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Linkage Study (linkage + study)
Kinds of Linkage Study Selected AbstractsComparing retention in treatment and mortality in people after initial entry to methadone and buprenorphine treatmentADDICTION, Issue 7 2009James Bell ABSTRACT Aim To compare retention in treatment and mortality among people entering methadone and buprenorphine treatment for opioid dependence. Data sources The Pharmaceutical Drugs of Abuse System (PHDAS) database records start- and end-dates of all episodes of methadone and buprenorphine treatment in New South Wales, and the National Death Index (NDI) records all reported deaths. Methods Data linkage study. First entrants to treatment between June 2002 and June 2006 were identified from the PHDAS database. Retention in treatment was compared between methadone and buprenorphine. Names were linked to the NDI database, and ,good matches' were identified. Deaths were classified as occurring during induction, maintenance and either post-methadone or post-buprenorphine, depending on the latest episode of treatment prior to death. The numbers of inductions into treatment, of total person-years spent in each treatment, and person-years post-methadone or buprenorphine, were calculated. Risk of death in different periods, and different treatments, was analysed using Poisson regression. Results A total of 5992 people entered their first episode of treatment,3349 (56%) on buprenorphine, 2643 on methadone. Median retention was significantly longer in methadone (271 days) than buprenorphine (40 days). During induction, the risk of death was lower for buprenorphine (relative risk = 0.114, 95% confidence interval = 0.002,0.938, P = 0.02, Fisher's exact test). Risk of death was lowest during treatment, significantly higher in the first 12 months after leaving both methadone and buprenorphine. Beyond 12 months after leaving treatment, risk of death was non-significantly higher than during treatment. Conclusions Buprenorphine was safer during induction. Despite shorter retention in treatment, buprenorphine maintenance was not associated with higher risk of death. [source] Involvement of fumarate hydratase in nonsyndromic uterine leiomyomas: Genetic linkage analysis and FISH studiesGENES, CHROMOSOMES AND CANCER, Issue 3 2004Karen L. Gross Recently, germline mutations of the fumarate hydratase (FH) gene, in 1q42.1, have been found to be involved in syndromes associated with uterine leiomyomas (ULs). Compelling evidence also supports a genetic liability to develop nonsyndromic UL, although susceptibility genes have not been reported to date. Loss of heterozygosity (LOH) studies have found no or rare evidence of LOH of FH in nonsyndromic UL. However, the karyotypes of these tumors were not reported, and cytogenetic aberrations of 1q42,44 have been observed infrequently in UL. To determine whether FH mutations also may predispose women to developing nonsyndromic UL, we performed a genetic linkage study with DNA from 123 families containing at least one affected sister pair. In addition, to assess the frequency of FH loss specifically in UL with 1q rearrangements, we performed a fluorescence in situ hybridization (FISH) analysis of UL with 1q rearrangements. Analysis of the genotyping data revealed evidence suggestive of linkage to the FH region among study participants who were less than 40 years of age at diagnosis (Zlr 1.7 at D1S547, P = 0.04). FISH results showed that one copy of FH was absent in 9 of 11 ULs. These data indicate that loss of FH might be a significant event in the pathogenesis of a subset of nonsyndromic ULs. © 2004 Wiley-Liss, Inc. [source] Interpreting analyses of continuous covariates in affected sibling pair linkage studiesGENETIC EPIDEMIOLOGY, Issue 6 2007Silke Schmidt Abstract Datasets collected for linkage analyses of complex human diseases often include a number of clinical or environmental covariates. In this study, we evaluated the performance of three linkage analysis methods when the relationship between continuous covariates and disease risk or linkage heterogeneity was modeled in three different ways: (1) The covariate distribution is determined by a quantitative trait locus (QTL), which contributes indirectly to the disease risk; (2) the covariate is not genetically determined, but influences the disease risk through statistical interaction with a disease susceptibility locus; (3) the covariate distribution differs in families linked or unlinked to a particular disease susceptibility locus. We analyzed simulated datasets with a regression-based QTL analysis, a nonparametric analysis of the binary affection status, and the ordered subset analysis (OSA). We found that a significant OSA result may be due to a gene that influences variability in the population distribution of a continuous disease risk factor. Conversely, a regression-based QTL analysis may detect the presence of gene-environment (G × E) interaction in a sample of primarily affected individuals. The contribution of unaffected siblings and the size of baseline lod scores may help distinguish between QTL and G × E models. As illustrated by a linkage study of multiplex families with age-related macular degeneration, our findings assist in the interpretation of analysis results in real datasets. They suggest that the side-by-side evaluation of OSA and QTL results may provide important information about the relationship of measured covariates with either disease risk or linkage heterogeneity. Genet. Epidemiol. 2007. © 2007 Wiley-Liss, Inc. [source] Inflammatory bowel disease is linked to 19p13 and associated with ICAM-1INFLAMMATORY BOWEL DISEASES, Issue 3 2004Jin Hong Low Abstract Genome-wide scans have implicated several susceptibility loci, but linkage of 19p13 (IBD6) to Crohn's disease (CD) has not been fully replicated. We report a replication study of IBD6 in a UK Caucasian population. Two hundred eighty-four affected sibling pairs from 234 families were used for the linkage study. Linkage between IBD6 linkage and CD was replicated (LOD score = 1.59). Two candidate genes (DDXL and ICAM-1) within the IBD6 locus were examined in a case/control study with a total of 228 CD and 243 ulcerative colitis (UC) patients and 407 healthy controls. No association to either UC or CD was found in three novel intronic single nucleotide polymorphisms (SNPs) in DDXL. For ICAM-1, a significant association was found between K469 homozygosity and CD overall (39.9% vs 29.4%; Pc = 0.0096) and between E469 and fistulating disease (21.8% vs 10.0%, Pc = 0.030). In the UC group, limited disease extent was associated with homozygosity of the G241 allele (82.7% vs 64.7%, Pc = 0.0040). These data support linkage for CD at 19p13 and suggest that the amino acid polymorphisms in ICAM-1 may be associated with IBD. [source] Identification of Susceptibility Loci for Alcohol-Related Traits in the Irish Affected Sib Pair Study of Alcohol DependenceALCOHOLISM, Issue 11 2006Po-Hsiu Kuo Background: Alcoholism is a phenotypically and probably genetically heterogeneous condition. Thus, one strategy for finding genes influencing liability to alcoholism is to study the components of alcoholism, which may be more directly related to the underlying pathophysiology than is clinical diagnosis. The goal of this study was to identify genomic regions containing susceptibility loci for alcohol-related traits. Methods: A 4-cM dense whole-genome linkage study was conducted in the Irish Affected Sib Pair Study of Alcohol Dependence. Probands, affected siblings, and parents were evaluated by structured interview. Variance component linkage analysis was applied to data from 485 families for 5 measures: initial sensitivity and tolerance (based on scales from the self-report of the effects of ethanol; maximum drinks within 24 hours, an empirically derived factor score based on withdrawal symptoms, and age at onset of alcohol dependence. Results: Evidence for linkage (p<0.005) was found on 9 chromosomes. For age at onset, 2 regions were found on chromosome 9 (highest Lod=2.3, p=0.0005). For initial level of response to alcohol, suggestive regions were on chromosomes 1 and 11 (highest Lod=2.9, p=0.0001 on chromosome 11), while those for tolerance signals were on chromosomes 1, 6, and 22. Maximum drinking was associated with regions on chromosomes 12 and 18. For withdrawal symptoms, the highest peak was on chromosome 2 (Lod=2.2, p=0.0007). Conclusions: Using quantitative measures of components of alcohol dependence, we identified several regions of the genome that may contain susceptibility loci for specific alcohol-related traits and merit additional study. [source] Perinatal risk factors and coeliac disease in children and young adults: a record linkage studyALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 2 2009S. E. ROBERTS Summary Background, Little is known about perinatal risk factors and coeliac disease. Aim, To investigate the relationship between perinatal risk factors and subsequent coeliac disease among offspring. Methods, Record linked abstracts of birth registrations, maternity, in-patient and day case records in a defined population of southern England. Results, Using univariate analysis, coeliac disease in the child was associated with maternal coeliac disease (odds ratio = 20.6; 95% CI = 5.04,84.0; based on two cases in both mother and child) and with social class, year of birth, maternal smoking and parity. Multivariate analysis confirmed an increased risk of coeliac disease of 3.79 (95% CI = 1.85,7.79) for classes IV and V compared with I and II, an increased risk of 1.92 (1.06,3.49) for births during 1975,1979 compared with 1970,1974 and an increased risk of 1.80 (1.05,3.09) for ,subsequent' compared with ,first' births. Smoking during pregnancy was no longer associated with coeliac disease. Because numbers were small, maternal coeliac disease was excluded from the multivariate anaylsis. Conclusions, This study shows increased risks of coeliac disease for manual social classes, births during the late 1970s and ,subsequent' births. Overall, perinatal risk factors seem to have a limited role in the aetiology of coeliac disease in children and young adults. [source] Aspirin increases mortality in diabetic patients without cardiovascular disease: a Swedish record linkage study,PHARMACOEPIDEMIOLOGY AND DRUG SAFETY, Issue 12 2009Lennart Welin MD Abstract Purpose Aspirin is effective in secondary prevention of cardiovascular disease. The results are less convincing when aspirin is used for primary prevention even in high-risk patients (i.e., patients with diabetes). We therefore analyzed the effect of aspirin on mortality and serious bleeding in diabetic patients with and without cardiovascular disease. Methods We performed a record linkage study of the patient registry of the Västra Götaland region in south-western Sweden, the Swedish mortality register and the Swedish register of dispensed drugs. All diabetic patients (n,=,58,465) from 1 July 2005 to 30 June 2006 were followed up with respect to bleeding until 31 October 2006, and mortality until 31 December 2006. Results When 19 confounding factors (diseases and interventions) were assessed, aspirin significantly increased mortality in diabetic patients without cardiovascular disease from 17% (95% confidence interval; 95%CI, 1,36) at age 50 years to 29% (16,43) at age 85 years. In contrast aspirin tended to decrease mortality among elderly diabetic patients with cardiovascular disease. Theoretical calculations indicated that aspirin caused 107 excess deaths among diabetic patients without cardiovascular disease and prevented 164 deaths among diabetic patients with cardiovascular disease. Aspirin also increased the risk of serious bleeding by 46% (95%CI, 22,75) in diabetic patients without cardiovascular disease but decreased the risk among those with cardiovascular disease. Conclusion Aspirin use in diabetes patients without cardiovascular disease remains controversial and current guidelines should be revised until results from ongoing large randomized controlled trials become available. Copyright © 2009 John Wiley & Sons, Ltd. [source] Women's fertility and mortality in late mid life: A comparison of three contemporary populationsAMERICAN JOURNAL OF HUMAN BIOLOGY, Issue 4 2009Emily Grundy Evolutionary theory suggests a trade-off between reproduction and somatic maintenance implying a negative relationship between parity and longevity, at least in natural fertility populations. In populations in which fertility control is usual, there are also a number of mechanisms that may link reproductive careers and later mortality, but evidence of associations between women's fertility patterns and their later life health has been judged inconclusive due to varying controls for socio-economic characteristics and marital status. Here, we build on three recent studies that followed a common framework to investigate associations between women's parity and timing of first and last birth with mortality in late middle age in three contemporary developed counties, Norway, England and Wales, and the USA. Data were drawn from whole population registers (Norway); a large census-based record linkage study (England and Wales), and a nationally representative survey linked to death records (USA). Results show that teenage childbirth was associated with higher mortality risks in late middle age in all three countries. Risks of death were significantly raised among nulliparous women in Norway and England and Wales, and also raised (although not significantly so) for childless US women. However, although higher parity was associated with a slight mortality disadvantage in England and Wales and the USA, the reverse seemed the case in Norway. These finding suggest that in populations in which fertility control is usual, contextual factors influencing the relative costs and benefits of childbearing may influence associations between fertility histories and later mortality. Am. J. Hum. Biol., 2009. © 2009 Wiley-Liss, Inc. [source] A genomewide linkage study of age at onset in schizophrenia,AMERICAN JOURNAL OF MEDICAL GENETICS, Issue 5 2001Alastair G. Cardno Abstract There is strong evidence for a genetic contribution to age at onset of schizophrenia, which probably involves both susceptibility loci for schizophrenia and modifying loci acting independent of disease risk. We sought evidence of linkage to loci that influence age at onset of schizophrenia in a sample of 94 affected sibling pairs with DSM-IV schizophrenia or schizoaffective disorder, and age at first psychiatric contact of 45 years or less. Individuals were genotyped for 229 microsatellite markers spaced at approximately 20 cM intervals throughout the genome. Loci contributing to age at onset were sought by a quantitative maximum-likelihood multipoint linkage analysis using MAPMAKER/SIBS. A nonparametric multipoint analysis was also performed. The genomewide significance of linkage results was assessed by simulation studies. There were six maximum-likelihood LOD score peaks of 1.5 or greater, the highest being on chromosome 17q (LOD,=,2.54; genomewide P,=,0.27). This fulfils Lander and Kruglyak's [1995: Nat Genet 11:241,247] criteria for suggestive linkage in that it would be expected to occur once or less (0.3 times) per genome scan. However, this finding should be treated with caution because the LOD score appeared to be almost solely accounted for by the pattern of ibd sharing at one marker (D17S787), with virtually no evidence of linkage over flanking markers. None of the linkage results achieved genomewide statistical significance, but the LOD score peak on chromosome 13q (LOD,=,1.68) coincided with the region showing maximum evidence for linkage in the study by Blouin et al. [1998: Nat Genet 20:70,73] of categorical schizophrenia. © 2001 Wiley-Liss, Inc. [source] Quantitative-trait-locus Mapping in the Presence of Locus HeterogeneityANNALS OF HUMAN GENETICS, Issue 6 2006K Wang Summary Locus heterogeneity is a concern for quantitative trait locus mapping where phenotypes are likely to be influenced by more than one gene. We introduce a model which generalizes the locus heterogeneity model of Smith (1961) from dichotomous traits to quantitative traits and consider some test statistics for this model. The type I error rates and the power of these statistics are assessed through simulation studies. These statistics are applied to a linkage study of asthma genes. [source] Termination of pregnancy according to immigration status: a population-based registry linkage studyBJOG : AN INTERNATIONAL JOURNAL OF OBSTETRICS & GYNAECOLOGY, Issue 10 2008S Vangen Objective, Frequency of termination of pregnancy (TOP) and associated risk factors according to immigration status were studied. Design, Population-based registry study linking hospital data with information from the Central Population Registry of Norway. Setting, Oslo, Norway. Population, All women 15,49 years undergoing TOP and resident in Oslo, Norway from 1 January 2000 to 31 July 2003. Methods, TOP rates per 1000 women/year were calculated. The association of socio-economic variables such as maternal age, marital status, number of children and education level within the study groups were estimated as odds ratios and using logistic regression. Main outcome measure, Termination of pregnancy. Results, Refugees (30.2, 95% CI = 28.5,31.8) and labour migrants (19.9, 95% CI = 18.7,21.3) had significantly higher TOP rates than nonmigrants (16.7, 95% CI = 16.3,17.1). Except in women less than 25 years, labour migrants had higher TOP rates than nonmigrants. Refugees had the highest rates in all age groups. Being unmarried was associated with a substantially increased risk of TOP among the nonmigrants; such effect was not observed among labour migrants and refugees. Two or more children were associated with increased risk among nonmigrants and refugees compared with four or more among the labour migrants. Generally, higher education showed a protective effect that was most pronounced among nonmigrants. Compared with nonmigrants, adjusted risk of TOP was 1.37 (95% CI = 1.25,1.50) for labour migrants and 1.94 (95% CI = 1.79,2.11) for refugees. Conclusion, Public health efforts to increase the use of contraceptives among refugees and labour migrants above 25 years should be encouraged. [source] Suggestive linkage of familial primary cutaneous amyloidosis to a locus on chromosome 1q23BRITISH JOURNAL OF DERMATOLOGY, Issue 1 2005M-W. Lin Summary Background, There is a high incidence of primary cutaneous amyloidosis (PCA) in South America, South-east Asia and Taiwan. To date, the aetiology of PCA remains unknown, but it is believed to be multifactorial. Although most cases are sporadic, some patients have a family history. Familial aggregation and different susceptibility to PCA among ethnic groups suggest that genetic factors may play an important role in its pathogenesis. However, no genetic loci for familial PCA (FPCA) have been identified so far. Objectives, In order to identify the susceptibility gene of FPCA, we took a candidate gene approach and performed linkage analysis on chromosome 1q21.3,24.2, including the 1q23.2 region where the gene encoding serum amyloid P component (APCS) is located. Patients and methods, Nine FPCA families including 29 individuals affected with PCA were recruited for this linkage study. Initially, 11 highly polymorphic microsatellite markers spanning the region from 1q21.3 to 1q24.2 were genotyped and revealed a suggestive linkage region. This region was further fine-mapped with seven additional markers. We also re-sequenced the 2·5-kb genomic region of the APCS gene in 29 affected and 42 control individuals. Two-point and multipoint linkage analyses were performed using the LINKAGE program. Nonparametric linkage (NPL) analysis and reconstruction of haplotypes were performed with the GENEHUNTER program. Results, Both two-point and multipoint linkage analysis for all 11 markers generated negative or small positive total lod scores for all nine families. However, when we considered only three families, a maximum two-point total lod score of 2·09 was obtained for the marker D1S2844 at , = 0·01. A plateau of multipoint total lod score between D1S2768 and D1S2878 with a maximum of 2·48 at the marker D1S2844 was observed. A maximum NPL score of 3·11 (P = 0·008) was also obtained for the marker D1S2878. However, re-sequencing of the APCS gene identified no functional mutation. Conclusions, Both parametric and nonparametric linkage evidence suggested that a possible susceptibility locus for a subset of FPCA might exist on chromosome 1q23. This is the first report demonstrating suggestive evidence of linkage of FPCA to a locus in this candidate region. No functional sequence variations of the APCS gene were found to be associated with this disease among the study families. Our data imply the existence of at least one additional locus responsible for FPCA in these families, confirming genetic heterogeneity of this skin disorder. [source] | |||||||||||||