Incorporating serotypes into family based association studies using the MFG test.

Family based association tests are widely used to detect genetic effects. The focus of this paper is the maternal-fetal genotype (MFG) incompatibility test, a family based association test which can be used to detect genetic effects that contribute to disease, including alleles in the child that increase disease risk, maternal alleles that increase disease risk in the child, and maternal-fetal genotype incompatibilities. Consideration of incomplete data resulting from using serotypes could expand the power of the MFG test for detecting genetic effects. Serotypes may be all that are available in certain families, or preferred because of convenience or low cost, and thus a modification of the MFG test will allow optimal use of such data. The modified MFG likelihood can accommodate the incomplete data that result from using serotypes rather than the corresponding codominant genotypes. The modified MFG test was evaluated with serotypes and genotypes from families with members affected with schizophrenia. In addition, simulation studies were performed. Results of the data analyses and simulation studies showed that serotypes can be used to augment genotypes within a sample, to increase power to detect effects when the candidate gene produces serotypes.

Life-threatening interactions between HIV-1 protease inhibitors and the illicit drugs MDMA and gamma-hydroxybutyrate.

Human immunodeficiency virus 1 (HIV-1) protease inhibitors have dramatically reduced the morbidity and mortality due to HIV-1 infection. However, most of these antiretrovirals are also potent inhibitors (and occasionally inducers) of hepatic and intestinal cytochrome P450 systems and, therefore, have the potential to alter the elimination of any substance that utilizes these metabolic pathways. We describe a patient infected with HIV-1 who was treated with ritonavir and saquinavir and then experienced a prolonged effect from a small dose of methylenedioxymetamphetamine (MDMA or ecstacy) and a nearly fatal reaction from a small dose of gamma-hydroxybutyrate (GHB). We also discuss the potential for HIV-1 protease inhibitors to alter the metabolism of other abusable prescribed and illicit substances.

Evidence that the dopamine D4 receptor is a susceptibility gene in attention deficit hyperactivity disorder.

Attention deficit hyperactivity disorder (ADHD) is a common neurobehavioral problem afflicting 5-10% of children and adolescents and persisting into adulthood in 30-50% or more of cases. Family, twin, and adoption studies suggest genetic factors contribute to ADHD and symptoms of inattention, impulsivity, and hyperactivity. Because stimulant intervention is effective in reducing ADHD symptoms in about 70-80% of cases, molecular genetic investigations of genes involved in dopamine regulation are currently underway by many groups. In a case control study of the dopamine D4 receptor gene (DRD4) and ADHD, La Hoste and colleagues found an increase of a 7-repeat variant of a 48-bp VNTR in exon 3 among ADHD subjects compared to controls. Swanson and colleagues replicated this finding in a sample of 52 ADHD probands and their biological parents using a haplotype relative risk analysis. Here, we describe linkage investigations of the VNTR and ADHD in affected sibling pair (ASP) families and singleton families using both the transmission disequilibrium test (TDT) and a mean test of identity-by-descent (IBD) sharing. Using the TDT in the total sample, the 7 allele is differentially transmitted to ADHD children (P = 0.03) while the mean test revealed no evidence of increased IBD sharing among ASPs. In the current sample, the 7 allele attributes a 1.5-fold risk for developing ADHD over non-carriers of the allele estimated under a model described by Risch and Merikangas.

A multivariate approach to affected-sib-pair analysis using highly dense molecular maps.

A multivariate approach to affected-sib-pair analyses was performed to localize disease-susceptibility genes with a minimum number of type I errors (false positives). Using 1,155 independent affected sib pairs extracted from Problem 2A of the GAW10 data set, we were able to localize major genes (MG) 1 and 2. Using 30% of the affected-sib-pair sample (N = 337) we were able to localize MG1. False positives were not detected in either of these samples.

A general statistical model for detecting complex-trait loci by using affected relative pairs in a genome search.

Scanning of the human genome by use of affected relative pairs and dense sets of highly polymorphic markers or by emerging techniques such as genomic mismatch scanning. (GMS) is making it possible to identify the genetic etiology of a disease through detection of susceptibility loci. We present a general statistical model and test to detect disease genes, using affected relative pairs and either markers or GMS technologies in a genome search. There are an exact test and large-sample normal approximation that control for the elevated probability of false detection of linkage in a genome search. The approach can be used to determine the sample size needed to obtain a prespecified power to detect a disease gene in the presence of etiologic heterogeneity for a single class or mixture of relative classes, with any number of markers, or clones, markers PIC values, or mapping function. The approach is used to examine differences in performance of markers and GMS technologies in a common statistical framework and to provide practical information for designing studies of complex traits.

Commingling analysis of memory performance in offspring of Alzheimer patients.

Dementia of the Alzheimer type (DAT) is a neurodegenerative disorder which afflicts approximately 3% of the population. Genetic influences are indicated from twin and family studies although genetic heterogeneity has been suggested from both pedigree analyses and linkage investigations. Autosomal dominant inheritance with age-dependent penetrance has been suggested in at least some families with DAT. In the present investigation, we examine memory and nonmemory task performance in 106 asymptomatic offspring (mean age 40.6 years) of 54 DAT probands. Intraclass sibling correlations revealed little evidence of sibling similarity for performance on three memory tasks which have been reported to be relatively sensitive to the memory losses accompanying DAT. Subsequent investigations of the distributions of the cognitive task scores in the offspring revealed evidence for a commingling of two distributions for the three memory tasks but not for the nonmemory measures. These findings are consistent with a hypothesis that these distributions reflect genotypic subgroups, carriers, and noncarriers, of a presumed DAT gene.

Interregional elderly migration and population redistribution in four industrialized countries. A comparative analysis.

Though differing in cultures, languages, and socioeconomic attributes, the industrialized nations of the world share a common characteristic: relatively low fertility levels and relatively high proportions of elderly people. These elderly persons are not spread uniformly across their national territories; they exhibit distinct population geographies. This article examines the elderly migration and population redistribution process in four industrialized countries, identifies their principal retirement regions, and analyzes the sources of regional elderly population growth in these regions. It concludes that the United Kingdom and the United States are approaching the final stages of their "elderly mobility transition," whereas Japan is only entering the first stage, with Italy occupying a position somewhere in between.

Effects of hypothyroidism and hyperthyroidism on GDP binding to brown-adipocyte mitochondria from rats.

1. Rats were made hypothyroid by giving them a low-iodine diet with propylthiouracil for 4 weeks, or were made hyperthyroid by injection with tri-iodothyronine (T3) over a 3-day period. 2. Brown adipocytes were isolated from the interscapular depots of these animals or from their euthyroid controls, followed by isolation of mitochondria from the cells. 3. Relative to cell DNA content, hypothyroidism decreased the maximum binding (Bmax.) of [3H]GDP to mitochondria by 50%. T3 treatment increased binding by 37%. 4. These findings, which are discussed in relation to previously observed changes in brown adipose tissue after alteration of thyroid status, suggest that mitochondrial uncoupling for thermogenesis is less or more effective in hypothyroidism or hyperthyroidism respectively.

Estimating the size of closed populations using inverse multiple-recapture sampling.

A log-linear model for estimating the size of a closed population is defined for inverse multiple-recapture sampling with dependent samples. Efficient estimators of the log-linear model parameters and the population size are obtained by the method of minimum chi-square. A chi-square test of the general linear hypothesis regarding the log-linear model parameters is defined.

Conditional factors of maturing out: personal resources and preaddiction sociopathy.

The study continues exploration of the conditional nature of the process of maturing out of narcotics addiction over time. It tests hypotheses about the relationship of selected personal resource/sociodemographic variables (including ethnicity and employability) and preaddiction sociopathy characteristics to maturing out. Hypotheses were tested using log-linear models on data from the California Civil Addict Program. Results suggest that while the process of maturing out over time is not substantially different depending upon level of preaddiction sociopathy or ethnicity, the process may be influenced by levels of other personal resource characteristics.

The impact of raising the minimum drinking age on driver fatalities.

Time series analysis was used to obtain statistical tests of the impact of raising the drinking age on monthly driver fatalities in Illinois, Michigan, and Massachusetts. A control series design permitted comparison between younger drivers (21 or less years) and older drivers (25 and older) within states where the minimum drinking age was raised. Since the two groups share the same driving conditions, it was important to demonstrate that any reduction in fatalities was limited to the young age group within which the drinking age change occurred. In addition, control states were selected to permit a comparison between driver fatalities of the young age group (21 or less) in states with the law change and young drivers in states without the law change. Significant immediate reductions in fatalities among 21 and younger drivers in Illinois and Michigan were observed after these states raised their minimum drinking age. No significant reductions in any control series were observed. A linear decrease in young driver fatalities was observed after the drinking age was raised in Massachusetts. There was also a significant linear decrease in young driver fatalities in the Connecticut control series, perhaps due to increasing awareness among young drivers of the dangers of drinking and driving.

Effect of adenosine deaminase, N6-phenylisopropyladenosine and hypothyroidism on the responsiveness of rat brown adipocytes to noradrenaline.

Adenosine deaminase (1 unit/ml) potentiated the lipolytic action of noradrenaline in adipocytes isolated from brown adipose tissue of 1- and 6-week-old rats by decreasing the EC50 (concn. giving 50% of maximal effect) for noradrenaline by 3-4-fold. With cells from neonatal rabbit tissue, adenosine deaminase only had a small, non-significant, effect on the EC50 for noradrenaline. Lipolysis in rat brown adipocytes was inhibited by low concentrations of N6-phenylisopropyladenosine (PIA). Rabbit cells were far less sensitive to PIA. PIA, prostaglandin E1 and nicotinate all inhibited noradrenaline-stimulated respiration in rat brown adipocytes. Hypothyroidism diminished the maximum response of respiration and lipolysis to noradrenaline in rat cells and increased the EC50 for noradrenaline. Responsiveness of lipolysis to noradrenaline was particularly decreased in hypothyroidism and was partially restored by addition of adenosine deaminase. Lipolysis in cells from hypothyroid rats was more sensitive to the anti-lipolytic action of PIA. Bordetella pertussis toxin increased lipolysis in the presence of PIA, suggesting an involvement of the Ni guanine-nucleotide-binding protein in the control of brown-adipocyte metabolism.

An empirical study of maturing out: conditional factors.

Using data from the California Civil Addict Program, the study tested hypotheses about the possible conditional nature of the process of maturing out of heroin addiction. Hypotheses were tested in a five-way contingency table using the log-linear model. Results show that maturing out of addiction with increasing age is inhibited by high levels of involvement in crime and drug dealing.

Some extensions of a linear model for categorical variables.

The Grizzle-Starmer-Koch (GSK) model is extended to include the traditional log-linear model and a general class of Poisson and conditional Poisson distributions. Estimators of the model parameters are defined under general exact and stochastic linear constraints.