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At least 217 records · Page 12Linked to original sources
PubMed2001

Effect of misspecification of gene frequency on the two-point LOD score.

In this study, we used computer simulation of simple and complex models to ask: (1) What is the penalty in evidence for linkage when the assumed gene frequency is far from the true gene frequency? (2) If the assumed model for gene frequency and inheritance are misspecified in the analysis, can this lead to a higher maximum LOD score than that obtained under the true parameters? Linkage data simulated under simple dominant, recessive, dominant and recessive with reduced penetrance, and additive models, were analysed assuming a single locus with both the correct and incorrect dominance model and assuming a range of different gene frequencies. We found that misspecifying the analysis gene frequency led to little penalty in maximum LOD score in all models examined, especially if the assumed gene frequency was lower than the generating one. Analysing linkage data assuming a gene frequency of the order of 0.01 for a dominant gene, and 0.1 for a recessive gene, appears to be a reasonable tactic in the majority of realistic situations because underestimating the gene frequency, even when the true gene frequency is high, leads to little penalty in the LOD score.

Computer Simulation↗
PubMed2025

Investigation of associations between the neonatal gut microbiota and severe viral lower respiratory tract infections in the first 2 years of life: a birth cohort study with metagenomics.

BACKGROUND: Early-life gut microbiota affects immune system development, including the lung immune response (gut-lung axis). We aimed to investigate whether gut microbiota composition in neonates in the first week of life is associated with hospital admissions for viral lower respiratory tract infections (vLRTIs). METHODS: The Baby Biome Study (BBS) is a prospective birth cohort, which enrolled mother-baby pairs between Jan 1, 2016, and Dec 31, 2017, at three UK hospitals. In the present study, we only included BBS babies with a sequenced first-week stool sample and successful data linkage. Stool was collected in the first week of life for shotgun-metagenomic sequencing. We examined the following microbiota features: alpha diversity (Chao1, Shannon, and Simpson indices) and community structures (cluster-partitioning against medoids method). The participants were followed up through linkage to the Hospital Episode Statistics-Admitted Patient Care (HES-APC) database to determine vLRTI hospital admission incidence in the first 2 years of life. We used Poisson mixed-effects models for univariable and multivariable analyses to evaluate the association between microbiota features and vLRTI hospital admission incidence, adjusting for confounders identified through direct acyclic graphs. FINDINGS: 3305 (95%) of the 3476 BBS-enrolled babies for whom consent to data linkage was obtained were included in the present study. 1111 (34%) babies had a first-week sequenced stool sample, of whom 1082 (97%; 564 born vaginally and 518 born by caesarean section) were successfully linked to HES-APC, and had median follow-up of 2·0 years (IQR 1·4-2·9). Most babies were born at term (996 [92%] ≥37 weeks gestational age and 1070 [99%] >35 weeks gestational age) and healthy (1050 [97%] had no comorbidities), and 520 (48%) were female and 562 (52%) were male. Higher first-week gut microbiota alpha diversity was associated with reduced rates of vLRTI hospital admission (Chao1 Index adjusted hazard ratio [HR] 0·92 [95% CI 0·85-0·99]; Shannon Index adjusted HR 0·57 [0·33-0·98]; and Simpson Index adjusted HR 0·36 [0·11-1·20]). Three microbiota clusters were identified. Cluster 1 had a mixed composition and cluster 2 was dominated by Bifidobacterium breve, with both clusters observed in babies born vaginally and by caesarean section. Cluster 3 was found only in vaginally born babies and was dominated by Bifidobacterium longum. Having cluster 1 (mixed) or cluster 2 (B breve dominated) was independently associated with increased rates of vLRTI hospital admission compared with cluster 3 (B longum dominated; cluster 1 [mixed] 3·05 [1·25-7·41] and cluster 2 [B breve dominated] 2·80 [1·06-7·44]). INTERPRETATION: We report observational evidence that first-week gut microbiota differences are associated with clinically severe vLRTI in young children. This study identified bacterial species that could be of interest for vLRTI prevention. This finding has important implications for the design of future research and intervention strategies. FUNDING: The Wellcome Trust and Wellcome Sanger Institute core funding.

Humans↗
PubMed1985

Recessive lethal mutations in Anopheles albimanus.

Six recessive lethal mutants of Anopheles albimanus are described. Homozygotes for three of the autosomal mutants, viz., bar eye, dot eye and hairy, die during the last larval or early pupal stages; complete linkage data are lacking for bar eye and hairy but dot eye is tightly linked to red eye on the right arm of chromosome 2. Larval and pupal mortality is high for homozygotes of the other two autosomal mutants, diseased larva and lunate. Survival to the adult stage of the lunate type is about 60% for both sexes, and for diseased larva the rates differed according to sex, 15% for males and 3% for females. A general lack of vitality of the surviving adults has prevented the establishment of homozygous stocks. From analyses of linkage data, diseased larva and lunate were assigned to chromosome 2, most probably on the left arm. The mutant, bubble head, is on the X chromosome, and therefore is expressed only in the hemizygous male, which usually dies during the early pupal stage.

Animals↗
PubMed2005

Improving the evidence base for promoting quality and equity of surgical care using population-based linkage of administrative health records.

This paper highlights the uses of population-based linkage of administrative health records to improve the quality, safety, and equity of surgical care. The primary focus of the paper is on the transfer of this type of research into policy and practice. In the modern era of evidence-based medicine, it is essential that not only is new evidence incorporated into clinical practice, but that the implementation and associated costs are monitored; this requires the setting of appropriate benchmarking criteria. Furthermore, it is imperative that all members of the population receive optimal health care and people are not discriminated against because of socio-economic, locational, or racial factors. The use of data linkage can assist with examining these aspects of health care and this paper provides real-life examples such as costs and adverse events from laparoscopic cholecystectomy, event monitoring for post-operative venous thrombosis, and inequalities in cancer care. The influence of these studies on clinical practice and policy is also discussed. Furthermore, this paper discusses the strengths and weaknesses of data linkage research and how to avoid pitfalls. Health researchers, clinicians, and policy-makers will find the discussion of these issues useful in their everyday practice.

Ethics, Medical↗
PubMed2004

Health Care Utilization by Canadian Women.

HEALTH ISSUES: While women are reported to be more frequent users of health services in Canada, differences in women's and men's health care utilization have not been fully explored. To provide an overview on women's healthcare utilization, we selected two key issues that are important for public policy purposes: access to care and patterns of utilization. These issues are examined using primarily data from the 1998/99 National Population Health Survey, complemented by the 2000 Canadian Community Health Survey and the 2001 Health Service Access Survey. KEY FINDINGS: * Women are twice as likely as men to report a regular family physician, but that proportion is very low (15.8%).* Women report significantly shorter specialist wait times (20.9 days) than men (55.4 days) for mental health, while the reverse is true for asthma and other breathing conditions (10.8 for men, 78.8 for women).* Reported mean wait times are significantly lower for men than for women pertaining to overall diagnostic tests: for MRI, 70.3 days for women compared to 29.1 days for men. DATA GAPS AND RECOMMENDATIONS: * Measurement of possible system bias and its implication for equitable and quality healthcare for women requires larger provincial samples of the national surveys, along with a longitudinal design.* Either a national database on preventive services, or better alignment of provincial databases pertaining to health promotion and preventive services, is needed to facilitate data linkage with national surveys to undertake longitudinal studies that support gender based analyses.en are reported to be more frequent users of health services in Canada, differences in women's and men's health care utilization have not been fully explored. To provide an overview on women's healthcare utilization, we selected two key issues that are important for public policy purposes: access to care and patterns of utilization. These issues are examined using primarily data from the 1998/99 National Population Health Survey, complemented by the 2000 Canadian Community Health Survey and the 2001 Health Service Access Survey. KEY FINDINGS: * Women are twice as likely as men to report a regular family physician, but that proportion is very low (15.8%).* Women report significantly shorter specialist wait times (20.9 days) than men (55.4 days) for mental health, while the reverse is true for asthma and other breathing conditions (10.8 for men, 78.8 for women).* Reported mean wait times are significantly lower for men than for women pertaining to overall diagnostic tests: for MRI, 70.3 days for women compared to 29.1 days for men. DATA GAPS AND RECOMMENDATIONS: * Measurement of possible system bias and its implication for equitable and quality healthcare for women requires larger provincial samples of the national surveys, along with a longitudinal design.* Either a national database on preventive services, or better alignment of provincial databases pertaining to health promotion and preventive services, is needed to facilitate data linkage with national surveys to undertake longitudinal studies that support gender based analyses.

Journal Article↗
PubMed1998

Localisation of a gene for non-specific X linked mental retardation (MRX46) to Xq25-q26.

We report linkage data on a new large family with non-specific X linked mental retardation (MRX), using 24 polymorphic markers covering the entire X chromosome. We could assign the underlying disease gene, denoted MRX46, to the Xq25-q26 region. MRX46 is tightly linked to the markers DXS8072, HPRT, and DXS294 with a maximum lod score of 5.12 at theta=0. Recombination events were observed with DXS425 in Xq25 and DXS984 at the Xq26-Xq27 boundary, which localises MRX46 to a 20.9 cM (12 Mb) interval. Several X linked mental retardation syndromes have been mapped to the same region of the X chromosome. In addition, the localisation of two MRX genes, MRX27 and MRX35, partially overlaps with the linkage interval obtained for MRX46. Although an extension of the linkage analysis for MRX35 showed only a minimal overlap with MRX46, it cannot be excluded that the same gene is involved in several of these MRX disorders. On the other hand, given the considerable genetic heterogeneity in MRX, one should be extremely cautious in using interfamilial linkage data to narrow down the localisation of MRX genes. Therefore, unless the underlying gene(s) is characterised by the analysis of candidate genes, MRX46 can be considered a new independent MRX locus.

Adult↗
PubMed2006

Factors affecting place of death in Western Australia.

Despite the growing international interest in place of death and its relationship to healthcare policy, virtually nothing is known about where people die in Australia. To address this gap our study employs a longitudinal, population-based retrospective cohort study of people who died in Western Australia over a 30-month period. Mortality, morbidity and palliative care service data sets from the Western Australian Data Linkage System were examined to provide demographic and disease-specific characteristics and healthcare service use in the last year of life for the 26882 people who died during this time. The main outcome variables of the study were accommodation setting at the time of death (usual place of residence, hospital, hospice, residential aged care facility and other) and specialist palliative care use (hospital, home-based, both or neither). Over half of Western Australians died in hospital, but as people age there is an increasing tendency to die in their usual place of residence, which may be a private residence or an aged care facility. People who accessed community-based specialist palliative care had a seven times higher chance of dying in their usual place of residence. Importantly, this information is provided, not just for cancer deaths, as has been the practice to date, but for a range of other painful and life-limiting conditions considered amenable to palliative care. The unique population data on palliative care service use, made possible by the data linkage system, provides a basis for planning health services and policies.

Adolescent↗
PubMed2005

Convergent functional genomics: a Bayesian candidate gene identification approach for complex disorders.

Identifying genes involved in complex neuropsychiatric disorders through classic human genetic approaches has proven difficult. To overcome that barrier, we have developed a translational approach called Convergent Functional Genomics (CFG), which cross-matches animal model microarray gene expression data with human genetic linkage data as well as human postmortem brain data and biological role data, as a Bayesian way of cross-validating findings and reducing uncertainty. Our approach produces a short list of high probability candidate genes out of the hundreds of genes changed in microarray datasets and the hundreds of genes present in a linkage peak chromosomal area. These genes can then be prioritized, pursued, and validated in an individual fashion using: (1) human candidate gene association studies and (2) cell culture and mouse transgenic models. Further bioinformatics analysis of groups of genes identified through CFG leads to insights into pathways and mechanisms that may be involved in the pathophysiology of the illness studied. This simple but powerful approach is likely generalizable to other complex, non-neuropsychiatric disorders, for which good animal models, as well as good human genetic linkage datasets and human target tissue gene expression datasets exist.

Animals↗
PubMed2005

Consensus genetic maps: a graph theoretic approach.

A genetic map is an ordering of genetic markers constructed from genetic linkage data for use in linkage studies and experimental design. While traditional methods have focused on constructing maps from a single population study, increasingly maps are generated for multiple lines and populations of the same organism. For example, in crop plants, where the genetic variability is high, researchers have created maps for many populations. In the face of these new data, we address the increasingly important problem of generating a consensus map - an ordering of all markers in the various population studies. In our method, each input map is treated as a partial order on a set of markers. To find the most consistent order shared between maps, we model the partial orders as directed graphs. We create an aggregate by merginging the transitive closure of the input graphs and taking the transitive reduction of the result. In this process, cycles may need to be broken to resolve inconsistencies between the inputs. The cycle breaking problem is NP-hard, but the problem size depends upon the scope of the inconsistency between the input graphs, which will be local if the input graphs are from closely related organisms. We present results of running the resulting software on maps generated from seven populations of the crop plant Zea Mays.

Chromosome Mapping↗
PubMed1994

Molecular analysis of 53 fragile X families with the probe StB12.3.

Fifty-three pedigrees with the fragile X syndrome have been studied for amplification of the CGG repeat sequence adjacent to the CpG island in the FMR1 gene. Probe StB12.3 allowed direct detection of affected males, carrier females, normal transmitting males, as well as prenatal diagnosis. Comparison of our molecular data with our previous linkage data from 38 families indicates the effectiveness of direct DNA analysis. A total of 325 individuals were studied and no new mutation was found. All daughters of males with a premutation had a premutation. When the mother had a full mutation no children had a premutation. In premutated mothers, the size of the premutation seems to be a determining factor for the transition to the full mutation. All affected males had a full mutation or mosaicism and only 42% of the females with a full mutation were mentally impaired. Analysis of large families over 3 generations illustrated clearly the Sherman paradox. Furthermore, the analysis of these families is in reasonable agreement with the multiallelic model of Morton and Macpherson [Proc Natl Acad Sci USA 89:4215-4217, 1992]. Mosaic cases in the offspring of the mothers with a full mutation suggest a maternal germinal mosaicism. Then an abnormal methylation and a somatic heterogeneity established in very early steps of embryogenesis could explain these cases.

Alleles↗
PubMed1980

Data on linkage relations between GLO and 21-hydroxylase.

Linkage between GLO and 21-hydroxylase was investigated in 11 families with 24 children. Positive lod score values with a maximum of +1.618 at theta = 0.05 indicate close linkage between these marker loci.

Adrenal Hyperplasia, Congenital↗
PubMed2006

Candidate genes, pathways and mechanisms for alcoholism: an expanded convergent functional genomics approach.

We describe a comprehensive translational approach for identifying candidate genes for alcoholism. The approach relies on the cross-matching of animal model brain gene expression data with human genetic linkage data, as well as human tissue data and biological roles data, an approach termed convergent functional genomics. An analysis of three animal model paradigms, based on inbred alcohol-preferring (iP) and alcohol-non-preferring (iNP) rats, and their response to treatments with alcohol, was used. A comprehensive analysis of microarray gene expression data from five key brain regions (frontal cortex, amygdala, caudate-putamen, nucleus accumbens and hippocampus) was carried out. The Bayesian-like integration of multiple independent lines of evidence, each by itself lacking sufficient discriminatory power, led to the identification of high probability candidate genes, pathways and mechanisms for alcoholism. These data reveal that alcohol has pleiotropic effects on multiple systems, which may explain the diverse neuropsychiatric and medical pathology in alcoholism. Some of the pathways identified suggest avenues for pharmacotherapy of alcoholism with existing agents, such as angiotensin-converting enzyme (ACE) inhibitors. Experiments we carried out in alcohol-preferring rats with an ACE inhibitor show a marked modulation of alcohol intake. Other pathways are new potential targets for drug development. The emergent overall picture is that physical and physiological robustness may permit alcohol-preferring individuals to withstand the aversive effects of alcohol. In conjunction with a higher reactivity to its rewarding effects, they may able to ingest enough of this nonspecific drug for a strong hedonic and addictive effect to occur.

Alcohol Drinking↗
PubMed2003

The tetranucleotide repeat polymorphism C2_4_4: population data and linkage disequilibria with HLA class I.

The tetranucleotide repeat locus C2_4_4 situated in the HLA class I region (6p21.3) and the HLA-ABC specificities were investigated in an Austrian population sample of 240 unrelated Caucasoid individuals. The analysis of the linkage disequilibrium between C2_4_4 and HLA class I showed several significant values, especially when factors coded for by so-called "superhaplotypes" were considered; such linkage disequilibria are of importance for the practical use of HLA coded short tandem repeats.

Austria↗
PubMed2005

SNPLINK: multipoint linkage analysis of densely distributed SNP data incorporating automated linkage disequilibrium removal.

SUMMARY: SNPLINK is a Perl script that performs full genome linkage analysis of high-density single nucleotide polymorphism (SNP) marker sets. The presence of linkage disequilibrium (LD) between closely spaced SNP markers can falsely inflate linkage statistics. SNPLINK removes LD from the marker sets in an automated fashion before carrying out linkage analysis. SNPLINK can compute both parametric and non-parametric statistics, utilizing the freely available Allegro and Merlin software. Graphical outputs of whole genome multipoint linkage statistics are provided allowing comparison of results before and after the removal of LD.

Algorithms↗
PubMedDate not supplied

Linkage analysis of the transferrin, albumin, and hemoglobin loci in leopard frogs.

Transferrin was found to be monomorphic in a sample of 20 wild-caught Rana pipiens and 20 R. blairi. Albumin was monomorphic in R. Blairi, but one of the 20 R. pipiens was heterozygous at the albumin locus. The homologous proteins of the two species differ in their mobility. Both parental proteins are represented in hybrids. Backcross offspring exhibit no significant deviation from the expected normal Mendelian ratios. Linkage data suggest a weak linkage between the albumin and transferrin loci with neither of them being linked with the hemoglobin linkage group.

Animals↗