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.

Inheritance of open-angle glaucoma in the Barbados family study.

The majority of genetic studies on open-angle glaucoma (OAG) have been conducted in primarily white populations, with investigations of inheritance patterns largely based on self-reported information. The Barbados Family Study of Open-Angle Glaucoma (BFSG) is the first study to investigate the transmission pattern(s) for OAG in a predominantly black population, based on standardized examinations. Each BFSG participant received a comprehensive examination including anthropometric and other measurements, best-corrected visual acuity, perimetry, tonometry, lens gradings, fundus photography, venipuncture, an extensive interview including ocular, medical and family history information and a comprehensive ophthalmologic evaluation. Conservative criteria were used to define glaucoma status, including the presence of both visual field defects and optic disc damage. The study included 207 OAG-affected probands (median age: 68 years) and 1,056 of their relatives (median age: 47 years). Among the relatives examined 10% (n = 106) had OAG and 13% (n = 141) had probable OAG. Segregation analyses were performed to determine the mode of inheritance for glaucoma in these families. The results indicate that transmission of OAG or probable OAG is most likely due to a major codominant gene. Both age and gender are shown to be significant factors as well; with an increase in risk being associated with each year of age over 54 years and an increase in risk for all ages and genotypes observed in males. These analyses do not, however, preclude the possible existence of an environmental component or other genetic determinants in OAG. Further evidence for the existence of a major gene may be obtained by additional follow-up of the relatively young cohort of relatives, as well as ongoing linkage analyses.

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.

Analyses of reported family history of glaucoma: a preliminary investigation. The Barbados Eye Study Group.

This study investigated the self-reported family history of open-angle glaucoma (OAG) among 4,314 black participants in the Barbados Eye Study (BES), which was based on a random sample of Barbados-born citizens between 40 and 84 years of age. Data collection included Humphrey perimetry, fundus photography, various ophthalmic and other measurements and a comprehensive interview, including family history. Results showed that participants with OAG and previous OAG treatment reported more family history; maternal history was reported twice as often as paternal history. In persons without previous OAG treatment, those with newly diagnosed OAG reported more sibling history (Odds Ratio = 4.5). The Statistical Analysis for Genetic Epidemiology (S.A.G.E.) system was used to test the transmission models for OAG in a subset of 1,048 families (5,806 individuals) with the most complete self-reported family information. The S.A.G.E. results are consistent with the existence of a major dominant allele for OAG. These results should be viewed as promising, but preliminary, since they are based on self-reported data. More definitive information is currently being collected by the Barbados Family Study of Open-angle Glaucoma.

Analyses of reported family history of glaucoma: a preliminary investigation: the Barbados Eye Study Group

This study investigated the self-reported family history of open-angle glaucoma (OAG) among 4,314 black participants in the Barbados Eye Study (BES), which was based on a random sample of Barbados-born citizens between 40 and 84 years of age. Data collection included Humphrey perimetry, fundus photography various ophthalmic and other measurements and a comprehensive interview, including family history. Results showed that participants with OAG and previus OAG treatment reported more family history; maternal history was repored twice as often as paternal history. In persons without previous OAG treatment, those with newly diagnosed OAG reported more sibling history (Odds Ratio = 4.5). The Statistical Analysis for Genetic Epidemiology (S.A.G.E.) system was used to test the transmission models for OAG in a subset of 1,048 families (5,806 individuals) with the most complete self-reported family information. The S.A.G.E. results are consistent with the existence of a major dominant allele for OAG. These results should be viewed as promising, but preliminary, since they are based on self-reported data. More definitive information is currently being collected by the Barbados Family Study of Open-angle Glaucoma.(AU)

Open-angle glaucoma and blood groups. The Barbados Eye Study.

OBJECTIVE: To evaluate the association of open-angle glaucoma (OAG) with ABO, Rh and Duffy blood groups in the population-based Barbados Eye Study. DESIGN: Case-control study. SETTING AND PARTICIPANTS: A subset of black Barbados Eye Study participants, which included 199 OAG cases and 1063 controls. DATA COLLECTION: ABO, Rh and Duffy blood groups were determined as part of a comprehensive study visit, which included assessment for OAG through perimetry, fundus photography, and ophthalmologic examination. OUTCOME MEASURES: Comparison of blood groups between OAG cases and nonOAG controls, expressed as odds ratio and 95% confidence intervals. RESULTS: Associations were found with the Duffy Fya+ group, which is more frequent in white than black populations. In Mantel-Haenszel analyses, OAG was positively associated with Duffy Fya+ in men (odds ratio, 2.67; confidence interval, 1.52 to 4.69) and in persons with intraocular pressure more than 21 mm Hg (odds ratio, 3.32; confidence interval, 1.49 to 7.38). Logistic regression analyses confirmed these findings (interaction of Duffy Fya+ and male gender, P = .01; interaction of Duffy Fya+ and intraocular pressure, P = .04). No associations between OAG and the ABO or Rh blood groups were seen. CONCLUSIONS: The associations with Duffy Fya+, which had not been reported previously in a black population, support the involvement of genetic factors in OAG. However, the lack of association between OAG and blood group markers of African ancestry is inconsistent with a genetic explanation for the differences in OAG prevalence between blacks and whites. Our findings suggest gene-environment interactions in OAG, to be explored by further studies of OAG and Fy markers by racial group and gender.

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.

Integration of linkage analyses and disease association studies.

The REGD procedure of the S.A.G.E. [1994] system was used to determine the mode of inheritance of the rare disease given in Problem 1. The likelihood ratio test statistic indicated that we should reject the hypotheses of dominant and recessive inheritance at the 0.01 level, so codominant inheritance was assumed. The estimated penetrance values computed from the beta estimates given by the S.A.G.E. output were 1.0, 0.7, and 0.0 for the AA, AB, and BB genotypes respectively. A sample of three markers from each chromosome was used to determine which chromosome(s) gave evidence of having loci linked to the disease locus. The lod minus 0.83 support interval, which has been shown to provide the best approximation to 95% coverage among interval estimates [Nemesure et al., in press], was obtained for each of these markers. The criterion for rejecting the hypothesis of close linkage using the support interval methodology required that the left side of the lod minus 0.83 support interval about the maximum likelihood estimate, theta, includes only values greater than theta = 0.10. This criterion suggested that chromosomes 2, 3, and 6 did not contain the disease genes. Classical lod-score linkage analysis using the usual criteria of 3.0 for linkage and -2.0 for exclusion did not result in any regions being identified. On dropping the required lod score to 1.0, chromosomes 1, 3, and 6 gave results in favor of linkage with lod scores of 1.94 (theta = 0.19), 1.20 (theta = 0.24), and 1.30 (theta = 0.23), respectively. Association studies comparing unrelated cases to unrelated controls were done for all markers on all chromosomes. Two associations were observed which were significant at the 0.05 level after adjusting for the large number of multiple comparisons being made. The strongest association observed was between allele 7 of marker 23 on chromosome 5 and the disease (chi 2(1) = 52.20, OR = 4.7) and the second strongest was between allele 8 of marker 31 on chromosome 1 (chi 2(1) = 20.10, OR = 3.4).

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.