(1/3578) A parametric copula model for analysis of familial binary data.

Modeling the joint distribution of a binary trait (disease) within families is a tedious challenge, owing to the lack of a general statistical model with desirable properties such as the multivariate Gaussian model for a quantitative trait. Models have been proposed that either assume the existence of an underlying liability variable, the reality of which cannot be checked, or provide estimates of aggregation parameters that are dependent on the ordering of family members and on family size. We describe how a class of copula models for the analysis of exchangeable categorical data can be incorporated into a familial framework. In this class of models, the joint distribution of binary outcomes is characterized by a function of the given marginals. This function, referred to as a "copula," depends on an aggregation parameter that is weakly dependent on the marginal distributions. We propose to decompose a nuclear family into two sets of equicorrelated data (parents and offspring), each of which is characterized by an aggregation parameter (alphaFM and alphaSS, respectively). The marginal probabilities are modeled through a logistic representation. The advantage of this model is that it provides estimates of the aggregation parameters that are independent of family size and does not require any arbitrary ordering of sibs. It can be incorporated easily into segregation or combined segregation-linkage analysis and does not require extensive computer time. As an illustration, we applied this model to a combined segregation-linkage analysis of levels of plasma angiotensin I-converting enzyme (ACE) dichotomized into two classes according to the median. The conclusions of this analysis were very similar to those we had reported in an earlier familial analysis of quantitative ACE levels.  (+info)

(2/3578) Immunodeficiency due to a unique protracted developmental delay in the B-cell lineage.

A unique immune deficiency in a 24-month-old male characterized by a transient but protracted developmental delay in the B-cell lineage is reported. Significant deficiencies in the number of B cells in the blood, the concentrations of immunoglobulins in the serum, and the titers of antibodies to T-dependent and T-independent antigens resolved spontaneously by the age of 39 months in a sequence that duplicated the normal development of the B-cell lineage: blood B cells followed by immunoglobulin M (IgM), IgG, IgA, and specific IgG antibodies to T-independent antigens (pneumococcal polysaccharides). Because of the sequence of recovery, the disorder could have been confused with other defects in humoral immunity, depending on when in the course of disease immunologic studies were conducted. Investigations of X-chromosome polymorphisms suggested that the disorder was not X linked in that the mother appeared to have identical X chromosomes. An autosomal recessive disorder involving a gene that controls B-cell development and maturation seems more likely. In summary, this case appears to be a novel protracted delay in the development of the B-cell lineage, possibly due to an autosomal recessive genetic defect.  (+info)

(3/3578) The Thr124Met mutation in the peripheral myelin protein zero (MPZ) gene is associated with a clinically distinct Charcot-Marie-Tooth phenotype.

We observed a missense mutation in the peripheral myelin protein zero gene (MPZ, Thr124Met) in seven Charcot-Marie-Tooth (CMT) families and in two isolated CMT patients of Belgian ancestry. Allele-sharing analysis of markers flanking the MPZ gene indicated that all patients with the Thr124Met mutation have one common ancestor. The mutation is associated with a clinically distinct phenotype characterized by late onset, marked sensory abnormalities and, in some families, deafness and pupillary abnormalities. Nerve conduction velocities of the motor median nerve vary from <38 m/s to normal values in these patients. Clusters of remyelinating axons in a sural nerve biopsy demonstrate an axonal involvement, with axonal regeneration. Phenotype-genotype correlations in 30 patients with the Thr124Met MPZ mutation indicate that, based on nerve conduction velocity criteria, these patients are difficult to classify as CMT1 or CMT2. We therefore conclude that CMT patients with slightly reduced or nearly normal nerve conduction velocity should be screened for MPZ mutations, particularly when additional clinical features such as marked sensory disturbances, pupillary abnormalities or deafness are also present.  (+info)

(4/3578) The impact of depression on the physical health of family members.

BACKGROUND: Depressive illness is common. Depression in one family member is associated with an increased incidence of psychopathology in other family members. There are no data on the physical well being of the families of depressed individuals. AIM: To compare physical morbidity of family members of depressed patients with that of family members of comparison patients. METHOD: A comparative follow-up study from case notes. Two hundred and one subjects from 88 families with an index family member diagnosed with depression ('depression families') were compared with 200 subjects from 88 families with a matched index subject without depression ('comparison families'), using the Duke University Illness Severity Scores (ISS) to assess burden of illness experienced by both groups. RESULTS: The cumulative incidence of depression over 11 months in depression families was 8.9% compared to 1.4% in the Family Practice Unit as a whole. Members of depression families had significantly greater ISS than members of comparison families (difference in means = 0.164; 95% confidence interval (CI) 0.113-0.215; P < 0.001). Excluding family members with depression (in addition to the index subject), ISS of members of depression families remained significantly greater than the comparison group (difference in means = 0.136; 95% CI 0.083-0.189; P < 0.001). Among depression families, mean ISS was significantly higher after presentation of depression in index subjects compared with before (difference in means = 0.155; 95% CI 0.115-0.194; P < 0.0001). No significant difference was seen between ISS of depression and comparison families before presentation of depression (difference in means = 0.008; 95% CI -0.004-0.058; P = 0.74). CONCLUSION: Depression in patients is associated with increased physical morbidity in their families.  (+info)

(5/3578) Patient removals from general practitioner lists in Northern Ireland: 1987-1996.

BACKGROUND: Being struck off a general practitioner's list is a major event for patients and a subject for much media attention. However, it has not hitherto received much research attention. AIMS: To quantify the numbers of patients removed at doctors' request in Northern Ireland between 1987 and 1996. To describe the characteristics of those removed and to determine if the rate of removal has increased. METHODS: This is a descriptive epidemiological study involving a secondary data analysis of records held by the Central Services Agency. RESULTS: Six thousand five hundred and seventy-eight new patients were removed at general practitioner (GP) request between 1987 and 1996. This equated to 3920 removal decisions, a rate of 2.43 per 10,000 person-years. The very young and young adults had the highest rates of removal; most of the young being removed as part of a family. Ten point six per cent of removed patients had a repeat removal, and 16.3% of first removal decisions required an assignment to another practice. Family removals have decreased and individual removals have increased over the 10 years. Disadvantaged and densely populated areas with high population turnover were associated with higher rates of removal, though heterogeneity is evident between general practitioners serving similar areas. Compared to the period 1987 to 1991, removal rates for the years 1992 to 1993 were reduced by 20.0% (95% confidence interval (CI) for rate ratio (RR) 0.73-0.87), and those for the years 1994 to 1996 increased by 8% (95% CI = 1.01-1.16). The greatest increase was in the over-75 years age group (standardized RR = 1.60; 95% CI = 1.57-1.62). CONCLUSIONS: Removals are relatively rare events for both patients and practices, though they have been increasing in recent years. Further research is needed to understand the processes that culminate in a removal.  (+info)

(6/3578) A wide variety of mutations in the parkin gene are responsible for autosomal recessive parkinsonism in Europe. French Parkinson's Disease Genetics Study Group and the European Consortium on Genetic Susceptibility in Parkinson's Disease.

Autosomal recessive juvenile parkinsonism (AR-JP, PARK2; OMIM 602544), one of the monogenic forms of Parkinson's disease (PD), was initially described in Japan. It is characterized by early onset (before age 40), marked response to levodopa treatment and levodopa-induced dyskinesias. The gene responsible for AR-JP was recently identified and designated parkin. We have analysed the 12 coding exons of the parkin gene in 35 mostly European families with early onset autosomal recessive parkinsonism. In one family, a homozygous deletion of exon 4 could be demonstrated. By direct sequencing of the exons in the index patients of the remaining 34 families, eight previously undescribed point mutations (homozygous or heterozygous) were detected in eight families that included 20 patients. The mutations segregated with the disease in the families and were not detected on 110-166 control chromosomes. Four mutations caused truncation of the parkin protein. Three were frameshifts (202-203delAG, 255delA and 321-322insGT) and one a nonsense mutation (Trp453Stop). The other four were missense mutations (Lys161Asn, Arg256Cys, Arg275Trp and Thr415Asn) that probably affect amino acids that are important for the function of the parkin protein, since they result in the same phenotype as truncating mutations or homozygous exon deletions. Mean age at onset was 38 +/- 12 years, but onset up to age 58 was observed. Mutations in the parkin gene are therefore not invariably associated with early onset parkinsonism. In many patients, the phenotype is indistinguishable from that of idiopathic PD. This study has shown that a wide variety of different mutations in the parkin gene are a common cause of autosomal recessive parkinsonism in Europe and that different types of point mutations seem to be more frequently responsible for the disease phenotype than are deletions.  (+info)

(7/3578) Germline E-cadherin gene (CDH1) mutations predispose to familial gastric cancer and colorectal cancer.

Inherited mutations in the E-cadherin gene ( CDH1 ) were described recently in three Maori kindreds with familial gastric cancer. Familial gastric cancer is genetically heterogeneous and it is not clear what proportion of gastric cancer susceptibility in non-Maori populations is due to germline CDH1 mutations. Therefore, we screened eight familial gastric cancer kindreds of British and Irish origin for germline CDH1 mutations, by SSCP analysis of all 16 exons and flanking sequences. Each family contained: (i) two cases of gastric cancer in first degree relatives with one affected before age 50 years; or (ii) three or more cases of gastric cancer. Novel germline CDH1 mutations (a nonsense and a splice site) were detected in two families (25%). Both mutations were predicted to truncate the E-cadherin protein in the signal peptide domain. In one family there was evidence of non-penetrance and susceptibility to both gastric and colorectal cancer; thus, in addition to six cases of gastric cancer, a CDH1 mutation carrier developed colorectal cancer at age 30 years. We have confirmed that germline mutations in the CDH1 gene cause familial gastric cancer in non-Maori populations. However, only a minority of familial gastric cancers can be accounted for by CDH1 mutations. Loss of E-cadherin function has been implicated in the pathogenesis of sporadic colorectal and other cancers, and our findings provide evidence that germline CDH1 mutations predispose to early onset colorectal cancer. Thus, CDH1 should be investigated as a cause of inherited susceptibility to both gastric and colorectal cancers.  (+info)

(8/3578) Genome-wide screen for systemic lupus erythematosus susceptibility genes in multiplex families.

Systemic lupus erythematosus (SLE) is the prototype of human autoimmune diseases. Its genetic component has been suggested by familial aggregation (lambdas = 20) and twin studies. We have screened the human genome to localize genetic intervals that may contain lupus susceptibility loci in a sample of 188 lupus patients belonging to 80 lupus families with two or more affected relatives per family using the ABI Prism linkage mapping set which includes 350 polymorphic markers with an average spacing of 12 cM. Non-parametric multipoint linkage analysis suggests evidence for predisposing loci on chromosomes 1 and 18. However, no single locus with overwhelming evidence for linkage was found, suggesting that there are no 'major' susceptibility genes segregating in families with SLE, and that the genetic etiology is more likely to result from the action of several genes of moderate effect. Furthermore, the support for a gene in the 1q44 region as well as in the 1p36 region is clearly found only in the Mexican American families with SLE but not in families of Caucasian ethnicity, suggesting that consideration of each ethnic group separately is crucial.  (+info)