Biomedical subjects

D Rabinowitz

Publications and source records attributed to D Rabinowitz.

At least 19 recordsLinked to original sources

PubMed2005

Familial clustering of seizure types within the idiopathic generalized epilepsies.

OBJECTIVE: To examine the genetic relationships among epilepsies with different seizure types--myoclonic, absence, and generalized tonic-clonic--within the idiopathic generalized epilepsies (IGEs). BACKGROUND: Careful phenotype definition in the epilepsies may allow division into groups that share susceptibility genes. Examination of seizure type, a phenotypic characteristic less complex than IGE syndrome, may help to define more homogeneous subgroups. METHODS: Using the approach that found evidence of distinct genetic effects on myoclonic vs absence seizures in families from the Epilepsy Family Study of Columbia University, the authors examined an independent sample of families from Australia and Israel. They also examined the familial clustering of generalized tonic-clonic seizures (GTCs) within the IGEs in two combined data sets. Families were defined as concordant if all affected members had the same type of seizure or IGE syndrome, as appropriate for the analysis performed. RESULTS: The proportion of families concordant for myoclonic vs absence seizures was greater than expected by chance in the Australian families. In addition, GTCs clustered in families with IGEs to a degree greater than expected by chance. CONCLUSIONS: These results provide additional evidence for distinct genetic effects on myoclonic vs absence seizures in an independent set of families and suggest that there is a genetic influence on the occurrence of generalized tonic-clonic seizures within the idiopathic generalized epilepsies.

Australia↗

PubMed2004

Enhanced APOE2 transmission rates in families with autistic probands.

We have previously described linkage/association between reelin gene polymorphisms and autistic disorder. APOE also participates in the Reelin signaling pathway, by competitively antagonizing Reelin binding to APOE receptor 2 and to very-low-density lipoprotein receptors. The APOE2 protein variant displays the lowest receptor binding affinity compared with APOE3 and APOE4. In this study, we assess linkage/association between primary autism and APOE alleles in 223 complete trios, from 119 simplex Italian families and 44 simplex and 29 multiplex Caucasian-American families. Statistically significant disequilibrium favors the transmission of epsilon2 alleles to autistic offspring, over epsilon3 and epsilon4 (allele-wise transmission/disequilibrium test [TDT], chi2 = 6.16, 2 degrees of freedom [d.f.], P<0.05; genotype-wise TDT, chi2 = 10.68, 3 d.f., P<0.05). A novel epsilon3r allele was also discovered in an autistic child and his mother. Autistic patients do not differ significantly from unaffected siblings (allele-wise TDT comparing autistic patients versus unaffected sibs, chi2 = 1.83, 2 d.f., P<0.40, not significant). The major limitation of this study consists of our small sample size of trios including one unaffected sibling, currently not possessing the statistical power necessary to conclusively discriminate a specific association of epsilon2 with autism, from a distorted segregation pattern characterized by enhanced epsilon2 transmission rates both to affected and unaffected offspring. Our findings are thus compatible with either (a) pathogenetic contributions by epsilon2 alleles to autism spectrum vulnerability, requiring additional environmental and/or genetic factors to yield an autistic syndrome, and/or (b) a protective effect of epsilon2 alleles against the enhanced risk of miscarriage and infertility previously described among parents of autistic children.

Apolipoprotein E2↗

PubMed2003

Genetic influences on myoclonic and absence seizures.

OBJECTIVE: To examine the relationship between genotype and phenotype in idiopathic generalized epilepsies (IGEs) using a novel approach that focuses on seizure type rather than syndrome. METHODS: The authors evaluated whether the genetic effects on myoclonic seizures differ from the genetic effects on absence seizures. For this purpose, they studied 34 families containing 2 or more members with IGEs and assessed whether the number of families concordant for seizure type exceeded that expected by chance. The authors performed a similar analysis to examine the genetic contributions to juvenile myoclonic epilepsy (JME), juvenile absence epilepsy (JAE), and childhood absence epilepsy (CAE). RESULTS: The observed number of families concordant for seizure type (myoclonic, absence, or both) was greater than expected (20 vs 7.51; p < 0.0001). The observed number of families concordant for syndrome was greater than expected when JME was compared with absence epilepsies (JAE+CAE) (17 vs 11.9; p < 0.012) but not when JAE was compared with CAE (8 vs 6.82; p = 0.516). CONCLUSIONS: These results provide evidence for distinct genetic effects on absence and myoclonic seizures, suggesting that examining the two seizure types separately would be useful in linkage studies of idiopathic generalized epilepsies. The approach presented here can also be used to discover other clinical features that could direct division of epilepsies into groups likely to share susceptibility genes.

Adolescent↗

PubMed2002

Serotonin transporter gene promoter variants do not explain the hyperserotoninemia in autistic children.

Autism is a biologically-heterogeneous disease. Distinct subgroups of autistic patients may be marked by intermediate phenotypes, such as elevated serotonin (5-HT) blood levels, potentially associated with different underlying disease mechanisms. This could lead to inconsistent genetic association results, such as those of prior studies on serotonin transporter (5-HTT) gene promoter variants and autistic disorder. Contributions of 5-HTT gene promoter alleles to 5-HT blood levels were thus investigated in 134 autistic patients and 291 first-degree relatives. Mean 5-HT blood levels are 11% higher in autistic patients carrying the L/L genotype, compared to patients with the S/S or S/L genotype; this trend is not observed in first-degree relatives. The probability of inheriting L or S alleles is significantly enhanced in patients with 5-HT blood levels above or below the mean, respectively (P < 0.05), but quantitative TDT analyses yield a non-significant trend (P = 0.10), as this polymorphism explains only 2.5% of the variance in 5-HT blood levels of autistic patients. In conclusion, 5-HTT gene promoter variants seemingly exert a small effect on 5-HT blood levels in autistic children, which largely does not account for hyperserotoninemia. Nonetheless, the inconsistent outcome of prior association studies could partly stem from a selection bias of hyper- or hypo-serotoninemic probands.

Autistic Disorder↗

PubMed2001

Antibiotic use and risk of ischemic stroke in the elderly.

PURPOSE: To determine whether treating infections with antibiotics that have antichlamydial activity decreases the risk of ischemic stroke in the elderly. SUBJECTS: We analyzed data from 199 553 subjects 65 years and older in a health care claims database who had continuous health and pharmacy coverage for at least 2 years between January 1, 1991, and September 30, 1997. Using proportional hazards models with time-dependent covariates for prior antibiotic prescription and adjusting for cardiovascular risk factors, we determined the associations between antibiotic use and first claim for ischemic stroke (n = 7,335) during the observation period. RESULTS: Rates of stroke (per 1,000 person-years) were 6.64 for macrolides, 9.27 for quinolones, 7.49 for tetracyclines, 6.88 for penicillins, 7.97 for cephalosporins, 8.58 for trimethoprim-sulfamethoxazole, and 7.29 for subjects with no antibiotic claims. The adjusted hazard ratios (HR) were 0.94 (95% confidence interval [CI]: 0.87 to 1.01) for macrolides, 1.04 (95% CI: 0.91 to 1.18) for tetracyclines, 1.02 (95% CI: 0.95 to 1.08) for penicillins, and 1.00 (95% CI: 0.82 to 1.22) for trimethoprim-sulfamethoxazole. Subjects with claims for quinolone antibiotics (HR = 1.17; 95% CI: 1.09 to 1.26) and cephalosporins (HR = 1.09; 95% CI: 1.02 to 1.16) had a slightly higher risk of stroke. CONCLUSION: Exposures to short courses of antibiotics are not associated with lower risk of ischemic stroke in patients aged 65 years and older.

Aged↗

PubMed2001

Evidence for familial aggregation of tremor in normal individuals.

BACKGROUND: Tremor occurs in most normal individuals, and this tremor may offer basic clues about the mechanisms of neuromuscular control. It is not known whether genetic factors influence the magnitude of tremor in normal families. OBJECTIVE: To assess the familial aggregation of tremor in normal families. METHODS: Control subjects from the Washington Heights-Inwood community in northern Manhattan, NY, were enrolled in a family study. These subjects and their first- and second-degree relatives underwent a videotaped tremor examination. Two neurologists rated the severity of tremor on the videotaped examination, assigning a total tremor score (0 to 36 [maximum]). Associations between the control subjects' and their relatives' total tremor scores were assessed using correlation coefficients and linear regression analysis. In addition, maximum likelihood methods were used to fit a linear mixed-effects model to the total tremor scores of probands and their siblings, after excluding any relatives with essential tremor. RESULTS: There were 56 control subjects and 226 relatives. Tremor was clinically detectable in 221 (97.8%) of 226 relatives. There was an association between the control subjects' total tremor scores and those of their siblings (r = 0.40; p = 0.018), those of all of their first-degree relatives (siblings and children combined, r = 0.20; p = 0.037), but not those of their second-degree relatives (r = 0.002; p = 0.99). In analyses of probands and normal siblings, the estimate of the variance of the family-specific component of the age-adjusted total tremor score was different from zero (p < 0.005), and the family specific component was estimated to account for 52% of the variability in the scores. CONCLUSIONS: Tremor aggregates in normal families, suggesting that genetic factors may contribute to its etiology. Other studies might be designed by investigators to identify these genes through genetic linkage or association analysis. Identification of such genes would help to elucidate the mechanisms underlying this ubiquitous condition.

Adult↗

PubMed2001

Unbiased discordant sib-pair tests when parental genotypes are missing.

Population admixture and stratification are potential sources of confounding in a variety of statistical analyses of genetic data. Many approaches to adjusting for such confounding have been developed in the context of association analyses. These approaches may generally be viewed as relying on nonparametric null hypotheses that specify certain, sometimes incompletely observed, conditional distributions; the conditional distributions are used to normalize test statistics to have expectation zero under the null hypothesis. Here, with a very simple example, it is shown that there is potentially information that is free of confounding, but that is not recovered by such normalized statistics. An approach presented here in the context of the simple example might be extended to methods for recovering information in more complex settings.

Bias↗

PubMed2001

Association tests for traits with variable age at onset.

This paper is concerned with testing association between marker genotypes and traits with variable age at onset. Two methods are proposed, one which makes use of both age-at-ascertainment and age-at-onset information, and one which may be applied when only age-at-ascertainment information is available. (Here, by age-at-ascertainment, is meant the subject's age when presence of onset and age at onset are determined; for subjects who have died or are otherwise censored before ascertainment, the censoring time should be used instead). Adjustment for confounding due to population stratification is carried out by conditioning on observed traits and parental genotypes, or, if complete parental genotypes are not available, by conditioning on observed traits and the minimal sufficient statistics under the null hypothesis for the parental genotypes. Proportional hazards regression models and logistic regression models are used to motivate the methods, but correct type I error rates result even if the models are not correct. An illustrative example is described.

Age of Onset↗

PubMed2001

Renal cell carcinoma with intravascular lymphomatosis: a case report of unusual collision tumors with review of the literature.

We report the case of a 77-year-old white woman who presented with a left breast mass, lethargy, and weight loss. Pelvic computed tomographic scan revealed a 9.5-cm mass in the right kidney. Surgical pathology demonstrated a diffuse large B-cell lymphoma of the subcutaneous tissue of the breast and renal cell carcinoma with concurrent extensive intravascular lymphomatosis. Systemic dissemination of malignant lymphoma to a concurrent visceral primary neoplasm is rare. To the best of our knowledge, this is the first case illustrating a renal cell carcinoma collision with intravascular lymphomatosis.

Aged↗

PubMed2000

The deletion polymorphism and Val1000Ile in alpha-2-macroglobulin and Alzheimer disease in Caribbean Hispanics.

The association between polymorphisms in the alpha-2-macroglobulin (a2m) gene and Alzheimer's disease remains in doubt because of conflicting results in independent case-control and family studies. We examined the association between Alzheimer's disease and alpha2m polymorphisms in Caribbean Hispanic families. The odds of having the alpha2m deletion/insertion polymorphism was increased 3-fold for family members with Alzheimer's disease compared to healthy family members, rising to 5-fold after adjusting for APOE-epsilon4. In contrast, there was no relationship between the alpha2m Val1000Ile polymorphism and Alzheimer's disease in these families. The inconsistencies in studies cited above and the modest association between alpha2m and Alzheimer's disease found in the Caribbean Hispanic families reported here, suggest that the overall effect of this gene on susceptibility is small and may be limited to certain populations or families.

Adult↗

PubMed2000

A reduced estimate of the number of kilometre-sized near-Earth asteroids.

Near-Earth asteroids are small (diameters < 10 km), rocky bodies with orbits that approach that of the Earth (they come within 1.3 AU of the Sun). Most have a chance of approximately 0.5% of colliding with the Earth in the next million years. The total number of such bodies with diameters > 1 km has been estimated to be in the range 1,000-2,000, which translates to an approximately 1% chance of a catastrophic collision with the Earth in the next millennium. These numbers are, however, poorly constrained because of the limitations of previous searches using photographic plates. (One kilometre is below the size of a body whose impact on the Earth would produce global effects.) Here we report an analysis of our survey for near-Earth asteroids that uses improved detection technologies. We find that the total number of asteroids with diameters > 1 km is about half the earlier estimates. At the current rate of discovery of near-Earth asteroids, 90% will probably have been detected within the next 20 years.

Earth, Planet↗

PubMed2000

Simple approximations for the maximal transmission/disequilibrium test with a multi-allelic marker.

Spielman et al. (1993) popularized the transmission/disequilibrium test (TDT) to test for linkage between disease and marker loci that show a population association. Several authors have proposed extensions to the TDT for multi-allelic markers. Many of these approaches exhibit a 'swamping' effect in which a marker with a strong effect is not detected by a global test that includes many markers with no effect. To avoid this effect, Schaid (1996) proposed using the maximum of the bi-allelic TDT statistics computed for each allele versus all others combined. The maximal TDT statistic, however, no longer follows a chi-square distribution. Here, a refinement to Bonferroni's correction for multiple testing provided by Worsley (1982) based on maximal spanning trees is applied to calculate accurate upper bounds for the type I error and p-values for the maximal TDT. In addition, an accurate lower Bonferroni bound is applied to calculate power. This approach does not require any simulation-based analysis and is less conservative than the standard Bonferroni correction. The bounds are given for both the exact probability calculations and for those based on the normal approximation. The results are assessed through simulations.

Alleles↗

PubMed2000

Using conditional logistic regression to fit proportional odds models to interval censored data.

An easily implemented approach to fitting the proportional odds regression model to interval-censored data is presented. The approach is based on using conditional logistic regression routines in standard statistical packages. Using conditional logistic regression allows the practitioner to sidestep complications that attend estimation of the baseline odds ratio function. The approach is applicable both for interval-censored data in settings in which examinations continue regardless of whether the event of interest has occurred and for current status data. The methodology is illustrated through an application to data from an AIDS study of the effect of treatment with ZDV+ddC versus ZDV alone on 50% drop in CD4 cell count from baseline level. Simulations are presented to assess the accuracy of the procedure.

Acquired Immunodeficiency Syndrome↗

PubMed2000

Approximating the distribution of maximally selected McNemar's statistics.

It is common in epidemiologic analyses to summarize continuous outcomes as falling above or below a threshold. With paired data and with a threshold chosen without reference to the outcomes, McNemar's test of marginal homogeneity may be applied to the resulting dichotomous pairs when testing for equality of the marginal distributions of the underlying continuous outcomes. If the threshold is chosen to maximize the test statistic, however, referring the resulting test statistic to the nominal chi 2 distribution is incorrect; instead, the p-value must be adjusted for the multiple comparisons. Here the distribution of a maximally selected McNemar's statistic is derived, and it is shown that an approximation due to Durbin (1985, Journal of Applied Probability 22, 99-122) may be used to estimate approximate p-values. The methodology is illustrated by an application to measurements of insulin-like growth factor-I (IGF-I) in matched prostate cancer cases and controls from the Physicians' Health Study. The results of simulation experiments that assess the accuracy of the approximation in moderate sample sizes are reported.

Case-Control Studies↗

PubMed1999

Deprenyl augmentation for treating negative symptoms of schizophrenia: a double-blind, controlled study.

Augmentation of dopaminergic neurotransmission has been suggested as a treatment strategy for negative symptoms of schizophrenia. On the basis of open studies that reported the potential benefit of deprenyl (selegiline) as augmentation to antipsychotic treatment, this double-blind, controlled study was designed to further address this question. Sixteen schizophrenic patients with predominately negative symptoms, manifesting clinical stability on maintenance antipsychotic treatment, were randomly assigned to receive either deprenyl 15 mg/day or placebo in addition to their antipsychotic treatment for 8 weeks. Clinical follow-up and ratings were done during this period and for 8 more weeks after deprenyl discontinuation. Both groups showed a statistically significant but clinically marginal improvement over the 8 weeks of deprenyl or placebo treatment. This improvement was abolished during the postdiscontinuation follow-up period. Deprenyl at a dose of 15 mg/day did not offer therapeutic benefit in our patients. A significant placebo effect was observed, which may be the result of increased patient-doctor contact during the study.

Adult↗

PubMed1999

Maximally selected chi2 statistics for k x 2 tables.

It is common in epidemiologic analyses to summarize continuous outcomes as falling above or below a threshold. With such a dichotomized outcome, the usual chi2 statistics for association or trend can be used to test for equality of proportions across strata of the study population. However, if the threshold is chosen to maximize the test statistic, the nominal chi2 reference distributions are incorrect. In this paper, the asymptotic distributions of maximally selected chi2 statistics for association and for trend for the k x 2 table are derived. The methodology is illustrated with data from an AIDS clinical trial. The results of simulation experiments that assess the accuracy of the asymptotic distributions in moderate sample sizes are also reported.

Anti-HIV Agents↗

PubMed1999

Testing for age-at-onset anticipation with affected parent-child pairs.

The tendency for the onset of a genetic disease to occur at progressively earlier ages or with progressively greater severity in successive generations is known as anticipation. Following the discovery of trinucleotide repeat expansion as a plausible genetic mechanism for anticipation, interest in testing for anticipation has increased. Studies of anticipation can be biased when parents with late onset or children with early onset are preferentially ascertained. This paper presents a nonparametric approach to testing for age-at-onset anticipation that adjusts for such preferential ascertainment. The approach is illustrated through application to data on panic disorder.

Adolescent↗

PubMed1999

A principal-components approach based on heritability for combining phenotype information.

For many traits, genetically relevant disease definition is unclear. For this reason, researchers applying linkage analysis often obtain information on a variety of items. With a large number of items, however, the test statistic from a multivariate analysis may require a prohibitively expensive correction for the multiple comparisons. The researcher is faced, therefore, with the issue of choosing which variables or combinations of variables to use in the linkage analysis. One approach to combining items is to first subject the data to a principal components analysis, and then perform the linkage analysis of the first few principal components. However, principal-components analyses do not take family structure into account. Here, an approach is developed in which family structure is taken into account when combining the data. The essence of the approach is to define principal components of heritability as the scores with maximum heritability in the data set, subject to being uncorrelated with each other. The principal components of heritability may be calculated as the solutions to a generalized eigensystem problem. Four simulation experiments are used to compare the power of linkage analyses based on the principal components of heritability and the usual principal components. The first of the experiments corresponds to the null hypothesis of no linkage. The second corresponds to a setting where the two kinds of principal components coincide. The third corresponds to a setting in which they are quite different and where the first of the usual principal components is not expected to have any power beyond the type I error rate. The fourth set of experiments corresponds to a setting where the usual principal components and the principal components of heritability differ, but where the first of the usual principal components is not without power. The results of the simulation experiments indicate that the principal components of heritability can be substantially different from the standard principal components and that when they are different, substantial gains in power can result by using the principal components of heritability in place of the standard principal components in linkage analyses.

Computer Simulation↗