The power and robustness of maximum LOD score statistics.

The maximum LOD score statistic is extremely powerful for gene mapping when calculated using the correct genetic parameter value. When the mode of genetic transmission is unknown, the maximum of the LOD scores obtained using several genetic parameter values is reported. This latter statistic requires higher critical value than the maximum LOD score statistic calculated from a single genetic parameter value. In this paper, we compare the power of maximum LOD scores based on three fixed sets of genetic parameter values with the power of the LOD score obtained after maximizing over the entire range of genetic parameter values. We simulate family data under nine generating models. For generating models with non-zero phenocopy rates, LOD scores maximized over the entire range of genetic parameters yielded greater power than maximum LOD scores for fixed sets of parameter values with zero phenocopy rates. No maximum LOD score was consistently more powerful than the others for generating models with a zero phenocopy rate. The power loss of the LOD score maximized over the entire range of genetic parameters, relative to the maximum LOD score calculated using the correct genetic parameter value, appeared to be robust to the generating models.

Application of a Bayesian method for optimal subset regression to linkage analysis of Q1 and Q2.

We explore an approach that allows us to consider a trait for which we wish to determine the optimal subset of markers out of a set of p > or = 3 candidate markers being considered in a linkage analysis. The most effective analysis would find the model that only includes the q markers closest to the q major genes which determine the trait. Finding this optimal model using classical "frequentist" multiple regression techniques would require consideration of all 2p possible subsets. We apply the work of George and McCulloch [J Am Stat Assoc 88:881-9, 1993], who have developed a Bayesian approach to optimal subset selection regression, to a modification of the Haseman-Elston linkage statistic [Elston et al., Genet Epidemiol 19:1-17, 2000] in the analysis of the two quantitative traits simulated in Problem 2. The results obtained using this Bayesian method are compared to those obtained using (1) multiple regression and (2) the modified Haseman-Elston method (single variable regression analysis). We note upon doing this that for both Q1 and Q2, (1) we have extremely low power with all methods using the samples as given and have to resort to combining several simulated samples in order to have power of 50%, (2) the multivariate analysis does not have greater power than the univariate analysis for these traits, and (3) the Bayesian approach identifies the correct model more frequently than the frequentist approaches but shows no clear advantage over the multivariate approach.

A study comparing precision of the maximum multipoint heterogeneity LOD statistic to three model-free multipoint linkage methods.

This study compared the performance of the maximum lod (MLOD), maximum heterogeneity lod (MHLOD), maximum non-parametric linkage score (MNPL), maximum Kong and Cox linear extension (MKC(lin)) of NPL, and maximum Kong and Cox exponential extension (MKC(exp)) of NPL as calculated in Genehunter 1.2 and Genehunter-Plus. Our performance measure was the distance between the marker with maximum value for each linkage statistic and the trait locus. We performed a simulation study considering: 1) four modes of transmission, 2) 100 replicates for each model, 3) 58 pedigrees (with 592 subjects) per replicate, 4) three linked marker loci each having three equally frequent alleles, and 5) either 0% unlinked families (linkage homogeneity) or 50% unlinked families (linkage heterogeneity). For each replicate, we obtained the Haldane map position of the location at which each of the five statistics is maximized. The MLOD and MHLOD were obtained by maximizing over penetrances, phenocopy rate, and risk-allele frequencies. For the models simulated, MHLOD appeared to be the best statistic both in terms of identifying a marker locus having the smallest mean distance from the trait locus and in terms of the strongest negative correlation between maximum linkage statistic and distance of the identified position and the trait locus. The marker loci with maximum value of the Kong and Cox extensions of the NPL statistic also were closer to the trait locus than the marker locus with maximum value of the NPL statistic.

Quantitative characterization of eye tracking dysfunction in schizophrenia.

The purpose of this study was to characterize the nature of the processes that are involved in eye tracking dysfunction (ETD). We identified a combination of quantitative measures that best distinguished qualitatively normal eye tracking from qualitatively abnormal eye tracking, using discriminant analysis. Discriminant scores distinguished schizophrenics with ETD from both schizophrenics with normal eye tracking and normal controls, but did not distinguish schizophrenics with normal eye tracking from normal controls, underscoring the heterogeneity of schizophrenic patients with respect to eye tracking. The results of the discriminant analysis indicated that ETD is a multivariate process involving a primary impairment in the smooth pursuit system characterized by increased catch-up saccades and reduced gain, and, secondarily, disinhibition of intrusive saccades, especially square-wave jerks. Quantitative characterization of ETD makes it possible to consider eye tracking as a quantitative trait in genetic investigations of a multidimensional phenotype.

Comparison of empirical strategies to maximize GENEHUNTER lod scores.

We compare four strategies for finding the settings of genetic parameters that maximize the lod scores reported in GENEHUNTER 1.2. The four strategies are iterated complete factorial designs, iterated orthogonal Latin hypercubes, evolutionary operation, and numerical optimization. The genetic parameters that are set are the phenocopy rate, penetrance, and disease allele frequency; both recessive and dominant models are considered. We selected the optimization of a recessive model on the Collaborative Study on the Genetics of Alcoholism (COGA) data of chromosome 1 for complete analysis. Convergence to a setting producing a local maximum required the evaluation of over 100 settings (for a time budget of 800 minutes on a Pentium II 300 MHz PC). Two notable local maxima were detected, suggesting the need for a more extensive search before claiming that a global maximum had been found. The orthogonal Latin hypercube design was the best strategy for finding areas that produced high lod scores with small numbers of evaluations. Numerical optimization starting from a region producing high lod scores was the strategy that found the highest maximum observed.

Performance of the nonparametric linkage analysis using GENEHUNTER for a complicated genetic disease.

The nonparametric linkage (NPL) analysis of the GENEHUNTER program was applied to one set of the simulated data of Problem 2, GAW11. We conducted a straightforward screening of the genome to evaluate the performance of the NPL test, with respect to its ability to detect linkage on specific disease loci. Our findings indicate that disease genes were detected with relatively good power, despite the presence of a complex inheritance pattern. We found that the NPL test varies depending on penetrance rates and gene frequencies, however, we conclude that it is a useful tool for linkage analysis.

A normalized identity-by-state statistic for linkage analysis of sib pairs.

A sib-pair analysis was performed on a simulated data set for a fictitious disease, with a prevalence of approximately 3% to 6%. The disease could manifest itself in a severe or mild form and the analyses focused primarily on families with the mild form, barring any misdiagnoses. The numbers of shared genes identical by descent (IBD) and identical by state (IBS) were used to detect linkage between the marker loci and the disease. The results of the two methods were compared. We considered the distribution of the number of shared alleles IBS (for different parental allele combinations) and suggest a normalized IBS method. A large proportion of pedigrees in this data set had at least one homozygous parent or both parents sharing a common gene, thus generating the need for an adjustment of the IBS method. Our results indicate that the normalized IBS method gives results similar to those obtained by the traditional IBD approach. The adjusted score requires no assumptions be made with regard to the allele frequencies.

Relationship of job strain to standard coronary risk factors and psychological characteristics in women and men of the Family Heart Study.

This study reports on standard coronary risk factors (plasma lipids and lipoproteins, blood pressure, heart rate, age, body mass index) and psychosocial variables (job strain, Type A behavior, hostility, illnesses, medical and psychological symptoms, health-damaging behavior) in a community sample of 324 employed men, 203 employed women, and 155 female homemakers. Employed women reported less hostility and fewer illnesses than homemakers and had lower cholesterol levels than homemakers and men. Job characteristics were unrelated to standard coronary risk factor levels in both sexes, but predicted medical symptoms and health-damaging behavior in men. These findings suggest that employment is associated with enhanced medical and physical well-being among women and point to possible behavioral and psychological pathways by which job strain may adversely influence men's health.

Thought disorder in adolescent-onset schizophrenia.

The nature of the thinking disturbances found in adolescent-onset psychotic conditions is not as well-characterized as the thought disorders found in adult psychotic patients. We used the Thought Disorder Index to examine whether schizophrenic patients in whom psychotic symptoms appear in adolescence show the same characteristic features of thought disorder as do adult schizophrenics. Quantitative and qualitative features of thought disorder were assessed in psychiatric inpatients with adolescent-onset schizophrenia, psychotic depression, and nonpsychotic conditions compared with normal control adolescents. Elevated thought disorder occurred in all groups of adolescents hospitalized for an acute episode of psychiatric illness. The magnitude of the elevation and the frequency of occurrence of disordered thinking were greatest in the psychotic adolescents. The qualitative features of the thought disturbances found in the schizophrenic adolescents were distinct from those observed in adolescents with psychotic depression. The thinking of the schizophrenic adolescents resembled that of adult schizophrenics. In both conditions thought disorder is characterized by idiosyncratic word usage, illogical reasoning, perceptual confusion, loss of realistic attunement to the task, and loosely related ideas.

Association of posterior p-values of S.A.G.E. SIBPAL proportion-IBD and Haseman-Elston statistics for ACTHR112.

A common practice among researchers performing linkage studies is the use of equal allele frequencies as input when reporting p-values from computer linkage programs such as S.A.G.E. SIBPAL. Our results, using 5,000 sets from a uniform-prior distribution of allele frequencies, showed that such input may be problematic. Further, we found that the S.A.G.E. SIBPAL test for proportion of alleles shared identical by descent among concordantly affected sib pairs showed a greater percentage of significant p-values with decreasing parental genotype information (Table III), while the S.A.G.E. SIBPAL Haseman-Elston test produced significant p-values comparatively less frequently (Table IV).

The power of iterated generalized least squares (GLS) method to detect direct relationships in the analysis of correlated quantitative traits.

We examined the power of the stepwise iterated generalized least squares (GLS) method by modeling the relationship between quantitative traits and other variables using the simulated data for Problem 2A. The comparison between the generating model provided by the workshop and the results of the stepwise iterated GLS model showed that this method could be used as a first step in identifying the underlying model for genetic data. The estimated covariance matrices also provide useful information about the genetic properties of the traits.

Postsynaptic gephyrin immunoreactivity exhibits a nearly one-to-one correspondence with gamma-aminobutyric acid-like immunogold-labeled synaptic inputs to sympathetic preganglionic neurons.

Peripheral regulation of cardiovascular function is fundamentally influenced by central excitation and inhibition of sympathetic preganglionic neurons in thoracic spinal cord. This electron microscopy study investigated whether the gamma-aminobutyric acid (GABA)-ergic and glycinergic inhibitory innervation of sympathetic preganglionic neurons arises from mutually exclusive afferent populations. Sympathetic preganglionic neurons were retrogradely labeled with cholera beta subunit. GABAergic terminals were identified using strict quantitative statistical analyses as those boutons containing significantly elevated levels of GABA-like immunogold labeling (GABA+). Glycinergic terminals were classified as those boutons opposite postsynaptic gephyrin immunostaining containing background levels of GABA-like immunogold labeling (gephyrin+/GABA- association). Approximately 43% of the synaptic terminals that contacted sympathetic preganglionic somata and proximal dendrites and that were opposite gephyrin were GABA-; the remaining 57% were GABA+. Only two GABA+ boutons (4%) that synapsed on identified sympathetic preganglionic neuron (SPN) processes were not opposite gephyrin immunostaining (GABA+/gephyrin- association). GABA-/gephyrin+ associations were anticipated given prior anatomical, physiological, and pharmacological data. The observed nearly one-to-one correspondence between postsynaptic gephyrin immunoreactivity and GABA+ boutons was unexpected. Prior physiological and pharmacological experiments suggest that the postsynaptic effects of GABAergic inputs to sympathetic preganglionic neurons are mediated by activation of GABAA receptors. Those data, the present results, and other molecular, biochemical, and anatomical studies of gephyrin in the central nervous system (CNS) are consistent with two hypotheses: 1) Postsynaptic gephyrin is associated with GABAA receptors in the membranes of sympathetic preganglionic neurons, and 2) GABA+/gephyrin+ associations do not necessarily predict colocalization of GABA and glycine within single boutons synapsing on sympathetic preganglionic somata and dendrites.

Simulation study comparing interval estimates for the recombination fraction.

Three interval estimation procedures were evaluated to determine the method which provides the most accurate estimates for the recombination fraction, 0. The lod-0.83 support interval, the jackknife confidence interval, and the confidence interval based on estimated asymptotic standard error were compared by calculating the coverage probabilities of each. Family data that were simulated under the model of a single fully penetrant, dominant disease locus at some distance, 0, from fully informative matings were used. Comparisons were based on 1,000 random samples of size 20,60, and 100 families. In addition, a methodology for obtaining prediction intervals for 0 was developed. This procedure is of practical use and does not require asymptotic assumptions based on large sample theory. The results provide an a priori idea about precision of the estimates, as well as empirical interval estimates of 0. Graphs of the authors' Monte Carlo intervals are presented for these simulations. Investigators studying different traits, however, could condition specifically on the family structure and distribution of the disease they are investigating and obtain similar graphs.

Eye tracking and schizophrenia: a selective review.

The replications of the finding of eye tracking dysfunction (ETD) in schizophrenia patients and their first-degree relatives suggest that ETD may be informative in studies of a schizophrenia genotype having broadly defined phenotypes. We review and critically assess the literature on ETD with respect to syndrome and familial specificity and discuss the quantitative assessment of eye tracking.

Where is the likelihood ratio test powerful for detecting two component normal mixtures?

We compare the power of the likelihood ratio test, the Engelman-Hartigan test, two outlier tests, four goodness-of-fit tests, and eight tests of normality to detect a mixture consisting of two components that are normally distributed with different means but equal variances. We consider the entire range of mixing proportions pi, 0 < pi < 1. For pi > .85 or pi < .15, overall Fisher's skewness statistic is best with Filliben's probability plot correlation coefficient test somewhat less powerful. A combined skewness and kurtosis test, the Anderson-Darling test, and the likelihood ratio test are also competitive. For .35 < pi < .65, the Engelman-Hartigan test is best. For other mixing proportions, the likelihood ratio test is best. For situations in which the preferred test had power 50% or more, the power of the likelihood ratio test is also above 50% and within 15 percentage points of the preferred test.

The application of jackknife statistics to estimates of the recombination fraction.

We develop and evaluate the jackknife statistics [Efron, 1982] for obtaining confidence intervals for the recombination fraction. We consider two cases: (1) a single sibship of size S with phase known parents (one doubly heterozygous and one doubly homozygous) and (2) a sample of 20 nuclear families. We compare the jackknife confidence interval to the -1.00 lod and -0.83 lod intervals. For the first case we compare our intervals with a confidence interval which we develop that has coverage of exactly 95%. For the second case, we do a simulation study and compare the coverage of the intervals and the endpoints of the intervals with the actual 2.5th and 97.5th percentiles. Our results indicate that in case (1) the lod intervals provide closer estimates to the 95% exact interval than does the jackknife approach. However, in case (2), although the lod intervals have better coverage probabilities, the jackknife interval endpoints are closer to the actual percentile points than either of the lod interval endpoints.

LISREL modeling of high density lipoprotein cholesterol (HDL) levels in male twins.

Based on the LISREL modeling approach for data from monozygotic (MZ) and dizygotic (DZ) twins [Heath et al., 1989; Neale and Cardon, 1992], the hypothesized variance of the logarithm of high density lipoprotein cholesterol due to additive genetic factors was estimated to equal 19% for males. Unobserved common environment accounted for 32% of the variance of log HDL. Both estimates controlled for body mass, alcohol consumption, and smoking. The model had very strong goodness-of-fit indices.

Eye tracking dysfunction and schizophrenia: a critical perspective.

Eye tracking dysfunction (ETD) has been found in large numbers of schizophrenia patients and their first-degree relatives. Because of the many replications of the central findings, ETD has been proposed as a useful way of expanding the schizophrenia phenotype in genetic studies. We critically review the literature on ETD with respect to issues of measurement and the search for quantitative indices of ETD; syndrome and familial specificity of ETD for schizophrenia; statistical, interpretive, and methodological considerations in the use of mixture analysis; the association of ETD with clinically and psychometrically defined schizotypy; and the questions of trait stability and medication effects.

Family stress and coronary risk in children.

This study examined children of 64 families for associations between a) family conflict and cohesion and b) plasma lipids, lipoproteins, and aggressiveness. Ratings of conflict and cohesion were obtained from parents. Children rated themselves on aggressiveness, one component of Type A behavior. The presence of conflict in the family was positively related to an unfavorable lipid profile (total plasma cholesterol/high-density lipoprotein cholesterol) among boys, but not girls. Family conflict predicted increased levels of aggression in girls, and in boys whose family cohesion was low. These findings suggest that stress in the family may play an important role in the development of coronary risk.