bluuebunny/crossref_metadata_2025 huggingface dataset:
The collaborative lipid research clinics program family study: Detection of major genes influencing lipid levels by examination of heterogeneity of familial variances
Authors: Green Philip , Owen A. R. G. , Namboodiri Kadambari , Hewitt David , Williams Lynn R. , Elston R. C. , Rifkind Basil M. , Rao D. C.
Published: June 2005

Age, sex‐adjusted, and transformed lipid and lipoprotein data on over 1,200 white North American sibships in the Collaborative Lipid Research Clinics Family Study were analyzed for possible major genes causing high or low levels of these traits. The sibships were stratified on the basis of parents' trait values, and within‐sibship variance in the high (or low) families was compared to that in the normal families via an F‐test. The null hypothesis of multifactorial transmission was strongly rejected for low LDL, low total cholesterol, and high HDL families. An analysis of spouse‐pair variance gave similar results. This may reflect the presence of dominant genes for hyperalpha‐ and hypobetalipoproteinemia. There was weaker evidence for single genes causing hyperbetalipoproteinemia. There was no evidence for major genes influencing triglyceride levels. Methodological issues with significant bearing on these results and those of other studies are discussed.
Genetic analysis workshop II: Study of problem 2 linkage relationships by different methods
Authors: Demenais F. , Darlu P.
Published: June 2005

Segregation and linkage analyses were performed on Problem 2 simulated data. Segregation analysis showed evidence for a nearly recessive major susceptibility locus with parameter estimates close to the simulation input values. Linkage analyses between this susceptibility locus (X) and the ten marker loci (A to J) led us to propose the following map: X‐G‐F‐B.
No evidence for linkage between an insulin‐dependent diabetes mellitus‐susceptibility locus and immunoglobulin loci KM or GM
Authors: Field L. Leigh , Goldstein Alisa , Spence M. Anne , Anderson C. E. , Rimoin David L. , Rao D. C.
Published: June 2005

We studied 52 families having more than one member affected with insulin‐dependent diabetes mellitus (IDDM) for linkage of an IDDM‐susceptibility locus to the immunoglobulin loci KM and GM. Linkage was analyzed by the LOD score method using single‐locus recessive and dominant models of IDDM inheritance, with penetrances of the disease‐susceptible genotypes being dependent on age and reaching a maximum of 20% by age 40. We found no evidence for linkage of IDDM to KM or GM. Close linkage (recombination fraction <5%) was rejected for KM under the recessive model and for GM under both models. These results suggest either that there are no IDDM‐susceptibility loci closely linked to KM or GM or that use of a single‐locus model of IDDM (which ignores the effects of the susceptibility locus in the HLA region) is inadequate for their detection.
A statistical test for detection of ancestral genetic contributions to disease occurrence in finite populations
Authors: Hauck Walter W. , Martin Alice O. , Rao D. C.
Published: June 2005

We have been investigating cancer patterns in the Hutterites, a religious isolate residing on communal farms [Martin et al, 1980a,b,c]. Advantages of this population include extensive and accurate genealogies, essentially complete case ascertainment, and relatively uniform environmental background with regard to geographic location, lifestyle, and diet. However, application of the common epidemiological approach to familial risk assessment based on incidence in relatives of index cases [Haenszel, 1959] posed difficulties because all cases are probands. We also planned to employ matching to control for important confounders and thus had to deal with the problems of the matching of cases and controls as well as the existence of complex inbreeding [Hauck and Martin, 1982]. Our basic approach was to compare coefficients of kinship (Fm, a measure of coancestry) of cases with each other to coefficients between cases and matched controls drawn from the same population. We have developed a paired t‐type statistic to assess the significance of observed differences.

We present, as examples, application of our methods to the analysis of Hutterite data on neurofibromatosis, known to be inherited in autosomal dominant fashion, and on cancer. Neurofibromatosis showed significant familial aggregation, as expected. Breast, colon‐rectal, and stomach cancer did not. We then show how to evaluate power and to determine appropriate sample sizes for detecting specified increases in kinship.
A linkage analysis of the Gm locus and multiple sclerosis
Authors: Haile R. W. C. , Goldstein A. , Field L. , Marazita M. L. , Rao D. C.
Published: June 2005

We conducted linkage analyses of immunoglobulin G heavy chain marker (Gm) phenotypes and multiple sclerosis (MS) in 30 families, each having at least two first‐degree relatives with definite/probable MS. These families yielded positive evidence for linkage to human leukocyte antigen (HLA) loci in previous analyses. In the present analysis, however, the results for Gm were negative. Most lod scores were negative, particularly at the smaller recombination values (θ). We explored the possibility of heterogeneity by subgrouping our data on the basis of specific HLA types (A3, B7) and Gm types (Gm1, Gm1,2) within the pedigrees. The results were again negative with no substantial differences in estimates of θ between subgroups.
False‐positive reporting of Down syndrome on Ohio and New York birth certificates
Authors: Johnson Karen M. , Huether Carl A. , Hook Ernest B. , Crowe Carol A. , Reeder Barbara A. , Sommer Annemarie , McCorquodale Maureen M. , Cross Philip K. , Rao D. C.
Published: June 2005

Although correction for underreporting of congenital malformations on birth certificates is included in most studies, inaccuracy of reporting has not been widely examined. Two separate investigations were conducted on the inaccuracy of Down syndrome (DS) reporting on birth certificates; ie, false‐positive cases in which an individual coded as DS did not in fact have DS. In Ohio, 824 individuals were coded as DS on their birth certificate during 1970–1981. Of these, a definitive determination as to whether or not they had DS was made on 778 by using cytogenetic data, medical records, the state's birth defects registry, school records, and by questioning physicians. Fifty‐seven false‐positives were found, indicating a 7.8% level of coding inaccuracy for all races and 6.9% for whites only. Nine of these arose from miscodings during data processing; 48 were misdiagnosed as DS. This can be contrasted with false‐negatives also studied in Ohio, where 66.1% of DS cases were not reported on the birth certificate. No statistical differences were observed between false‐positives and true DS in the distribution of sexes, in population size of county of birth, or in year of birth (although there was a declining false‐positive rate over the 12 year period). The percentage of DS false‐positives, however, was significantly higher for younger maternal ages (⩾30 years) than older ones (⩾30 years) and for nonwhites compared to whites. Further, there was a strong negative correlation between the percentage of false‐positives and the degree of certainty expressed in reporting DS on the birth certificate.
Genetic analysis workshop III: Two‐point linkage analysis on pedigrees, nuclear families, and sibships
Authors: Cox Nancy J. , Suarez Brian K.
Published: June 2005

Two‐point linkage analyses yielded correct identification of linkage groups and good estimates of recombination frequencies in both males and females. Additional analyses compared various family structures for the total number of typed individuals necessary to detect linkage. Results suggest that for codominant markers with moderate recombination frequency, pedigrees may not provide substantial savings over nuclear families.
Genetic analysis workshop III: Combining two‐point analyses under the constraints of a linear map and a constant female/male distance ratio
Authors: Ott Jurg
Published: June 2005

For each pair of loci among the four loci in a linkage group, a two‐point analysis was performed. It consisted of estimating means, variances, and correlation of male and female recombination fractions and approximating the joint likelihood by a bivariate normal density. The pairwise results were assumed independent and combined. The resulting likelihood was maximized over five parameters: three map distances, a constant ratio of female‐to‐make distance, and the parameter in Felsenstein's mapping function.
Genetic analysis workshop III: Sampling considerations and assumptions in gene mapping
Authors: Arlen Price R. , Kramer Patricia L. , Pakstis Andrew J. , Kidd Kenneth K.
Published: June 2005

We comment on three aspects of genetic linkage studies: 1) estimation of interference, 2) determining order of loci, and 3) sex differences in recombination.
Genetic analysis workshop III: Two‐point analysis of multipoint data
Authors: Anne Spence M. , Marazita Mary L. , Hodge Susan E.
Published: June 2005

A three‐step procedure was employed to analyze the workshop data. Pairwise lod scores were computed using LIPED and were utilized for estimating the recombination frequencies and thereby order among loci, This approach proved sufficient to identify accurately and to order the two linkage groups. Coincidence and interference were estimated. Associations between the alleles were tested. The following is a brief summary of this study. Detailed results or program listings are available upon request.
Studies on vitiligo. II. Familial aggregation and genetics
Authors: Das S. K. , Majumder Partha P. , Majumdar T. K. , Haldar B. , Rao D. C.
Published: June 2005

Data on 298 pedigrees, each collected through an affected proband, have been analyzed to study familial aggregation and genetics of vitiligo. The extent of familial aggregation is statistically significant at the 5% level. The disease does not appear to be inherited in a simple dominant or recessive fashion. The herita‐bility of liability to the disease is 46% ± 4.82%. Neither common family environment nor a major locus with additional sources (environmental and/or polygenic) can be excluded as a cause of familial aggregation. Association of the disease with six polymorphic genetic marker loci have been studied. Significant associations with ACP1 and RH loci have been found. This and earlier studies indicate that the disease is associated with genetic loci on different chromosomes, which points to a polygenic nature of the disease.
Effects of household sharing on high density lipoprotein and its subfractions
Authors: Hasstedt Sandra J. , Kuida Hiroshi , Owen Ash K. , Williams Roger R. , Rao D. C.
Published: June 2005

Household effects accounted for significant proportions of the observed variance of high density lipoprotein cholesterol (HDL‐C) and subfractions HDL2 and HDL3. It was found that 19.3% of HDL‐C variance could be attributed to a juvenile sib effect (under age 18); 17.4% of HDL2 variance could be attributed to a sib effect (of any age); and 22.1% and 32.6% of the HDL3 variance could be attributed to a parent‐offspring effect and a sib effect (of any age), respectively. In addition, additive genetic effects accounted for 56.5%, 37.3%, and 28.3% of the variances of HDL‐C, HDL2, and HDL3, respectively. These are maximum likelihood estimates obtained using a variance components model on 2,149 HDL‐C levels measured on members of 54 Utah pedigrees, and 337 HDL2 and HDL3 levels measured on a subset of 14 pedigrees.
Interaction of genetics and epidemiology in the literature
Authors: Khoury Muin J. , Beaty Terri H. , Cohen Bernice H. , Rao D. C.
Published: June 2005

To evaluate the extent of interraction between genetics and epidemiology in studies reported in the literature, we reviewed all the “familial/genetic” papers published in a standard epidemiology journal (American Journal of Epidemiology, AJE) and all the “epidemiology” papers published in a standard human genetics journal (American Journal of Human Genetics, AJHG) between 1966 and 1984. A variety of medline subject headings were used in this search. Computerized listings of titles, subject headings, and abstracts were reviewed. It could be shown that familial/genetic papers constituted 4.3% of all papers published in AJE and epidemiology papers constituted 16.4% of papers published in AJHG. Over time, familial/genetic studies published in AJE increased both in number and in proportion of all papers, and more family studies are using complex statistical genetic techniques. On the other hand, epidemiology papers published in AJHG did not increase in number over time, and actually decreased in relation to all papers. These papers were mostly either descriptive (eg, defining frequencies of Mendelian traits in populations) or analytical (eg, defining risk factors for chromosomal abnormalities, and other reproductive outcomes). This analysis suggests that epidemiologic methods have been widely used in the genetic literature, and that genetic methods are gaining more access to the recent epidemiology literature. Because of increasing recognition of the role of genetic factors in disease, there is a growing need to incorporate both genetic and epidemiologic methods in etiologic studies of complex disorders.
Complex segregation analysis of low levels of plasma high‐density lipoprotein cholesterol in a sample of nuclear families in Jerusalem
Authors: Friedlander Y. , Kark J. D. , Stein Y. , Rao D. C.
Published: June 2005

Low levels of high‐density lipoprotein cholesterol (HDL‐C) are associated with increased risk of coronary heart diesease (CHD). Therefore, assessment of the mode of inheritance of HDL‐C is of importance. HDL‐C concentrations in 3,074 nuclear families in the multiethnic Jerusalem Lipid Research Center study population were analyzed for possible involvement of major genes in determination of low levels of this trait. Complex segregation analysis under the mixed model of inheritance (major gene and multifactorial components) was performed on transformed HDL‐C concentrations after adjustment for age, sex, and environmental measures. Evidence for segregation of a recessive major gene for depressed HDL‐C, with an allele frequency of q = 0.06, in addition to multifactorial transmission (H = 0.45) was found in these families. Estimates from the mixed model were homogeneous across the different ethnic groups. When the substantial multifactorial background was excluded from the model, we found evidence for an additive (codominant) Mendelian gene (d = 0.48), which demonstrates the necessity of using the mixed model. Our previous results were inconclusive with respect to the involvement of a major gene in determination of high levels of HDL‐C. However, we tentatively postulate an uncommon recessive gene for low levels of HDL‐C in the Israeli population in addition to polygenic and environmental determinants.
Coagulation factor XIII: Genetic linkage studies with F13B
Authors: Bender Klaus , Bissbort Siegbert , Klein Anne , Mauff Gottfried , Mayerová Antonia , Nagel Marcela , Schilling Annette , Wienker Thomas F. , Rao D. C.
Published: June 2005

Linkage relations of the F13B gene with 38 marker genes are analyzed, which, along with the data of earlier reports on the same subject, brings the number of comparisons to a total of 49. Practically all the lod scores are totally negative. This will mean that the F13B gene can hardly be located on the chromosomes/chromosome arms 1p, 2p, 4q, 6p, 14p, 15p, 20q, 21p, 22 and also not on longer segments of 3q, 6q, 7q, 9p, 9q, 11q, 13q, 14q, 16p, and 16q.
Estimation of segregation and ascertainment probabilities by discarding the single probands
Authors: Li C. C. , Chakravarti Aravinda , Halloran Susan L. , Rao D. C.
Published: June 2005

The first portion of this communication reiterates the method of discarding single probands for studying the segregation ratio under incomplete ascertainment. The organization of the algebra leads to the second portion, in which the “self‐contained” subsets are constructed with respect to both the segregation ratio and the ascertainment ratio. These subsets make a more detailed study of segregation and ascertainment possible.
Robust inference for variance components models in families ascertained through probands: II. Analysis of spirometric measures
Authors: Beaty T. H. , Liang K. Y. , Seerey S. , Cohen B. H. , Rao D. C.
Published: June 2005

Three spirometric measures of pulmonary function were used to estimate genetic and nongenetic components of variance for 781 members of 158 families ascertained through a proband with obstructive pulmonary disease. Forced expiratory volume in 1 sec (FEV1), forced vital capacity (FVC), and the ratio of these two (FEV1/FVC) were adjusted for age, sex, race, smoking, and height and used in a robust approach to estimate variance components after conditioning on the proband's observed value. The best fitting model for both residual FEV1/FVC and FEV1 included an additive genetic component representing 25% and 9% of the variation in these two traits, respectively. In addition, there was a significant correlation between parents in residual FEV1/FVC, and a component shared among full sibs was statistically significant for residual FEV1. No evidence of a genetic component for residual FVC was found in this analysis. Although these results agree with previous reports based on other populations in showing a substantial degree of direct genetic control over spirometric measures of pulmonary function, they also raise the possibility of etiologic heterogeneity.
Social selection in human populations: Protected polymorphism of deleterious alleles with incomplete penetrance
Authors: Yokoyama Shozo , Crow James F.
Published: June 2005

Population dynamics of two alleles, A1 and A2, at a locus under social selection have been studied by considering incomplete penetrance of the three genotypes. A social selection model is constructed by assuming that the fitness of an individual is determined by his or her own phenotype as well as parental phenotypes. For both multiplicative and additive fitness models, sufficient conditions for a protected polymorphism depend on the reduced fitness of affected individuals (γ), the reduced fitness of all individuals resulting from affected parents (β), and the penetrance probabilities, f1, f2, and f3, for the three genotypes, A1A1, A1A2, and A2A2. These conditions reduce to two biologically important cases: 1) f1 < f2 > f3 and β < −γ/(1 − γ) and 2) f1 > f2 < f3 and β > − γ/(1 − γ), and the most common form of the equilibrium frequency of the allele A2 is given by (f1 − f2)/(f1 − 2f2 + f3).
Association between polymorphic blood markers and risk factors for cardiovascular disease in a large pedigree
Authors: George Varghese T. , Elston Robert C. , Amos Chris I. , Ward Laura J. , Berenson Gerald S. , Rao D. C.
Published: June 2005

A large pedigree with high prevalence of heart disease is investigated to analyse the association between polymorphic blood markers and quantitative risk factors for cardiovascular disease. The analysis incorporates a familial correlation structure among the individuals in the pedigree and a generalized power transformation to induce approximate residual normality of the risk factors. A total of 380 marker/ risk factor combinations are analysed, and at the nominal 1 % significance level, positive associations are found between the A antigen of the ABO locus and both serum total cholesterol and low‐density lipoprotein cholesterol, and negative associations are found between the B antigen of the ABO locus and serum total cholesterol, and between the B allele of acid phosphatase (AP) locus and systolic blood pressure.
Further tests of nonrandom segregation with special reference to linkage
Authors: Majumder Partha P. , Rao D. C.
Published: June 2005

For an autosomal recessive disease, a statistical procedure is developed for detecting nonrandom segregation of marker haplotypes from an unaffected parent to affected children, specifically for the case when the alternative hypothesis of linkage between the disease and marker loci is postulated. The test procedure is locally most powerful and, depending on family size and number of families sampled, any one of the three test statistics proposed can be used. An application of this procedure provides evidence of linkage between tuberculoid leprosy and HLA.
Etiologic heterogeneity in alcoholism
Authors: Gilligan Sheila B. , Reich Theodore , Cloninger C. Robert , Sing Charles F.
Published: June 2005

Etiologic heterogeneity in alcohol abuse was evaluated in 195 extended pedigrees, comprising 288 nuclear families of 140 male and 55 female Caucasian American hospitalized alcoholics. Previous adoption studies in Sweden demonstrated differential heritability of two patterns of alcohol abuse in men: type‐2 alcoholism exhibited early onset of abuse associated with criminal behavior, while type‐1 abuse began at a later age, uncomplicated by antisocial traits. Alcohol abuse in female Swedish adoptees was relatively homogeneous and similar to the lateonset, type‐1 abuse. The notion of etiologic heterogeneity, as suggested by the Stockholm Adoption Studies, was examined in the American pedigrees by contrasting the models of familial transmission of susceptibility to alcoholism obtained via segregation analyses of families of male versus female probands. Families of male probands demonstrated significant familial resemblance, accounted for by a multifactorial‐polygenic background in addition to a major (gene) effect. In contrast, familial resemblance in the pedigrees of female probands was attributed solely to a multifactorial‐polygenic effect. We considered whether some families of male alcoholics were similar to families of female probands, who expressed type‐1 abuse predominantly. Pedigrees of male probands were separated in two groups: (1) “female‐like” families had a better likelihood for the model obtained for families of female probands than the one for families of all male probands, (2) “male‐like” families had a better likelihood for the model of familial transmission describing families of all male probands. A statistically significant difference in the pattern of familial transmission was observed between the “male‐like” and “female‐like” groups. Discriminant function analysis of alcohol‐related symptoms showed that the familial subtypes differed in clinical features as well. Alcohol abuse by male relatives in “male‐like” families was characterized by the early onset of inability to abstain entirely from alcohol or lack of desire to stop drinking; in contrast abuse in “female‐like” families was characterized by late onset of guilt feeling and loss of control over binge drinking.
Genetic epidemiology of duchenne muscular dystrophy in Japan: Classical segregation analysis
Authors: Kanamori Masao , Morton Newton E. , Fujiki Keiko , Kondo Kiyotaro , Rao D. C. , Borecki I. B.
Published: June 2005

Classical segregation analysis was performed on 651 male probands in 597 families with Duchenne muscular dystrophy (DMD) collected from 20 of 25 National Institutions for Muscle Diseases in Japan. The proportion of sporadic cases is compatible with 1/3 expected for an X‐linked lethal trait with an equal mutation rate in egg and sperm, the estimated mutation rates being 9.2 × 10−5 and 10.9 × 10−5 /gamete/generation, respectively. The incidence and prevalence among males were estimated to be 29.2 × 10−5 and 6.7 × 10−5, respectively. These results indicated no difference from the patterns of DMD in Western countries.
Inheritance of human platelet thermolabile phenol sulfotransferase (TL PST) activity
Authors: Price R. Arlen , Cox Nancy J. , Spielman Richard S. , Van Loon Jon A. , Maidak Bonnie L. , Weinshilboum Richard M. , Borecki I. B. , Rao D. C.
Published: June 2005

Sulfate conjugation is an important pathway in the biotransformation of drugs and neurotransmitters. The thermolabile (TL) form of the enyzme phenol sulfotrans‐ferase (PST) catalyzes the sulfation of catecholamine neurotransmitters and drugs such as methyldopa and acetaminophen. Platelet TL PST activity was measured in blood samples from 232 individuals in 49 nuclear families. Correlations ranged from 0.43 to 0.45 for parent–offspring pairs and from 0.44 to 0.47 for siblings. Mother‐father correlations were not significantly different from zero. Although evidence was not unequivocal, both segregation and commingling analyses provided some support for a major gene influence on TL PST activity, with other variation due to polygenic background. In both sets of analyses, however, support for a major gene hypothesis depended upon skewness in the TL PST activity distribution. A polygenic model with high heritability (0.77) was most strongly supported with the log transformed data. These results confirm and extend a previous report of high heritability of TL PST based on a study of twins. In addition, our results raise the possibility of a major gene effect on this important catecholamine‐ and drug‐metabolizing enzyme–a possibility that can now be evaluated using biochemical techniques.
The effect of nutritional factors on sex hormone levels in male twins
Authors: Bishop D. Timothy , Meikle A. Wayne , Slattery Martha L. , Stringham John D. , Ford Marilyn H. , West Dee W. , Borecki I. B. , Rao D. C.
Published: June 2005

Dietary intake has been hypothesized as being associated with several hormonally related cancers including prostate, breast, ovarian, and endometrial cancer. Because diet may affect hormones directly, it is logical to examine the effects of dietary factors on hormone production and levels. Therefore, a set of 72 male MZ and 83 male DZ twin pairs was ascertained from the Utah birth certificates. A quantitative food frequency questionnaire was administered and blood samples were drawn for hormonal assays. Heritability estimates for hormonal levels were calculated indicating a range from no heritability for sex hormone binding globulin (SHBG), estrone, and testosterone glucuronide to 70% for androstanediol glucuronide and luteinizing hormone. To examine nutritional factors, the difference in hormone and SHBG levels between each MZ twin and his co‐twin were correlated with the difference in nutrient intake. Weight and obesity were significantly correlated with plasma testosterone and follicle stimulating hormone. Fat intake showed a significant association with testosterone. Androstanediol glucuronide, a steroid that reflects tissue formation of dihydrotestosterone, was inversely correlated with caloric intake, theobromine and caffeine. Testosterone glucuronide exhibited significant correlations with calories and vitamin A. This study suggests that dietary intake affects plasma sex‐steroid levels in men.
Cytogenetic studies of couples with repeated spontaneous abortions of known karyotype
Authors: Hassold Terry , Jacobs Patricia A. , Pettay Dorothy , Rao D. C.
Published: June 2005

Several cytogenetic studies have reported an increased frequency of aneuploidy in peripheral blood cultures of couples with multiple spontaneous abortions. However, in none of the studies have the chromosome constitutions of the fetuses been known, making it difficult to interpret these observations. In the present study, we summarize our cytogenetic observations on 23 couples with multiple miscarriages, 12 of whom had repeated chromosomally normal spontaneous abortions, and 11 repeated trisomic spontaneous abortions. We were unable to demonstrate a significant difference in the level of aneuploidy between the two groups. Therefore, it seems unlikely that aneuploidy detectable in peripheral blood preparations is an important indicator of fetal aneuploidy.
Estimating the age‐at‐onset function using life‐table methods
Authors: Chidambaram A. , Chakravarti A. , Ferrell RE , Lyengar S. , Rao D. C.
Published: June 2005

In the analysis of dominantly inherited diseases, the age‐at‐onset function is often estimated from the observed age‐at‐onset distribution of cases. This estimate is confounded with the age distribution of the population from which the cases were sampled and is accurate only if there are no competing causes of death. In this paper, we present a straightforward method for calculating a more accurate age‐at‐onset function under etiologic heterogeneity. We use the life‐table approach and survival analysis methods. This method is illustrated using data on first‐degree relatives of probands from two sets of families with high cancer incidence: one with breast/ovarian cancer and the other with colon cancer. A comparison of the estimated age‐at‐onset function obtained by the two methods is presented. In both cases, colon cancer as well as breast/ovarian cancer, the estimates of onset probabilities based on proportion of cases, are consistently higher than those obtained by the life‐table method. For breast/ovarian cancer, this difference is not as striking as it is in the case of colon cancer; nevertheless, the method using proportion of cases tends to give a lower estimate of the age‐at‐onset function (higher probability of being affected at lower age) than the life‐table approach.
Lifestyle factors in monozygotic and dizygotic twins
Authors: Heller RF , O'Connell D.L , Roberts DCK , Allen JR , Knapp JC , Steele PL , Silove D. , Rao D. C. , Vogler G. P.
Published: June 2005

In examining genetic influences on biological variables using twins, it may be important to examine the distribution between and within twin pairs of demographic and lifestyle factors that may themselves affect the biological variable being studied. We explored the distribution of demographic and lifestyle factors that may affect blood lipid levels or ischaemic heart disease (IHD) risk among a sample of 106 monozygotic (MZ) and 94 like‐sex dizygotic (DZ) twin pairs. In our sample, MZ twins were statistically significantly different from DZ twins only in marital status, cigarette smoking habits, and the ratio of polyunsaturated to saturated fat (P:S ratio) in their dietary intake. The latter variable was among many dietary variables examined (using 4‐day weighed food diaries), and the size of the difference in intake was small. When comparisons were made of the similarities within twin pairs, we found members of MZ twin pairs to be statistically significantly closer than DZ twins in educational achievement, occupation, cigarette smoking, and exercise habits, and the number of days a week on which alcohol was consumed. These last three variables were consistently closer among twins with closer contact than among those with a smaller degree of current shared environment. For 12 of the 13 nutrients examined, the within‐pair correlations were higher for MZ than for DZ twins, although our test for significant genetic variance showed statistical significance only for intake of complex carbohydrates. We conclude that MZ twins share demographic and lifestyle factors that might influence the risk of IHD and blood lipid levels to a greater degree than do DZ twins, although it is difficult to say if these similarities in lifestyle result from genetic influences or not. Nevertheless, ascribing differences between correlations in MZ and DZ twin pairs for lipid levels as being purely “genetic”–as implicit in conventional measures of heritability–is likely to overestimate the influence of genetic factors.
Relationship of epithelial ovarian cancer to other malignancies within families
Authors: Schildkraut Joellen M. , Thompson W. Douglas , Vogler G. P. , Rao D. C.
Published: June 2005

The relationship of family history of cancer of the breast, colon/rectum, cervix, endometrium, lung, and thyroid to the risk of epithelial ovarian cancer was investigated in a large population‐based case‐control study. The data consisted of family histories from 493 epithelial ovarian cancer cases and 2,465 controls aged 20–54 years. After controlling for potential confounders, risk for epithelial ovarian cancer was found to be significantly elevated among women reporting breast cancer and colo/rectal cancer in a first‐degree relative. Adjusted odds ratios were 1.5 (95% CI = 1.1‐2.1) and 1.9 (95% CI = 1.1‐3.3), respectively. None of the remaining four types of cancer was found to be statistically associated with the risk of epithelial ovarian cancer. However, when histologic subtypes of epithelial ovarian cancer were considered, a family history of breast cancer was found to be associated with an elevated risk of endometrioid ovarian cancer (odds ratio = 2.3; 95% CI = 1.1‐4.7), as was a family history of endometrial cancer (odds ratio = 2.7; 95% CI = 1.0‐6.9). The results are considered in the context of other studies of familial patterns of cancer and are compared with published findings concerning the occurrence of multiple primary cancers in the same individual. The findings indicate that further study is warranted regarding possible genetic relationships between epithelial ovarian cancer and cancers arising in other organs.
Familial risk of cancer among randomly selected cancer probands
Authors: Sellers Thomas A. , Elston Robert C. , Stewart Cecily , Rothschild Henry , Vogler G. P.
Published: June 2005

Several investigators have reported that relatives of lung cancer probands have a greater‐than‐normal likelihood for developing some form of cancer. To evaluate whether this familial risk is general for probands with cancer at any site or limited to lung cancer probands, we did a case‐control study in which probands having cancer affecting any body site were identified and their pedigree data were tabulated. Telephone interviews and a mailed questionnaire were used to obtain cancer histories and environmental exposures on the families of 41 lung cancer probands, 105 probands with cancer other than lung, and 127 spouse families. Cumulative tobacco exposure (P<.05), occupational hazards (P<.005), and age of the family relatives (P<.0001) were found to be statistically significant predictors of cancer risk. With consideration given for these variables, we determined that siblings of lung cancer probands were at slightly greater risk of cancer of any kind (odds ratio [OR] = 1.43, P = .06) than siblings in the control group. Much of the elevated risk was attributable to an excess of lung cancer (OR = 2.49, P = .06). Siblings of non‐lung/non‐breast cancer probands were also determined to be at increased risk of lung cancer as well (OR = 1.61, P = .06). For parents, the risk was lower, although parental information may have been underreported.
An expected decrease in the incidence of autosomal recessive disease due to decreasing consanguineous marriages
Authors: Saito Tomohiro , Vogler G. P. , Rao D. C.
Published: June 2005

A recent decline in consanguineous marriages in Japan should have resulted in a decrease in the incidence of autosomal recessive disorders. Theoretical estimates were made of the chronological decrease in the incidence using a formula for Hardy‐Weinberg expectation in a partially inbred population and applying appropriate consanguinity rates, taken from the literature, during the period from 1942 to 1983. Theoretically estimated also, using Nei's extended Dahlberg's formula, is a chronological decrease in the proportion of first‐cousin marriages among the parents of affected individuals.

The estimated decrease in both indices during the period was substantial, and greater in disorders of low gene frequencies. The incidence of major autosomal recessive disorders was estimated to have decreased by 40 to 80% during the period. The proportion of first‐cousin marriages among the parents of affected individuals dropped from 40–70% in 1945 to 5–15% in 1983.

Theoretical estimates of the magnitude of the decrease in the incidence and in the proportion of first‐cousin marriages among the parents agreed fairly well with those of observed figures in phenylketonuria and Wilson's disease.
Circulatory disease mortality and diabetes incidence in 27 families with Friedreich ataxia
Authors: Morrell Daphne , Chase Charles L. , Swift Michael , Vogler G. P. , Rao D. C.
Published: June 2005

Friedreich ataxia (FRA) is an autosomal recessive neuromuscular disorder in which nearly all affected homozygotes eventually develop significant cardiomy‐opathy and a substantial proportion also develop diabetes mellitus. Diabetes and early heart disease have been observed previously in close blood relatives of FRA patients. To test the hypothesis that FRA heterozygotes may have elevated rates of heart disease mortality and diabetes incidence, we compared the rates of these conditions in 1,191 adult blood relatives to those in 745 nonblood relative spouse controls in 27 families of FRA patients.

We found no evidence for an excess of diabetes in the blood relatives. For three broad categories of circulatory disease mortality, the FRA blood relatives had significantly higher rates than the spouse controls. However, when each relative's prior probability of heterozygosity for the FRA gene was taken into account, the resulting estimates of relative risk of dying from circulatory disease for FRA heterozygotes compared to nonheterozygotes were not significantly elevated. Since the latter analysis provides the best test of the hypothesis, our data did not strongly support the hypothesis that FRA heterozygotes are at increased risk of cardiac death.
HLA class II typing using oligonucleotide probes
Authors: Robinson David M. , Holbeck Susan , Seyfried Christine , Byers Patricia , Palmer Jerry , Nepom Gerald T.
Published: June 2005

A DQβ locus‐specific oligonucleotide probe is used to identify DQβ alleles present in six insulin‐dependent diabetes mellitus (IDDM) multiplex families. Results of genotyping using this technique agree with those from cDNA probes and are often clearer. Allele‐specific oligonucleotide probes for the DRβ locus are used to identify subtypes (Dw4 and Dw14) of the DR4 specificity in five IDDM multiplex families. This distinction cannot be made with available cDNA probes.
Genetic epidemiology of persistent islet cell antibodies among IDDM patients
Authors: Newman Beth , Selby Joseph , Lee Ming , King Mary‐Claire
Published: June 2005

The persistence of cytoplasmic islet cell antibodies (ICA) more than a year after diagnosis of insulin‐dependent diabetes mellitus (IDDM) was investigated in 43 families with at least two children with IDDM. The prevalence of persistent ICA among IDDM patients was 16%. Persistence of ICA appeared to be familial in that siblings with IDDM were significantly more concordant for the presence or for the absence of ICA than expected by chance (P = 0.04). Patients with persistent ICA were older on average at onset of IDDM than patients without persistent ICA after adjusting for duration of disease (P = 0.004). Persistence of ICA was not significantly associated with HLA DR type, immunoglobulin genotype, insulin allele class, sex, history of viral diseases, or prior vaccinations.
Description of amish study data set
Authors: Egeland Janice A. , Gerhard Daniela S. , Pauls David L.
Published: June 2005

A brief description is given on the ascertainment methods and diagnostic procedures for bipolar affective disorder patients and their relatives in Amish pedigrees. Data on a sample of five bipolar families are provided, including conventional blood typings, serum protein and RFLP data.
Regressive logistic models for ordered and unordered polychotomous traits: Application to affective disorders
Authors: Bonney George E. , Dunston Georgia M. , Wilson Jerome
Published: June 2005

Regressive models are extended to disease phenotypes with two or more affection classes through the use of polychotomous logistic regression. The classes of affection may be ordered (ranked as on a liability continuum), or unordered. Data on affective disorders are used for illustration.
Familial analysis of bipolar affective disorder using logistic models
Authors: Blangero John , Elston Robert C.
Published: June 2005

Data on bipolar affective disorder in 187 pedigrees from the Collaborative Depression Study were analyzed using logistic models that have been extended to incorporate age of onset information. Logistic regression analysis and segregation analysis revealed evidence for complex familial effects on this disorder.
Modelling sibship environment in the regressive logistic model for familial disease
Authors: Hopper John L.
Published: June 2005

Recently analytical models for pedigree disease data have been developed that combine genetic and epidemiological modelling techniques. The regressive logistic model [Bonney, Biometrics 42:611–625; 1986] relies on decomposing the likelihood of a pedigree into the product of conditional probabilities, one for each individual, by imposing a (natural) order on pedigree members. In addition to modelling measured epidemiological variables, vertical transmission, transmission of unmeasured ousiotypes (a special case being genotypes), and some modelling of sibship dependencies have been proposed. In this paper the model is extended to include an unmeasured sibship environment factor using a log‐linear model for binary pedigree traits [Hopper et al., Genet Epidemiol 1:183–188; 1984], which breaks the pedigree into conditionally independent groups. Statistical issues, such as designs for which these factors will be discernible and tests of fit, are discussed.
Affective disorders: Evaluation of a three‐allele model accounting for clinical heterogeneity
Authors: Sandkuyl Lodewijk A. , Ott Jurg
Published: June 2005

The group of major affective disorders is clinically heterogeneous. In the genetic linkage study of the Old Order Amish [Egeland et al., 1987] the same disease gene appears to be responsible for the occurrence in one family of several clinically variant forms of affective disorders. Apparently other genetic or environmental factors determine the clinical presentation of this disease gene. We evaluated a three‐allele model where the clinical expression of the disease allele is determined by the other allele at the same locus. In the presence of a proposed modifying allele the disease allele is expressed as major depression, in the presence of the normal (neutral) allele as bipolar disorder (I or II). We applied this model in our analysis of the Old Order Amish data. In analysis of linkage between the locus for affective disroders and two DNA markers on chromosome 11p, we obtained considerably higher likelihood values under the three‐allele model than under a comparable two‐allele model. Also, lodscores were higher under the three‐allele model, with differences in lodscores between both models ranging from 0.95 to 1.34.
Relationship between body mass index, cigarette smoking, and plasma sex steroids in normal male twins
Authors: Meikle A. Wayne , Bishop D. Timothy , Stringham John D. , Ford Marilyn H. , West Dee W. , Rao D. C.
Published: June 2005

Smoking has been observed to affect plasma sex hormones and body mass index. The relationship between smoking, body mass index, and plasma concentration of sex hormones was studied in normal adult male twins. The analyses were performed for between 150 and 159 twin pairs for whom hormonal data were available on both twins. With bivariate analysis, neither body mass index nor smoking affected estrone, luteinizing hormone, follicle‐stimulating hormone, ratio of testosterone to estradiol, or ratio of testosterone to dihydrotestosterone. Body mass index significanly (P < 0.05) affected sex hormone binding globulin, whereas smoking had no effect. The plasma contents of testosterone and dihydrotestosterone and the luteinizing hormone/testosterone ratio were affected by both body mass index and smoking, although, after allowing for body mass, smoking was less significant (0.05 < P < 0.10). A path model was formulated to examine the relationship of body mass and sex steroid levels. Our results suggest that body mass index affects sex steroids, since common environmental factors do not account for the strength of the relationship. The bivariate analysis suggests that the smoking effect on sex hormones (except perhaps for dihydrotestosterone) is secondary to an effect on body mass index.
Modeling the age‐of‐onset function in segregation analysis: A causal scheme for leprosy
Authors: Abel Laurent , Mallet Alain , Demenais Florence , Bonney George E. , Rao D. C.
Published: June 2005

Several methods have been proposed to take into account the variable age of onset of a disease in genetic analysis. A different approach is presented from an etiological point of view. To illustrate the method, we used leprosy, an infectious disease with a variable age of onset depending on both the time of contamination with the bacillus and the latency of the disease; the role of a major gene in the susceptibility to this disease has been recently detected. The age‐of‐onset function was modeled to account for the two temporal processes: contamination event and incubation period. For genetic analysis, this function was combined with the probability of being susceptible to the disease, which was expressed by the use of regressive models. To test this new approach, ten sets of 500 nuclear families were simulated considering different hypotheses of contamination risks, which were either constant or dependent on contacts with contagious leprosy patients, and varying the extent to which the disease is heritable. Analyses of these data using two versions of the model indicate that the model can detect familial correlations in variable age of onset and discriminate between the different simulated effects.
Predicting intrauterine growth reterdation in sibships while considering maternal and infant covariates
Authors: Yang Ping , Beaty Terri H. , Khoury Muin J. , Liang Kung‐Yee , Connolly Margaret A. , Rao D. C.
Published: June 2005

Data on 6,210 full‐term sibships (gestational age > 36 weeks) reconstructed from birth certificates registered in Maryland between 1980 and 1984 were used to study sibship aggregation and recurrence risk of intrauterine growth retardation (IUGR) while considering maternal and infant covariates. In this study, IUGR was defined as being below the 10th percentile for race‐, sex‐, and gestational‐age‐specific birth weight based on all births registered in Maryland during 1984. Maternal factors (race, age at delivery, marital status, amount of prenatal care, concurrent illnesses, and complications during pregnancy) and infant factors (congenital malformations and first born child or not) were used as covariates in a modified logistic regression model which allowed correlation among sibs. First‐time mothers who were under age 30 years, unmarried, received too little prenatal care, or had any reported pregnancy complications were at high risk of delivering an infant with IUGR. Even given the effects of these risk factors, however, there was a significant correlation in risk among full sibs (r = .237 $ .028), which, combined with information on risk factors, can be used to estimate sibling recurrence risk for IUGR.
Inferences on the inheritance of congenital anomalies from temporal and spatial patterns of occurrence
Authors: Barbujani Guido , Russo Antonella , Farabegoli Alessandra , Calzolari Elisa , Rao D. C.
Published: June 2005

Most congenital anomalies are believed to result from interactions between genetic and environmental determinants, whose relative importance is not generally established. Temporal and spatial patterns allow inferences on the underlying transmission processes; in particular, it is possible to discriminate between sporadic and nonsporadic genetic factors, and to find evidence for the effects of environmental heterogeneity in time and space. We studied the occurrence of 14 anomalies in 14 registries of Western Europe. Four basic patterns have been identified: (1) Chromosomal abnormalities have uniform incidences and do not show significant geographical variation, in agreement with the expected consequences of randomly scattered nondisjunction events. (2) The homogeneous spatial distributions of three severe malformations (renal agenesis, oesophageal atresia, ano‐rectal atresia) are consistent with both the effects of fresh mutation and segregation of detrimental alleles. (3) A decrease of similarity of incidences with distance has been observed for neural tube defects, and this is the expected consequence of isolation by distance on genetically determined traits. (4) For facial clefts, polydactyly, and hypospadias, all postulated processes poorly account for the observed temporal and spatial patterns.