Search PubMed⌕ Search

Biomedical subjects

D J Schaid

Publications and source records attributed to D J Schaid.

At least 19 recordsLinked to original sources
PubMed2003

Validity of family history data on PD: evidence for a family information bias.

OBJECTIVE: To study the validity of information provided by case and control subjects (or their proxies) about PD among their first-degree relatives. METHODS: Secondary cases of PD were assessed both through a single informant (family history method) and through the study of each relative (family study method). The family study method was considered as the standard for comparison, and the sensitivity and specificity of the family history method were studied. RESULTS: A total of 133 population-based case subjects and their 655 relatives were recruited, and 119 population-based control subjects and their 511 relatives. Sensitivity was 68% (95% CI = 47 to 85) for cases and 45% (95% CI = 17 to 77) for controls. Specificity was 99% (95% CI = 98 to 99) for cases and 100% (95% CI = 99 to 100) for controls. The odds ratio (OR) for family history of PD was 4.34 (95% CI = 1.63 to 11.58, p = 0.003) using the family history method and 1.86 (95% CI = 0.78 to 4.44, p = 0.16) using the family study method. The former significant OR more than doubled the latter not significant OR (relative bias = 133%). Bias was more pronounced for proxy interviews and for women informants, and when the relatives were siblings, were living, and were examined or had medical record documentation. CONCLUSIONS: Case subjects with PD (or their proxies) are more aware of PD among their first-degree relatives than control subjects (or their proxies); however, they overreport PD in relatives who are not affected. This causes a substantial family information bias.

Adult↗
PubMed2003

The gene for HMSN2C maps to 12q23-24: a region of neuromuscular disorders.

BACKGROUND: Hereditary motor and sensory neuropathy type 2C (HMSN2C, Charcot-Marie-Tooth 2C [CMT2C]) is an autosomal dominant motor and sensory neuropathy involving limb, diaphragm, vocal cord, and intercostal muscles. OBJECTIVE: To identify the chromosome localization for this disorder in one large American family of English and Scottish ethnicity. METHODS: Variable clinical severity led the authors to combine several approaches to accurately identify affected patients. Genome-wide two-point linkage analysis, high-definition mapping, and multipoint and recombinant haplotype analyses were performed. Mutation analysis of the triplet repeat region of ataxin-2 was also carried out. RESULTS: The initial genome-wide scan identified a region at 12q24, and fine mapping provided a maximal lod score of 4.73 (D12S1645 and D12S1583 at theta = 0.01 and 0, respectively). With multipoint analysis, a higher lod score of 5.17 was obtained and localized to the same region at 119.0 cM. Haplotype analysis narrowed the region to approximately 5.0 cM between D12S1646,D12S1330 and D12S105,D12S1339 (12q23.3-24.21). Ataxin-2, the gene responsible for spinocerebellar ataxia type 2 (SCA2), localizes to this region, but no triplet repeat expansion or point mutations within the repeat were found. CONCLUSIONS: The gene for HMSN2C maps to 12q23-24. This region is associated with SCA2, scapuloperoneal spinal muscular atrophy, and congenital distal spinal muscular atrophy. Further studies are needed to demonstrate the specific gene alteration and its relationship with nearby genes.

Age of Onset↗
PubMed2003

Confirmation of linkage of prostate cancer aggressiveness with chromosome 19q.

Regions on chromosomes 7 and 19 were recently reported to contain susceptibility loci that regulate tumor aggressiveness of prostate cancer. To confirm these findings, we analyzed genome scan data from 161 pedigrees affected with prostate cancer. Using the Gleason score as a quantitative measure of tumor aggressiveness, we regressed the squared trait difference, as well as the mean-corrected cross product, on the estimated proportion of alleles shared identical-by-descent at each marker position. Our results confirm the previous linkage results for chromosome 19q (D19S902, P<.00001). In addition, we report suggestive evidence for linkage on chromosome 4 (D4S403, P=.00012). The results of previous findings, together with our results, provide strong evidence that chromosome 19 harbors a gene for tumor aggressiveness.

Chromosome Mapping↗
PubMed2003

Candidate-gene association studies with pedigree data: controlling for environmental covariates.

Case-control studies provide an important epidemiological tool to evaluate candidate genes. There are many different study designs available. We focus on a more recently proposed design, which we call a multiplex case-control (MCC) design. This design compares allele frequencies between related cases, each of whom are sampled from multiplex families, and unrelated controls. Since within-family genotype correlations will exist, statistical methods will need to take this into account. Moreover, there is a need to develop methods to simultaneously control for potential confounders in the analysis. Generalized estimating equations (GEE) are one approach to analyze this type of data; however, this approach can have singularity problems when estimating the correlation matrix. To allow for modeling of other covariates, we extend our previously developed method to a more general model-based approach. Our proposed methods use the score statistic, derived from a composite likelihood. We propose three different approaches to estimate the variance of this statistic. Under random ascertainment of pedigrees, score tests have correct type I error rates; however, pedigrees are not randomly ascertained. Thus, through simulations, we test the validity and power of the score tests under different ascertainment schemes, and an illustration of our methods, applied to data from a prostate cancer study, is presented. We find that our robust score statistic has estimated type I error rates within the expected range for all situations we considered whereas the other two statistics have inflated type I error rates under nonrandom ascertainment schemes. We also find GEE to fail at least 5% of the time for each simulation configuration; at times, the failure rate reaches above 80%. In summary, our robust method may be the only current regression analysis method available for MCC data.

Case-Control Studies↗
PubMed2003

Progression of familial and non-familial dilated cardiomyopathy: long term follow up.

BACKGROUND: It is unknown whether progression of familial idiopathic dilated cardiomyopathy differs from progression in the non-familial form. It has been suggested that familial disease indicates a worse prognosis, and that this should be considered when planning the timing of heart transplantation. OBJECTIVE: To compare five year survival or time to heart transplantation in an unselected series of patients with dilated cardiomyopathy who had been evaluated for familial v non-familial disease through the echocardiographic investigation of first degree relatives. DESIGN: Medical records were reviewed and questionnaires were mailed to all patients who had previously participated in a family based study of dilated cardiomyopathy. Information was gathered about survival, heart transplantation, and left ventricular ejection fraction (LVEF) measurements. Survival data were censored at the time of cardiac transplantation. RESULTS: Follow up data were obtained for 99 of 101 patients (69 with non-familial and 30 with familial disease). Five year survival was 55% for non-familial and 51% for familial patients (NS). The main predictor of mortality was an LVEF of < 30%. Familial status did not predict mortality. There was no significant difference in follow up LVEF values between the groups. CONCLUSIONS: Five year survival is not significantly different in the familial and non-familial forms of dilated cardiomyopathy.

Adolescent↗
PubMed2003

Estimation and tests of haplotype-environment interaction when linkage phase is ambiguous.

In the study of complex traits, the utility of linkage analysis and single marker association tests can be limited for researchers attempting to elucidate the complex interplay between a gene and environmental covariates. For these purposes, tests of gene-environment interactions are needed. In addition, recent studies have indicated that haplotypes, which are specific combinations of nucleotides on the same chromosome, may be more suitable as the unit of analysis for statistical tests than single genetic markers. The difficulty with this approach is that, in standard laboratory genotyping, haplotypes are often not directly observable. Instead, unphased marker phenotypes are collected. In this article, we present a method for estimating and testing haplotype-environment interactions when linkage phase is potentially ambiguous. The method builds on the work of Schaid et al. [2002] and is applicable to any trait that can be placed in the generalized linear model framework. Simulations were run to illustrate the salient features of the method. In addition, the method was used to test for haplotype-smoking exposure interaction with data from the Childhood Asthma Management Program.

Algorithms↗
PubMed2001

Identification of an association between HLA class II alleles and low antibody levels after measles immunization.

This is the first large cohort study to report a genetic association between humoral antibody level after measles vaccine and the HLA class II genes. The WHO goal to eradicate measles world-wide magnifies the importance of data relating to the influence of immunogenetics on measles vaccine-induced antibody responses. We present here the analysis of 242 individuals who received one dose of measles-mumps-rubella-II (MMR-II) vaccine at the age of 15 months and were genotyped for HLA class II alleles. These subjects fit into one of three categories; 72 were classified as seronegative, 93 were seropositive and 77 were serohyperpositive. HLA-DRB1*03 (odds ratio (OR), 2.22) and HLA-DPA1*0201 (OR, 1.71) were significantly associated with measles vaccine seronegativity, while additional alleles provided suggestive evidence of association with seronegativity: DQA1*0201, DQB1*0201, and DQA1*0501. The alleles DRB1*03 and DQA1*0201 remained statistically significant after accounting for the effects of other alleles. These findings are crucial in designing both measles eradication by the use of vaccine, and future vaccines to be used in genetically heterozygous populations.

Alleles↗
PubMed2001

Efficacy of bilateral prophylactic mastectomy in BRCA1 and BRCA2 gene mutation carriers.

BACKGROUND: In women with a family history of breast cancer, bilateral prophylactic mastectomy is associated with a decreased risk of subsequent breast cancer of approximately 90%. We examined the association between bilateral prophylactic mastectomy and breast cancer risk in women at high risk for breast cancer who also had mutations in BRCA1 and BRCA2 genes. METHODS: We obtained blood samples from 176 of the 214 high-risk women who participated in our previous retrospective cohort study of bilateral prophylactic mastectomy. We used conformation-sensitive gel electrophoresis and direct sequence analysis of the blood specimens to identify women with mutations in BRCA1 and BRCA2. The carriers' probabilities of developing breast cancer were estimated from two different penetrance models. RESULTS: We identified 26 women with an alteration in BRCA1 or BRCA2. Eighteen of the mutations were considered to be deleterious and eight to be of uncertain clinical significance. None of the 26 women has developed breast cancer after a median of 13.4 years of follow-up (range, 5.8-28.5 years). Three of the 214 women are known to have developed a breast cancer after prophylactic mastectomy. For two of these women, BRCA1 and BRCA2 screening was negative, and no blood specimen was available for the third. Estimations of the effectiveness of prophylactic mastectomy were performed, considering this woman as both a mutation carrier and a noncarrier. These calculations predicted that six to nine breast cancers should have developed among the mutation carriers, which translates into a risk reduction, after bilateral prophylactic mastectomy, of 89.5%-100% (95% confidence interval = 41.4% to 100%). CONCLUSIONS: Prophylactic mastectomy is associated with a substantial reduction in the incidence of subsequent breast cancer not only in women identified as being at high risk on the basis of a family history of breast cancer but also in known BRCA1 or BRCA2 mutation carriers.

Breast Neoplasms↗
PubMed2001

Efficacy of contralateral prophylactic mastectomy in women with a personal and family history of breast cancer.

PURPOSE: To estimate the efficacy of contralateral prophylactic mastectomy in women with a personal and family history of breast cancer. PATIENTS AND METHODS: We followed the course of 745 women with a first breast cancer and a family history of breast and/or ovarian cancer who underwent contralateral prophylactic mastectomy at the Mayo Clinic between 1960 and 1993. Family history information and cancer follow-up information were obtained from the medical record, a study-specific questionnaire, and telephone follow-up. Life-tables for contralateral breast cancers, which consider age at first breast cancer, current age, and type of family history, were used to calculate the number of breast cancers expected in our cohort had they not had a prophylactic mastectomy. RESULTS: Of the 745 women in our cohort, 388 were premenopausal (age < 50 years) and 357 were post- menopausal. Eight women developed a contralateral breast cancer. Six events were observed among the premenopausal women, compared with 106.2 predicted, resulting in a risk reduction of 94.4% (95% confidence interval [CI], 87.7% to 97.9%). For the 357 postmenopausal women, 50.3 contralateral breast cancers were predicted, whereas only two were observed, representing a 96.0% risk reduction (95% CI, 85.6% to 99.5%). CONCLUSION: The incidence of contralateral breast cancer seems to be reduced significantly after contralateral prophylactic mastectomy in women with a personal and family history of breast cancer.

Adult↗
PubMed2001

Role of HPC2/ELAC2 in hereditary prostate cancer.

The HPC2/ELAC2 gene on chromosome 17p was recently identified as a candidate gene for hereditary prostate cancer (HPC). To confirm these findings, we screened 300 prostate cancer patients (2 affected members/family) from 150 families with HPC for potential germ-line mutations using conformation-sensitive gel electrophoresis, followed by direct sequence analysis. The minimum criteria for our families with HPC was the presence of 3 affected men with prostate cancer. A total of 23 variants were identified, including 13 intronic and 10 exonic changes. Of the 10 exonic changes, 1 truncating mutation was identified, a Glu216Stop nonsense mutation. This nonsense variant was found in 2 of 3 affected men in a single family. The remaining nine alterations included five missense, three silent, and one variant in the 3' untranslated region. To additionally test for potential associations of polymorphic variants and increased risk for disease, we genotyped two common polymorphisms, Ser217Leu and Ala541Thr, in 446 prostate cancer patients from 164 families with HPC and 502 population-based controls. The frequency of the Leu217 variant was similar for patients (32.3%) and controls (31.8%), as was the frequency of the Thr541 variant (5.4% among patients versus 5.2% among controls). In contrast to previous reports, we found no association of the joint effects of Leu271 and Thr541 (odds ratio, 1.04; 95% confidence interval, 0.57-1.89). Overall, our results did not reveal any association between these two common polymorphisms and the risk for HPC. The finding of a nonsense mutation in the HPC2/ELAC2 gene confirms its potential role in genetic susceptibility to prostate cancer. However, our data also suggest that germ-line mutations of the HPC2/ELAC2 are rare in HPC and that the variants Leu217 and Thr541 do not appear to influence the risk for HPC. Cumulatively, these results suggest that alterations within the HPC2/ELAC2 gene play a limited role in genetic susceptibility to HPC.

Adult↗
PubMed2001

The frequency of hereditary defective mismatch repair in a prospective series of unselected colorectal carcinomas.

A comprehensive analysis of somatic and germline mutations related to DNA mismatch-repair (MMR) genes can clarify the prevalence and mechanism of inactivation in colorectal carcinoma (CRC). In the present study, 257 unselected patients referred for CRC resection were examined for evidence of defective DNA MMR. In particular, we sought to determine the frequency of hereditary defects in DNA MMR in this cohort of patients. MMR status was assessed by testing of tumors for the presence or absence of hMLH1, hMSH2, and hMSH6 protein expression and for microsatellite instability (MSI). Of the 257 patients, 51 (20%) had evidence of defective MMR, demonstrating high levels of MSI (MSI-H) and an absence of either hMLH1 (n=48) or hMSH2 (n=3). All three patients lacking hMSH2, as well as one patient lacking hMLH1, also demonstrated an absence of hMSH6. DNA sequence analysis of the 51 patients with defective MMR revealed seven germline mutations-four in hMLH1 (two truncating and two missense) and three in hMSH2 (all truncating). A detailed family history was available for 225 of the 257 patients. Of the seven patients with germline mutations, only three had family histories consistent with hereditary nonpolyposis colorectal cancer. Of the remaining patients who had tumors with defective MMR, eight had somatic mutations in hMLH1. In addition, hypermethylation of the hMLH1 gene promoter was present in 37 (88%) of the 42 hMLH1-negative cases available for study and in all MSI-H tumors that showed loss of hMLH1 expression but no detectable hMLH1 mutations. Our results suggest that, although defective DNA MMR occurs in approximately 20% of unselected patients presenting for CRC resection, hereditary CRC due to mutations in the MMR pathway account for only a small proportion of patients. Of the 257 patients, only 5 (1.9%) appear to have unequivocal evidence of hereditary defects in MMR. The epigenetic (nonhereditary) mechanism of hMLH1 promoter hypermethylation appears to be responsible for the majority of the remaining patients whose tumors are characterized by defective DNA MMR.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Major histocompatibility complex class I-recognizing receptors are disease risk genes in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a heterogeneous syndrome of which a subset of patients develops vascular inflammation. The genetic determinants that confer risk for rheumatoid vasculitis are not known, but patients with vascular complications are known to have an expansion of CD4(+)CD28(null) T cells, a cell population potentially involved in endothelial damage. CD4(+)CD28(null) T cell clones isolated from RA patients with vasculitis were found to express killer cell immunoglobulin-like receptors (KIRs) with the stimulatory KIR2DS2 often present in the absence of opposing inhibitory receptors with related specificities. To test the hypothesis that the KIR2DS2 gene is involved in the development of vasculitis, association studies were performed. The KIR2DS2 gene was significantly enriched among patients with rheumatoid vasculitis compared with normal individuals (odds ratio 5.56, P = 0.001) and patients with RA but no vasculitis (odds ratio 7.96, P = 0.001). Also, the distribution of human histocompatibility leukocyte antigen (HLA)-C, the putative ligand for KIRs, was significantly different in patients with rheumatoid vasculitis in comparison with the control populations. These data suggest that HLA class I-recognizing receptors and HLA class I genes are genetic risk determinants that modulate the pattern of RA expression. Specifically, KIR2DS2 in conjunction with the appropriate HLA-C ligand may have a role in vascular damage by regulating CD4(+)CD28(null) T cells.

Antigens, CD↗
PubMed2001

Evaluation of candidate genes in case-control studies: a statistical method to account for related subjects.

Traditional case-control studies provide a powerful and efficient method for evaluation of association between candidate genes and disease. The sampling of cases from multiplex pedigrees, rather than from a catchment area, can increase the likelihood that genetic cases are selected. However, use of all the related cases without accounting for their biological relationship can increase the type I error rate of the statistical test. To overcome this problem, we present an analysis method that is used to compare genotype frequencies between cases and controls, according to a trend in proportions as the dosage of the risk allele increases. This method uses the appropriate variance to account for the correlated family data, thus maintaining the correct type I error rate. The magnitude of the association is estimated by the odds ratio, with the variance of the odds ratio also accounting for the correlated data. Our method makes efficient use of data collected from multiplex families and should prove useful for the analysis of candidate genes among families sampled for linkage studies. An application of our method, to family data from a prostate cancer study, is presented to illustrate the method's utility.

Alleles↗
PubMed2001

Regression models for linkage heterogeneity applied to familial prostate cancer.

Linkage heterogeneity frequently occurs for complex genetic diseases, and statistical methods must account for it to avoid severe loss in power to discover susceptibility genes. A common method to allow for only a fraction of linked pedigrees is to fit a mixture likelihood and then to test for linkage homogeneity, given linkage (admixture test), or to test for linkage while allowing for heterogeneity, using the heterogeneity LOD (HLOD) score. Furthermore, features of the families, such as mean age at diagnosis, may help to discriminate families that demonstrate linkage from those that do not. Pedigree features are often used to create homogeneous subsets, and LOD or HLOD scores are then computed within the subsets. However, this practice introduces several problems, including reduced power (which results from multiple testing and small sample sizes within subsets) and difficulty in interpretation of results. To address some of these limitations, we present a regression-based extension of the mixture likelihood for which pedigree features are used as covariates that determine the probability that a family is the linked type. Some advantages of this approach are that multiple covariates can be used (including quantitative covariates), covariates can be adjusted for each other, and interactions among covariates can be assessed. This new regression method is applied to linkage data for familial prostate cancer and provides new insights into the understanding of prostate cancer linkage heterogeneity.

Age of Onset↗
PubMed2001

Analysis of the prostate cancer-susceptibility locus HPC20 in 172 families affected by prostate cancer.

A recent study of hereditary prostate cancer has provided evidence for a prostate cancer-susceptibility locus, HPC20, which maps to 20q13. To assess further the potential contribution of this locus to prostate cancer susceptibility, we studied 172 unrelated families affected by prostate cancer, using 17 polymorphic markers across a 98.5-cM segment of chromosome 20 that contains the candidate region. Parametric analysis, allowing for heterogeneity, resulted in an overall HLOD score of 0.09 (P=.39) at D20S171, under the assumption of linkage in 6% of families. Mode-of-inheritance-free analysis of the entire data set resulted in a maximal Zlr score of 0.76 (LOD 0.13; P=.22) at the same location. The strongest evidence for linkage was seen in the subset of 16 black families (LOD 0.86; Zlr=1.99; P=.023) between markers D20S893 and D20S120, near the putative location of HPC20. Although some positive results were observed, our linkage study does not provide statistically significant support for the existence of a prostate cancer-susceptibility locus HPC20 at 20q13.

Aged↗
PubMed2001

Correlations between measles, mumps, and rubella serum antibody levels in Olmsted County school children.

We examined correlations between serum antibody levels to determine whether individuals with low levels of antibody to one component of the measles, mumps, and rubella (MMR) vaccine were also likely to have low antibody levels to the other MMR vaccine components. Our results indicate that children who had a low antibody level to one component of the MMR vaccine had a modest probability of having a low antibody level to either of the other MMR vaccine components. Overall, we found small, but statistically significant, correlations between antibody levels that were largely unaffected by race, sex, age at immunization, and time since immunization. While the correlations we observed were modest, approximately 25% of our population was seronegative for at least one component of the MMR vaccine. Therefore, our results support the current policy of continuing to administer the trivalent MMR vaccine even when only a single low antibody titer is observed.

Adolescent↗