis (Diptera: Psychodidae) at an endemic focus of visceral leishmaniasis in Colombia.

Ecological studies on the sand fly Lutzomyia longipalpis (Lutz & Neiva) were conducted during 1990-1993 in a small rural community in Colombia where American visceral leishmaniasis is endemic. Standardized weekly sand fly collections made from pigpens and natural resting sites displayed a bimodal annual abundance cycle, with a small peak occurring in October-November and a larger one in April-May. Time series analysis was employed to quantify the associations between sand fly abundance and weather factors (temperature, relative humidity, and rainfall). In addition to a prominent 6-mo cycle. Fourier analysis of the collection data demonstrated that the L. longipalpis population also exhibited a 5- to 8-wk cycle that may represent the length of larval development. Autoregressive moving average models were fit to weekly collection data and their residuals were regressed against rainfall, temperature, and relative humidity. A significant positive association between female L. longipalpis abundance and the relative humidity and rainfall recorded 3 wk earlier was found, indicating that these factors may be of value in predicting sand fly abundance. Additionally, these data indicated that L. longipalpis larvae may become quiescent during adverse conditions.

Animals↗
PubMed1994

A novel beta-globin mutation, beta Durham-NC [beta 114 Leu-->Pro], produces a dominant thalassemia-like phenotype.

Mutations within exon 3 of the beta-globin gene are relatively uncommon, and many of these mutations produce a dominant thalassemia-like phenotype. We describe a novel thalassemic hemoglobinopathy caused by a single nucleotide substitution (CTG-->CCG) at codon 114 resulting in a leucine to proline substitution and designate it beta Durham-NC [beta 114 Leu-->Pro]. The mutation producing this thalassemic hemoglobinopathy is located near to the beta Showa-Yakushiji mutation (beta 110 Leu-->Pro). Both of these hemoglobinopathies share similar phenotypic features with moderately severe microcytic anemia. Using computer imaging of the hemoglobin molecule, we examined several reported point mutations within exon 3 of the beta-globin gene. These point mutations cause a single amino acid substitution in the G helix, and result in a thalassemic and/or hemolytic phenotype. Computer imaging of nine separate examples suggests that amino acid substitutions affecting side chains that project into the heme pocket may destabilize the heme moiety within the beta-globin chain, resulting in a thalassemic phenotype. Hemolytic phenotypes may be the result of decreased alpha 1 beta 1 interactions. The beta Durham-NC mutation further characterizes a novel group of thalassemias/hemoglobinopathies that are clinically difficult to identify and require accessory laboratory testing.

Adult↗
PubMed1994

Comparative hospital databases: value for management and quality.

OBJECTIVES: To establish an accurate and reliable comparative database of discharge abstracts and to appraise its value for assessments of quality of care. DESIGN: Retrospective review of case notes by trained research abstractors and comparison with matched information as routinely collected by the hospitals' own information systems. SETTING: Three district general hospitals and two major London teaching hospitals. PATIENTS: The database included 3905 medical and surgical cases and 2082 obstetric cases from 1990 and 1991. MAIN MEASURES: Accessibility of case notes; measures of reliability between reviewers and of validity of case note content; application of high level quality indicators. RESULTS: The existing hospital systems extracted insufficient detail from case notes to conduct clinical comparative analyses for medical and surgical cases. The research abstractors at least doubled the diagnostic codes extracted. Interabstractor agreement of about 70% was obtained for primary diagnosis and assignment to diagnosis related group. These data were sufficient to create a comparative database and apply high level quality indicators designed to flag topics for further study. For obstetric-specific indicators the rates were comparable for abstractors and the hospital information systems, which in each case was a departmentally based system (SMMIS) producing more detailed and accessible data. CONCLUSIONS: Current methods of extracting and coding diagnostic and procedural data from case notes in this sample of hospitals is unsatisfactory: notes were difficult to access and recording is unacceptably incomplete. IMPLICATIONS: Improvements as piloted in this project, are readily available should the NHS, hospital managers, and clinicians see the value of these data in their clinical and managerial activities.

Data Collection↗
PubMed1994

Comments on the statistical aspects of the NRC's report on DNA typing.

The goal of the NRC report on DNA typing was to answer a "crescendo of questions concerning DNA typing," many of them in the areas of population genetics and statistics. Unfortunately, few of these questions were answered adequately. In lieu of answering these questions, the panel proposed another conservative method of forensic inference, the "ceiling principle." Aside from its extreme conservativeness, this new method is difficult to justify because it is based on inadequate population genetics and statistical theory. Moreover, in its ultimate implementation, the panel's method will depend on a population genetics study whose rationale is questionable. In this article, we elaborate some of the general comments we made about the NRC report in a recent article [1]. Specifically we cover three topics. First we question the statistical basis for the ceiling principle, showing that the empirical results that motivated the method are likely to be misinterpreted and showing, by power calculations, that the effects of population substructure cannot be substantial. Second, we show that the study design to determine "ceiling" allele frequencies has several undesirable statistical properties. Finally, we discuss the estimation of handling errors from the statistical perspective, a subject treated inadequately by the report.

DNA Fingerprinting↗
PubMed1993

An association between the risk of cancer and mutations in the HRAS1 minisatellite locus.

BACKGROUND: The role of mutations in protooncogenes and their regulatory sequences in the pathogenesis of cancer is under close scrutiny. Minisatellites are unstable repetitive sequences of DNA that are present throughout the human genome. The highly polymorphic HRAS1 minisatellite locus just downstream from the protooncogene H-ras-1 consists of four common progenitor alleles and several dozen rare alleles, which apparently derive from mutations of the progenitors. We previously observed an association of the rare mutant alleles with many forms of cancer, and we undertook the present study to pursue this observation further. METHODS: We conducted a case-control study, typing 736 HRAS1 alleles from patients with cancer and 652 from controls by Southern blotting of leukocyte DNA. We also carried out a meta-analysis of this study and 22 other published studies, estimating the relative risk of cancer (such as bladder, breast, or colorectal cancer) when one of the rare HRAS1 alleles was present. RESULTS: Both the present case-control study (odds ratio, 1.83; 95 percent confidence interval, 1.28 to 2.67; P = 0.002) and the present study combined with our previous study (odds ratio, 2.07; 95 percent confidence interval, 1.47 to 2.92; P < 0.001), as well as the meta-analysis of all 23 studies (odds ratio, 1.93; 95 percent confidence interval, 1.63 to 2.30; chi-square = 57.58; P < 0.001), replicated our original finding and demonstrated a significant association of rare HRAS1 alleles with cancer. We found significant associations for four types of cancer: carcinomas of the breast, colorectum, and urinary bladder and acute leukemia. We also identified suggestive but not statistically significant associations for cancers of the lung and prostate and for non-Hodgkin's lymphoma. CONCLUSIONS: Mutant alleles of the HRAS1 minisatellite locus represent a major risk factor for common types of cancer. Although the relative risk associated with the presence of one rare allele is moderate, the aggregate prevalence of one rare allele is moderate, the aggregate prevalence of this class of mutant alleles implies an extremely important attributable risk: 1 in 11 cancers of the breast, colorectum, and bladder.

Aged↗
PubMed1993

Genotypic divergence precedes clinical dissemination in a case of synchronous bilateral B-cell malignant lymphoma of the testes.

Malignant lymphoma of the testis occurs bilaterally more often than any other tumor type. We report the case of a 62-year-old man who presented with synchronous, bilateral, testicular malignant lymphomas without clinical or radiologic evidence of extratesticular disease. The patient received no therapy other than bilateral orchiectomy and subsequently developed widespread disease 6 months later. Southern blot DNA analysis was performed on the initial orchiectomy samples for immunoglobulin (Ig) gene rearrangements. These genotypic analyses showed different clonal rearrangements in the Ig heavy chain JH region but identical clonal rearrangements in the Ig light chain C Kappa region. To our knowledge this is the first genotypic demonstration of a common clonal origin in synchronous, bilateral, testicular malignant lymphomas. We interpret these findings as molecular evidence that the patient's malignant lymphoma was already disseminated at initial presentation, although it was clinically undetectable at that time.

Antigens, CD↗
PubMed1993

Communicating the diagnosis of lung cancer.

In order to assess their reaction to the information given, 50 patients underwent a semi-structured interview with a social worker within 1 week of having been told the diagnosis of lung cancer. There were 32 men and 18 women with a mean age of 63 (range 38-82) years. Thirty-eight (76%) belonged to Registrar General social class IV or V, and 45 (90%) had left school at the age of 15 years. Two patients were unaware of the diagnosis despite having been told that they had lung cancer. Two patients would have preferred not to have been told the diagnosis and two were unsure, while 46 (92%) felt that telling them the diagnosis truthfully had been correct. No patient felt that they had been given too much information, but 13 (26%) indicated a lack of information about prognosis. Despite being told 'bad news', 31 (62%) felt more reassured after their interview with the doctor, 5 (10%) felt less reassured, and 14 (28%) were uncertain. Twenty-one (42%) patients were experiencing a sense of guilt or regret at having smoked. Many patients had concerns about specific symptoms which they expected to suffer. In general, patients wanted to be told their diagnosis truthfully and required a high level of information. Many patients felt reassured by the discussion of such details.

Adult↗
PubMed1993

Forensic inference from genetic markers.

This review provides an overview of forensic inference from genetic markers. Because the judge and jurors are charged with decision-making, the forensic expert's job is to provide a useful summary of the evidence to the court. Hence, this review focuses on the likelihood ratio as a means of summarizing the genetic data for either criminal or civil cases. The properties of the genetic markers frequently used in today's court cases, those being VNTR loci, are discussed in detail. Unlike traditional markers, the data from VNTR loci are complicated because current molecular methods generate data that follow a finite mixture distribution. Critical ancillary issues are also covered, though not in detail.

Bayes Theorem↗
PubMed1993

Population genetics of the HRAS1 minisatellite locus.

Several years ago it was reported that rare HRAS1 VNTR alleles occurred more frequently in U.S. Caucasian cancer patients than in unaffected controls. Such an association, in theory, could be caused by undetected population heterogeneity. Also, in a study clearly relevant to this issue, it was recently reported that significant deviations from Hardy-Weinberg equilibrium exist at this locus in a sample of U.S. Caucasians. These considerations motivate our population genetic analysis of the HRAS1 locus. From published studies of the HRAS1 VNTR locus, which classified alleles into types, we found only small differences in the allele frequency distributions of samples from various European nations, although there were larger differences among ethnic groups (African American, Caucasian, and Oriental). In an analysis of variation of rare-allele frequencies among samples from four European nations, most of the variance was attributable to molecular methodology, and very samples from four European nations, most of the variance was attributable to molecular methodology, and very little of the variance was accounted for by nationality. In addition, we showed that mixture of European subpopulations should result in only minor deviations from expected genotype proportions in a Caucasian database and demonstrated that there was no significant deviation from Hardy-Weinberg equilibrium in our HRAS1 data.

Alleles↗
PubMed1993

Physical properties of VNTR data, and their impact on a test of allelic independence.

In this article we describe the physical properties of VNTR data, as well as their effects on the two-dimensional distribution of fragment pairs. Tests of independence of alleles at a locus may confound those physical properties with allele independence. A recently proposed test by Geisser and Johnson is an example. We show that alleles can be strictly independent, yet the proposed test suggests large violations of allele independence because it is sensitive to well-known electrophoretic phenomena.

Alleles↗