bluuebunny/crossref_metadata_2025 huggingface dataset:
Segregation analysis of autosomal dominant polycystic kidney disease
Authors: Dobin A. , Kimberling W. J. , Pettinger W. , Bailey‐Wilson J. E. , Shugart Y. Y. , Gabow P.
Published: June 2005

The results of classical segregation analysis on 159 families with polycystic kidney disease (PKD) are presented. It had been previously estimated that about 95 % of autosomal dominant PDK (ADPKD) families have PKD 1, the gene localized to chromosome 16p. The main purpose of the study was to determine if PKD shows any segregation distortion and to obtain new estimates of the age‐dependent penetrance. Penetrance at the early ages of onset has increased during the last decade, presumably because of improvements in renal imaging and consequent earlier age of diagnosis. In the current study, the mean age of diagnosis was estimated to be 20 years, with a standard deviation (SD) of 15.94. Under the best fitting model (autosomal dominant), over 70 % penetrance was estimated by age 30 years, over 95 % by 50 years, and 99 % by 55 years. Thus, diagnosis of this disease at an early age is possible without total reliance on DNA typing. The segregation ratio defined through the transmission probability in our model was not significantly different from 0.50, but its confidence limits were broad: 0.36 to 0.64. Neither transmission probability nor penetrance was significantly influenced by gender. The mutation rate was estimated to be 6.9 × 10−5, in accordance with the previously observed high mutation rate for PKD. However, the mutation rate in our study may be overestimated because it neglects low penetrance alleles and phenocopies. © 1993 Wiley‐Liss, Inc.
Some empirical properties of an all‐relative‐pairs linkage test
Authors: Olson Jane M.
Published: June 2005

Olson and Wijsman [Genet Epidemiol 10:87–102, 1993] recently proposed a single test of linkage which combines information from different types of relative pairs in a pedigree. Relative‐pair‐type‐specific regression parameters that relate the squared pair trait difference to the estimated number of marker genes shared identical by descent between the pair are estimated using generalized estimating equation methodology, then combined to give a single linkage test statistic. Questions remain concerning the small sample and robustness properties of this test statistic; these questions are addressed in the present paper using simulation. The test is substantially anti‐conservative for samples with fewer than about ten families and are approximately valid for samples larger than about 15 families. In addition, the test appears robust in the presence of trait genotype by environment interaction, trait family‐specific errors, a second major trait locus, and trait dominance. Surprisingly, the sibpair test was more powerful than the all‐relative‐pairs test for dominant traits with high heritability. Finally, adjusting for the presence of a marker known to be linked to one trait locus only marginally improves the power for detecting a second trait locus. © 1994 Wiley‐Liss, Inc.
Sources of variability of human plasma apolipoprotein A‐IV levels and relationships with lipid metabolism
Authors: Zaiou Mohamed , Visvikis Sophia , Gueguen René , Steinmetz Josiane , Parra Henri‐Joseph , Fruchart Jean‐Charles , Siest Gérard
Published: June 2005

Plasma apolipoprotein (apo) A‐IV concentration was determined by immunoelectrophoretic assay (EIA) in 119 nuclear families. No significant effect of concomitants such as age, weight, height, body mass index, tobacco, and alcohol consumption was observed on apo A‐IV levels in men and in boys. In women, contraceptive use and hormonal status affected apo A‐IV levels. In girls, only age influenced the quantitative phenotype. After adjusting by specific concomitants significant correlations were observed between apo A‐IV levels and triglycerides, apolipoprotein A‐I and apo B levels, suggesting a role of apolipoprotein A‐IV in the hepatic lipid metabolism. Intrafamilial correlations were estimated to investigate the plausibility of a common family factor. The results obtained in this study showed a significant correlation between family members with the exception of mother‐daughter pairs. Using a variance components model, the contribution of genetic and environmental factors was then investigated. Different statistical models were used and two major hypotheses were statistically acceptable: the first hypothesis supports that shared and specific environmental factors explain 35 and 65%, respectively, of the total adjusted plasma apo A‐IV variation. The fraction of apo A‐IV variability attributable to genetic factors was null. The second hypothesis supports that the fraction of variability attributable to apo A‐IV genetic variation is 67% and the common spouse environmental factors are responsible for 33% of the total variability and no specific environmental effect was found. Among the two hypotheses, taking account of the metabolism function, we support the first one without excluding gene‐ environment interactions which could mask the genetic influence. © 1994 Wiley‐Liss, Inc.
Affected sib pair identity by state analyses
Authors: Thomson Glenys , Motro Uzi
Published: June 2005

Four methods using identity by state (IBS) data from affected sib pairs are compared for their ability to detect linkage between a diallelic marker and disease. A joint null hypothesis of no linkage and no linkage disequilibrium between the marker and disease must be considered. Two tests have undesirable properties in the case of linkage disequilibrium. Which of the other two tests has more power is dependent on the presence or not of linkage disequilibrium. The procedure of choice when possible is to type parents of affected sib pairs: the null hypothesis of no linkage can then be tested using identity by descent (IBD) values from informative parents, and the null hypothesis of no marker association with disease (linkage equilibrium) can be tested independently using the marker allele frequencies in the affected sib pairs.
Power of segregation analysis for detection of major gene effects on quantitative traits
Authors: Borecki I. B. , Province M. A. , Rao D. C.
Published: June 2005

The power to detect major gene effects by rejection of the “no major gene” null hypothesis against a mixed model alternative was determined in random samples of nuclear families over a variety of conditions. Benchmarks have been developed using a varying number of families whose structure includes both parents and three children. Phenotypes were simulated assuming a Mendelian major gene under either recessive or dominant inheritance, with 0–30% residual polygenic heritability. Three trait prevalences—5, 10, and 20%—were considered in combination with increasing displacement between homozygous means, spanning a range of 14 to 36% of the phenotypic variance attributable to the major gene effect. All other assumptions of the traditional mixed model were adopted in the generating models. Segregation analysis was carried out on the simulated data sets, and the proportion of samples out of 200 replications in which the null hypothesis q = 0 was rejected is reported as the power. Thus, failure to detect a major gene effect in this context is solely due to sampling variation, since no other perturbations were introduced. In general, there appears to be greater power to detect dominant major gene effects as opposed to recessive ones using otherwise comparable parameter values, and the effect of varying sibship size under dominant models appears to be greater as well. The use of joint vs. conditional likelihood calculations also was evaluated; substantial drops in power were observed when using conditional likelihoods under recessive inheritance, while the differences in power appeared to be nominal under dominant inheritance. The results of this investigation are offered as a guide to assist in the design of family studies whose aim is to detect major gene effects.
Evidence for multiple genes determining sodium transport
Authors: Hasstedt Sandra J. , Hunt Steven C. , Wu Lily L. , Williams Roger R.
Published: June 2005

Sodium transport comprises a set of interacting systems. Consequently, a defective sodium transport gene affects multiple sodium transport systems, and a sodium transport variable measured on a sample of individuals reflects genetic variation from a number of different genes, complicating the task of identifying the effect of a single gene. To test for genes which affect sodium transport, we first applied principal components analysis to 14 variables related to sodium transport, thereby defining uncorrelated sources of variation in the variables. The sample consisted of 1,218 members of 68 pedigrees ascertained through probands with early‐onset stroke, hypertension, or coronary heart disease. Segregation analysis of the 14 principal components scores provided evidence for 8 genetic variants which alter sodium transport. One of the 8 variants is recessive, has homozygous genotype frequency estimated as 8.8% of the population, and increases sodium‐lithium countertransport, the passive sodium leak, body mass index, and triglyceride; the genetic variant may coincide with an insulin resistance gene. A second of the 8 variants is also recessive, has homozygous genotype frequency estimated as 7.4% of the population, and increases intraerythrocytic sodium and the passive sodium leak while decreasing sodium pump number; the genetic variant may reduce pump number. Two of the 8 variants substantially increase sodium‐lithium countertransport; frequency estimates for heterozygotes for the dominant variant and homozygotes for the recessive variant equal 1.8% and 3.1 %, respectively. Another of the 8 variants is recessive, has homozygous genotype frequency estimated as 1.9%, and increases body mass index. Each of the 3 remaining variants is rare and expressed in less than 1 % of the sample. © 1994 Wiley‐Liss, Inc.
ARCAD: A method for estimating age‐dependent disease risk associated with mutation carrier status from family data
Authors: Le Bihan Christine , Moutou Céline , Brugières Laurence , Feunteun Jean , Bonaïti‐Pellié Catherine
Published: June 2005

We present ARCAD, a method to estimate the disease risk associated with mutation carrier status using data on families ascertained by affected individuals, in which a germline mutation has been detected. Because the event of interest, the age of onset, is a censored variable, the method uses the survival analysis approach to formulate the likelihood. Provided that selection criteria are clearly defined, the ascertainment bias is removed by including a correction term in the likelihood computation. We simulated family data and selected those with a proband affected before age 17, and at least one or at least two relatives affected before age 46. We show that including the correction for the ascertainment provides reliable estimates of the risk, even when many individuals are not tested for the mutation. An application to cancer risk and germline p53 mutations is presented. We routinely investigate the p53 status for all the children treated in the Department of Pediatric Oncology at the Institute Gustave Roussy, whose family displays at least one relative affected by cancer before age 46. We identified 5 families with an inherited germline p53 mutation. The risk for any cancer for a mutation carrier estimated by ARCAD was 42% within the age class 0–16 years, 38% within the age class 17–45 years, and 63% after 45 years, with a lifetime risk of 85%. These risks are almost entirely explained by the occurrence of the six most frequent cancers encountered in the Li‐Fraumeni syndrome. © Wiley‐Liss, Inc.
Sex‐specific effects for body mass index in the new Norwegian twin panel
Authors: Harris Jennifer R. , Tambs Kristian , Magnus Per
Published: June 2005

Sex‐specific effects for body mass index (BMI) were explored in a newly established, population‐based Norwegian twin panel. The sample includes 5,864 individuals, aged 18–25 years, who responded to a questionnaire containing items for zygosity classification, height, weight, health, health‐related behaviors, well‐being, and demographic information. Among the 2,570 intact pairs who returned the questionnaire there were 416 identical (MZ) male pairs, 387 fraternal (DZ) male pairs, 528 MZ female pairs, 443 DZ female pairs, and 796 unlike‐sexed pairs. Alternate sets of models testing for either sex‐specific genetic or environmental parameters were evaluated using structural equation analysis. Results from the most parsimonious model indicated that the genes contributing to variation in BMI are not identical for men and women; rather, some genetic effects were shared by the sexes and some were unique to each sex. Total variation in BMI could be explained by sex‐specific additive genetic effects, as well as genetic and non‐shared environmental effects common to men and women. Estimates of heritability were .708 for men and .789 for women, and the male‐female genetic correlation was 0.622. The series of models specifying sex‐specific shared environment also fit the data and suggests that shared environmental factors may be important for males but not for females. The findings raise questions concerning the relationship between sex‐specific effects for BMI and sex differences in health outcomes. ©1995 Wiley‐Liss, Inc.
Evaluating a new algorithm for linking maternal and newborn medical records
Authors: Grace Kimberly R. , Waters Grady , Huether Carl A. , Edmonds Lawrence D. , McClain Phillip
Published: June 2005

Linking maternal and newborn medical records is a valuable tool for assessing the relationship between maternal variables and fetal outcome. This study evaluated the Center for Disease Control's newly developed maternal and newborn medical record linkage system, a computer program that uses weighted variables to determine the most likely maternal and newborn pairs. Any newborn record not achieving a set minimum score with a maternal record remains nonmatched. The objectives of the study were to estimate the program's matching accuracy, determine causes of incorrect matches and nonmatches, develop suggestions for program revisions, and evaluate the effects of the revisions. The study sample included 521 matched and 247 nonmatched maternal and newborn medical records from seven Ohio hospitals. Of all available newborn records (10,068), 574 (5.7%) did not match with maternal records; for those in which a match occurred, the authors ascertained a 98% matching accuracy and determined explanations for nonmatched and incorrectly matched records. The authors noted a greater prevalence of birth defects and prematurity among newborns with nonmatched records than among those with matched records. Program revisions, therefore, focused on reducing the prevalence of nonmatched records. The revised program reduced the prevalence of nonmatched records from 5.7% to 3% but reduced matching accuracy. ©1995 Wiley‐Liss, Inc.
Epidemiologic and genetic follo‐up study of 544 Minnesota breast cancer families: Design and methods
Authors: Sellers Thomas A. , Anderson V. Elving , Potter John D. , Bartow Susan A. , Chen Ping‐Ling , Everson Lenore , King Richard A. , Kuni Christopher C. , Kushi Lawrence H. , McGovern Paul G. , Rich Stephen S. , Whitbeck Jan , Wiesner Georgia
Published: June 2005

In 1944, a case‐control family study was initiated at the Dight Institute for Human Genetics at the University of Minnesota to study the influences of childbearing, breastfeeding, and hereditary susceptibility on the occurrence and age‐of‐onset of breast cancer. Index cases (probands) were women ascertained at the Tumor Clinic of the University of Minnesota Hospital. Medical history and life style information were obtained on probands and relatives, and all cancers were histologically verified. A total of 544 families were studied, with probands diagnosed between 1931 and 1952. All of the records and pathology slides have been maintained from the original study; for most probands this includes the original tissue blocks.

We are conducting a historical cohort study of selected first‐ and second‐degree female relatives (sisters, daughters, nieces, granddaughters) of the probands and a group of control women identified as the spouses of all male first‐ and second‐degree relatives (brothers, sons, grandsons, and nephews). The subsequent development of breast cancer is being determined to quantify the absolute risk associated with a positive family history. Current disease status is ascertained with mammography, and stromal density is measured using digital imaging. Segregation analysis will be applied to examine how non‐genetic factors such as diet, exogenous hormone use, and body fat distribution influence risk in women at high risk because of family history. A subset of families are being selected for molecular analysis of the BRCA1 gene or for linkage analyses to identify putative susceptibility loci other than BRCA1. Documented cancer histories were known for at least three generations, and the current study extends the pedigrees up to four or five generations for every family, allowing a detailed description of familial risk.

This cohort study of breast cancer families is likely to be important in both quantity and quality of data and will serve as a major genetic epidemiologic resource, being free of selection bias and having relevant non‐genetic exposure determined in at least four generations. ©1995 Wiley‐Liss, Inc.
Major gene with sex‐specific effects influences fat mass in Mexican Americans
Authors: Comuzzie Anthony G. , Blangero John , Mahaney Michael C. , Mitchell Braxton D. , Hixson James E. , Samollow Paul B. , Stern Michael P. , MacCluer Jean W.
Published: June 2005

Increased adiposity has repeatedly been identified as a major risk factor for a variety of chronic diseases. However, the question still remains whether the amount of adipose tissue itself is genetically mediated. To address this question, a segregation analysis, using maximum likelihood techniques as implemented in the computer program Pedigree Analysis Package (PAP), was performed on fat mass (kilograms of body fat) in a large sample of extended Mexican American families residing in San Antonio, TX. The only model not rejected was a Mendelian mixed model for fat mass, incorporating genotype X sex interaction. In males the major gene accounted for 37% of the total variance compared with 43% in females. In both sexes homozygous recessive individuals have a fat mass more than double that of individuals of the other two genotypes. It was possible to reject linkage of the anonymous major gene for fat mass with several candidate loci for obesity. However, tentative evidence of linkage was detected with markers on both chromosomes 2 and 11, thereby providing hypotheses for future testing. ©1995 Wiley‐Liss, Inc.
Underexpression of the apolipoprotein E2 and E4 alleles in the Greek Cypriot population of Cyprus
Authors: Cariolou Marios A. , Kokkofitou Avgousta , Manoli Panayiotis , Christou Soteroula , Karagrigoriou Alexandros , Middleton Lefkos
Published: June 2005

Apolipoprotein E (APOE) plays an important role in the multifactorial etiology of both cardiovascular disease and Alzheimer's disease. Polymerase chain reaction (PCR) was used to investigate the APOE gene polymorphism in 335 unrelated Greek Cypriots living on the island of Cyprus. For the most common APOE genotypes, the Greek Cypriots followed the general Caucasian European pattern of having higher genotypic frequencies of E3/3, followed by E3/4, and then E2/3. Among the European populations compared, Greek Cypriots exhibited the lowest relative frequency of the E3/4 genotype (12.83%). Also, the relative frequencies of the E2 and E4 alleles in Greek Cypriots were among the lowest around the world (5.4% and 7.0%, respectively). This was also demonstrated by using the complete and the average clustering methods of analysis where the APOE allele relative frequencies in Greek Cypriots were compared to 46 other populations. The Greek Cypriot population in these analyses clustered with populations mainly from south Europe and Japan which have low E2 and E4 allele frequencies. The Greek Cypriot population will be studied further for elucidating the effect(s) and the role of APOE in cardiovascular disease and the APOE4 allele as a possible metabolic factor affecting the rate of expression of both Alzheimer's disease and vascular dementia. ©1995 Wiley‐Liss, Inc.
An oliogenic disease displaying weak marker assocations: A summary of contributions to problem 1 of GAW9
Authors: Hodge Susan E.
Published: June 2005

Problem 1 consisted of artificial data simulated from an oligogenic (four‐locus) disease model. The data set contained 200 nuclear families with at least one affected child and 100 control families with no affected members. Two of the disease loci were intended to be detectable via association analysis but not necessarily via linkage analysis, and the other two were virtually undetectable in this data set. Participants used association analysis, linkage analysis, and segregation analysis to analyze these data. Their findings are summarized, and analysis strategies are discussed. ©1995 Wiley‐Liss, Inc.
Genetic analysis workshop 9: Development of problem 1
Authors: Hodge Susan E.
Published: June 2005

Problem 1 was designed to involve an oligogenic model with four “disease susceptibility” loci, such that all individuals with at least four “upper‐case” alleles were at equal risk to be affected (and those with three or fewer were not at risk). Two of these loci were identical to marker loci, thus giving rise to weak disease‐marker associations. The other two were located between marker loci, with no linkage disequilibrium. Participants were given 200 nuclear families with at least one affected child, along with 100 control families with no affected individuals. The first two loci were intended to be detectable via association analysis. The remaining two loci were virtually undetectable in this data set. ©1995 Wiley‐Liss, Inc.
Use of sibling risk ratios and components of genetic variance in the characterization of a simulated oligogenic disease
Authors: Almasy L. , Tierney C. , Risch N.
Published: June 2005

Sibling risk ratios are used to quantify the genetic effect of two simulated disease loci, identified through TDT and association methods and characterized via components of variance derived from a relative penetrance matrix. Inconsistencies between the data set and the simulating model are also discussed. ©1995 Wiley‐Liss, Inc.
Systematic search of susceptibility loci with methods using gametic disequilibrium
Authors: Bickeböller H. , Margaritte‐Jeannin P. , Babron M.‐C. , Clerget‐Darpoux F.
Published: June 2005

Susceptibility genes are identified for a simulated complex trait by a systematic genome search for linkage between disease and a genetic marker in the presence of gametic disequilibrium. The transmission/disequilibrium tests TDTa or TDTg for multiallelic markers compare transmitted and nontransmitted alleles or the genotypes formed by the two transmitted alleles and the genotypes formed by the two nontransmitted alleles, respectively. With these two tests we were able to identify the two markers D1G31 and D5G23. Under the simulating model these are in fact two susceptibility genes involved in the disease. ©1995 Wiley‐Liss, Inc.
Modeling the role of two susceptibility loci by the MASC method
Authors: Dizier Marie‐Hélène , Babron Marie‐Claude , Clerget‐Darpoux Françoise
Published: June 2005

Two susceptibility genes, in linkage disequilibrium with alleles of the markers D1G31 and D5G23, have been identified for the disease in the simulated data set of Problem 1. Here we apply the MASC (marker association segregation chi‐square) method to model the joint effect of these two genes, by testing two‐locus models. The model we obtain, that is the most parsimonious and that best fits the data, corresponds to a direct involvement of the alleles D1G31‐8 and D5G23‐7, with a nonmultiplicative effect of the two alleles. This was indeed assumed in the true model used for simulating the data. ©1995 Wiley‐Liss, Inc.
Screening for linkage and association in nuclear families
Authors: Knapp M. , Durner M. , Baur M. P.
Published: June 2005

We applied linkage analysis with a sib‐pair method, which also takes into account information on unaffected siblings, and family‐based methods of association analysis to determine the disease affecting loci in Problem 1. Whereas the first two disease loci were correctly identified by association analysis, the sib‐pair linkage method failed to detect the disease loci 3 and 4. We therefore determined the data structure and sample size necessary for demonstrating linkage to these loci. ©1995 Wiley‐Liss, Inc.
Detection of vulnerability loci by association and sib‐pair methods
Authors: Levinson Douglas F.
Published: June 2005

A haplotype‐based haplotype relative risk (HHRR) analysis of simulated data for 200 affected offspring and their parents (Genetic Analysis Workshop 9, Problem 1) detected linkage disequilibrium at 2 of 360 marker loci. An additive model was suggested but not proven by haplotypes of affected vs. unaffected offspring. These findings were consistent with the generating model. Affected sib pair analysis failed to detect additional loci. Discussion among workshop participants suggested that the chi‐square test used here (2 [transmitted vs. nontransmitted] x n [alleles] for each locus) was invalid because of the nonindependence of proportions of transmitted alleles. In post‐workshop analyses, transmission disequilibrium tests (TDTs) for each allele at each locus detected only the true associations if p values were corrected by one of two methods: Bonferroni correction for 2,035 TDTs, or correcting each test for n (number of tests at the locus) minus 1 and then for the number of loci tested. Screening loci for linkage disequilibrium requires careful attention to correction for multiple comparisons. ©1995 Wiley‐Liss, Inc.
Genome scanning for complex disease genes using the transmission/disequilibrium test and haplotype‐based haplotype relative risk
Authors: Matise Tara Cox
Published: June 2005

Two tests for allelic association were applied to a simulated complex disease for the Genetic Analysis Workshop 9. The transmission/disequilibrium test [Spielman et al., 1993] and the haplotype‐based haplotype relative risk approach [Terwilliger and Ott, 1992] were used to detect disease‐associated alleles in a set of 360 computer‐simulated markers located on six chromosomes and genotyped in 200 nuclear families. This analysis emulates a genome‐based search for linked markers. Computer simulations were also performed to clarify statistical properties of the TDT. ©1995 Wiley‐Liss, Inc.
Interval mapping of quantitative trait loci using a sib‐pair linkage method
Authors: Borecki Ingrid B. , Vogler George P.
Published: June 2005

Fulker and Cardon's interval mapping extension of Haseman and Elston's sib‐pair linkage method was used to map loci affecting the quantitative phenotypes presented as part of Problem 2, both adjusted and not adjusted for covariates: Q1 was adjusted for age and the environmental factor (EF); Q2 and Q3 for EF; and Q4 for age, sex, and EF. Adjusted Q2 and Q4 were also log‐transformed. The effect of candidate locus C5 (D5G28) on Q1 was detected by a test of association – apparently, allele 1 of C5 is protective (leading to lower values of Q1), allele 2 has no effect, and allele 3 contributes to elevated levels of Q1. C5 accounted for 5.2% of the variation in Q1; it was included as an additional concomitant in the adjustment procedure. Analysis of the correlational structure among the variables revealed that Q4 was not associated with either affected status or Q1 after controlling for the effects of age, and we concluded that Q4 probably does not itself play a role in the etiology of the disease. Mapping studies using a significance level of 0.05 lead to the detection of all the genes, but also resulted in a high frequency of false positive results. On the other hand, using a 0.0005 significance level resulted in the detection of D2G10‐11 for both Q1 and Q3, and D1G2 was detected for Q2. One false positive was detected using this significance level and the effects of D1G2 on Q1 and D5G22‐23 on Q4 were missed. There was no systematic effect of adjustment for covariates on the detection of loci, although in general, analysis of adjusted phenotypes yielded substantially higher rates of false positives. Finally, this mapping approach correctly located D1G2 and D2G10‐11 for Q1 using the nonadjusted phenotype, and D1G10‐11 for Q3 using the adjusted phenotype. The maximum difference between the estimated map location from the true location was 1.5 cM. It would be important to estimate the error interval around these inferred locations in order to assess the utility of this method for fine mapping over small (e.g., 2 cM) intervals. © 1995 Wiley‐Liss, Inc.
A genetic analysis of common disease data
Authors: Cantor Rita M.
Published: June 2005

Simulated common disease data have been analyzed to identify a model of disease expression that involves the complex interaction of quantitative traits controlled by major genes and an environmental factor. Correlation and multiple regression analyses in conjunction with quantitative sib‐pair linkage analyses revealed a portion of the model involved. © 1995 Wiley‐Liss, Inc.
Weighted pairwise correlation and transmission disequilibrium in a common oligogenic disease
Authors: Corder Elizabeth H.
Published: June 2005

Weighted pairwise correlation (WPC) linkage analysis and the transmission disequilibrium test (TDT) for allelic association were applied to simulated family data for a common oligogenic disorder in order to localize genes that increase levels of Q1. Preliminary linear models indicated that Q1 increases with age, Q2, Q3, and the occurrence of D5G28 allele 3 (D5G28(3). WPC provided evidence for linkage of Q1 to Major Gene 1, D5G28 (p < 0.0001), and to other loci when ranks based on age and affection status (Q1 < or > 87.5) were used to define the phenotype. D5G28 was the only locus linked to Q1 (p = 0.01) when the phenotype was defined as Q1 adjusted for age, Q2, Q3, and D5G28(3). The TDT indicated linkage disequilibirum between a gene for elevated Q1 (> 87.5) and alleles at loci adjacent to D5G28: D5G29(2) was apparently protective (p = 0.008) while allele 8 was associated with risk (p = 0.007); D5G30(7) was also apparently protective (p = 0.02). However, significant disequilibirum was not found for D5G28(3), possibly due to lack of adjustment of Q1 and small sample size. These results imply that the combined use of WPC and the TDT may be an effective strategy for genomic screens in complex disorders defined by quantitative traits, especially when the trait can be adjusted for age and other relevant factors. © 1995 Wiley‐Liss, Inc.
Analysis of quantitative risk factors for a common oligogenic disease
Authors: Goddard K. A. B. , Jarvik G. P. , Graham J. , McNeney B. , Hsu L. , Siegmund K. , Grosser S. , Olson J. , Wijsman E. M.
Published: June 2005

All three simulated loci influencing the quantitative variables Q1, Q2, and Q3 were successfully mapped by using a strategy of covariate adjustment and segregation analysis, coupled with association analyses and lod‐score analyses. © 1995 Wiley‐Liss, Inc.
Association and linkage with quantitative traits
Authors: King Terri M. , Zhu Dakai , Amos Christopher I.
Published: June 2005

This paper examines two approaches for the analysis of quantitative traits: (1) association studies and (2) linkage studies. The trait studied was Q1 from simulated Problem 2 data set in Genetic Analysis Workshop 9. Our purpose was to evaluate associations present in the data, to identify nongenetic and genetic predictors of the trait, and to explore the simulated genome for linkage. Through the association study, we found evidence for the primary major gene associated with this trait. The linkage study found evidence of residual genetic effect acting through other traits. Adjustments of Q1 for Q2 and Q3 led to a failure to find significant effects of MG2 and MG3. This supports the suggestion that adjustment for genetically influenced traits for effects of other genetic traits can reduce the power to detect major gene effects. In summary, we detected the major gene directly associated with the trait of interest through association studies. Linkage analysis detected evidence for two other genes associated to a lesser degree with the trait. © 1995 Wiley‐Liss, Inc.
Screening for linkage using a multipoint identity‐by‐descent method
Authors: Lewis Cathryn M. , Goldgar David E.
Published: June 2005

The multipoint identity‐by‐descent method (MIM) was used to analyze simulated data for quantitative traits from GAW9. A two‐stage method of implementation was used. First, polymorphic markers spaced 6‐12 cM apart were used to identify chromosomes of interest for each trait Q1‐Q4; and second, for each of these chromosomes, markers spaced 2 cM apart were used to confirm the linkage detected and refine the region for the susceptibility loci. MIM performed well at both levels of mapping, correctly detecting major genes for trait Q3 on chromosome 2, trait Q2 on chromosome 1, and trait Q4 on chromosome 5. © 1995 Wiley‐Liss, Inc.
How can maximum likelihood methods reveal candidate gene effects on a quantitative trait?
Authors: Martinez M. , Abel L. , Demenais F.
Published: June 2005

Different maximum likelihood approaches were used to explore the role of candidate genes in the variability of quantitative trait Q1 while accounting for the effects of age, Q2, and Q3. Segregation analysis, under the class D regressive model, provides evidence for a Mendelian gene effect on the adjusted trait Q1. Results of gene mapping through lod‐score analyses remain puzzling. Pairwise lod scores indicate a possible linkage with the candidate gene C5 which is excluded when using tightly linked informative marker loci. Finally, our combined segregation and linkage analysis clearly shows that a C5 linked gene is involved in Q1 variability. However, given the lod‐score results within the C5 region, we postulate a more complex mechanism for Q1 than a single di‐allelic C5 linked gene. The knowledge of the true model (C5 is MG1 and has three alleles) permits a partial explanation of our results. This study demonstrates the advantages of using complementary approaches to reveal the role of candidate genes in complex traits, and the value of simultaneous estimation of linkage and segregation parameters. © 1995 Wiley‐Liss, Inc.
Multivariate genetic analysis of an oligogenic disease
Authors: Moldin Steven O. , Van Eerdewegh Paul
Published: June 2005

Joint multivariate segregation and linkage analysis provides a method for simultaneously analyzing data on affection status, correlated phenotypic traits, environmental risk factors, and other covariates. The power of this approach for mapping disease susceptibility loci of small effect (oligogenes) was evaluated by analyzing the GAW9 Problem 2 data set. The program REGRESS, which assumes a pleiotropy model in which one locus influences both affection status (AF) and a quantitative trait, was used to conduct joint segregation and linkage analysis of bivariate phenotypes, each comprising AF and one quantitative trait (Q2,Q3,Q4). A genome‐wide search using markers spaced approximately 10 cM apart was conducted and regions on chromosomes 1, 2, and 5 were identified as demonstrating linkage with three respective bivariate phenotypes at the following markers: AF/Q2 ‐ D1G2; AF/Q3 ‐ D2G10; and AF/Q4 ‐ D5G18. The effects of other loci were included in a general model by specifying the quantitative traits they influenced as covariates along with age, sex, and an environmental effect. Use of covariate and quantitative trait data in each analysis resulted in respective χ2 values with 1 df of 38.4, 65.4, and 22.0 to reject the no linkage hypothesis at \documentclass{article}\pagestyle{empty}\begin{document}$ {\rm \hat \theta } $\end{document} = 0, with respective equivalent lod scores of 8.3, 14.2, and 4.8. Rejection at p < 0.0002 occurred using markers as far away as 20 cM. These loci were not detected when AF alone was analyzed. © 1995 Wiley‐Liss, Inc.
An investigation to determine whether clusters of cancer types exist in nine breast‐ovary families
Authors: Bansal A. , Bishop D. T. , Cannings C.
Published: June 2005

Monte‐Carlo simulations were carried out on nine BRCA1‐linked families selected from the 1993 Breast Cancer Linkage Consortium. These families all displayed a prevalence of both breast and ovarian cancers, but little evidence was found to conclude that sufferers of either type formed clusters in particular branches of families. It was noted that the application of these methods to larger pedigrees with known probands would be useful in further clarifying the issue. © 1995 Wiley‐Liss, Inc.
Variability of genotype‐specific penetrance probabilities in the calculation of risk support intervals
Authors: Leal Suzanne M. , Ott Jurg
Published: June 2005

Previously, a maximum likelihood method was described to construct a support interval for the risk. This method is extended to incorporate genotype specific penetrance probabilities in the calculation of a risk support interval. As an empirical example, the support interval for the risk is calculated for a member of a published breast‐ovarian cancer kindred. © 1995 Wiley‐Liss, Inc.
Gain in efficiency from using generalized least squares in the Haseman‐Elston test
Authors: Single R. M. , Finch S. J.
Published: June 2005

Techniques that test for linkage between a marker and a trait locus based on the regression methods proposed by Haseman and Elston [1972] involve testing a null hypothesis of no linkage by examination of the regression coefficient. Modified Haseman‐Elston methods accomplish this using ordinary least squares (OLS), weighted least squares (WLS), in which weights are reciprocals of estimated variances, and generalized estimating equations (GEE). Methods implementing the WLS and GEE currently use a diagonal covariance matrix, thus incorrectly treating the squared trait differences of two sib pairs within a family as uncorrelated. Correctly specifying the correlations between sib pairs in a family yields the best linear unbiased estimator of the regression coefficient [Scheffe, 1959]. This estimator will be referred to as the generalized least squares (GLS) estimator. We determined the null variance of the GLS estimator and the null variance of the WLS/OLS estimator. The correct null variance of the WLS/OLS estimate of the Haseman‐Elston (H‐E) regression coefficient may be either larger or smaller than the variance of the WLS/OLS estimate calculated assuming that the squared sib‐pair differences are uncorrelated. For a fully informative marker locus, the gain in efficiency using GLS rather than WLS/OLS under the null hypothesis is approximately 11% in a large multifamily study with three siblings per family and 25% for families with four siblings each. © 1995 Wiley‐Liss, Inc.
Germ layer formation and the role of the primitive streak in the chick. I. Basic architecture and morphogenetic tissue movements
Authors: Spratt Nelson T. , Haas Hermann
Published: June 2005

Histological studies, carbon, carmine and vital dye marking of in ovo and explanted blastoderms have provided evidence for the following: (1) The cellular precursors of all three primary germ layers in the unincubated blastoderm are topographically represented by a disc‐shaped, epithelial‐like and complete uppermost layer; and ring‐shaped, incomplete and congruent middle and lowest layers below the uppermost layer. (2) There is a gradient in cell population density decreasing from posterior to anterior. (3) Centripetal extension of a sheet of lowest and adjacent middle layer cells, primarily from the posterior portion of the ring but also from all points on its circumference, results in closing of the ring and completion of the middle and lowest layers as coherent discs. (4) No movement (invagination or involution) of uppermost, surface areas as coherent sheets into either the middle or lowest layers could be demonstrated in any region, including the primitive streak. (5) Embryonic germ layers arise in situ by proliferation from the streak. (6) The streak in its morphology and function is more like a blastema than a blastopore. (7) As an elongated growth center, the streak has its origin from the marginal zone ring, itself a circular blastema with multiple streak‐ and embryo body‐forming capacities.
Studies on the development of mouse embyros in vitro. III. The effect of fixed‐nitrogen source
Authors: Brinster Ralph L.
Published: June 2005

There has been considerable discussion as to whether the developing mouse ova requires an exogenous protein supply. A series of experiments were performed to determine the effect of various fixed‐nitrogen sources on the development in vitro of two‐cell mouse ova into blastocysts. It was found that two‐cell mouse ova would not develop into blastocysts in medium that did not contain a fixed‐nitrogen source. Crystalline bovine serum albumin (BSA) at 1 mg/ml or, alternatively, the constituent amino acids of BSA could supply this requirement for fixed‐nitrogen. In the presence of single amino acids at 10−3 M or 8 × 10−3 M, only an occasional two‐cell ova developed into a blastocyst.

Single amino acids were omitted from the medium containing the constituent amino acids of BSA in an attempt to demonstrate an essential amino acid requirement of two‐cell mouse ova. The omission of no single amino acid from the medium, completely prevented the development of some two‐cell ova into blastocysts. The only amino acid whose omission resulted in a significant decrease in development was cystine. In the medium where amino acids were used in place of BSA, a non‐protein polymer was used to replace the physical properties of albumin. The non‐protein polymers which appeared best were Polyvinylpyrrolidone (MW = 150,000), Acacia, Dextran, and Ficoll.
Adipose tissue of Drosophila melanogaster. I. An experimental study of larval fat body
Authors: Butterworth Francis M. , Bodenstein Dietrich , King Robert C.
Published: June 2005

Morphological, cytochemical and developmental studies were undertaken of the adipose cells present in third instar larvae and in adult females of Drosophila melanogaster. The adipose cells of the adult type in the abdomens of recently emerged and seven‐day‐old adult females contain deposits of lipid and glycogen. Although the cells increase in size during this period, their nuclei do not. During the third instar the larval adipose cells and their nuclei undergo a five‐ and twofold increase in average cross‐sectional area, respectively. Deposits of lipid and glycogen are present throughout this period. Proteinaceous globules first appear in the middle of the third instar. They increase in diameter and number until just before pupation they comprise one fourth of the cytoplasm of the cells. In the young adult the surviving larval adipose cells and their nuclei have decreased in average cross‐sectional area by two and three times, respectively, from the late third instar values. The surviving larval adipose cells contain droplets of unsaturated lipids, protein globules, and deposits of glycogen which completely fill the remaining cytoplasmic area. By the third day of adult life these cells histolyze. When late second instar larvae are starved for three days, the average cross‐sectional area of their fat body cells decreases ten times. Despite the absence of glycogen and a huge decrease in lipid, protein globules form, and by the third day of starvation comprise one fourth of the cytoplasm. Transplantation experiments demonstrate that a hormone produced by the ring gland during the late third instar induces the formation of these protein globules.
Oogenesis in rabbits
Authors: Peters Hannah , Levy Emilia , Crone Monna
Published: June 2005

Oogenesis in rabbits was investigated by examining the development of germ cells after birth. The transformation of oogonia to oocytes begins in the one day old animal. The appearance of the different stages of meiotic prophase was noted and their differential distribution in the germ cell population determined. The early stages of meiotic prophase develop within the first two weeks of life, however, they are transitory and have transformed into the “stationary” phase of prophase by the end of the third week of life, when all nuclei of oocytes are in diplotene.

DNA synthesis in germ cells was studied with the aid of H3‐thymidine, which was injected into animals within the first ten days of life. The number of labeled germ cells varies with the age of the animal at the time of injection. Injection between the day of birth and the age of four days results in the labeling of 20 to 35% of the germ cells. After this age the labeling index falls, reaching 3% in the ten day old animal.

The synthesis of the oocyte DNA takes place in the premeiotic interphase and may extend into the early phase of prophase, i.e. leptotene.
Neural regulation of adenohypophysial prolactin secretion in tetrapods: Indications from in vitro studies
Authors: Nicoll Charles S.
Published: June 2005

The in vitro prolactin‐secreting capacities of adenohypophyses of Columba livia (pigeon) and Necturus maculosus (salamander) were compared with those of living and dead rat adenohypophyses over an eight‐day culture period. The living rat adenohypophysis produced prolactin at a constantly high rate. The dead rat tissue showed no evidence of active prolactin secretion. The secretion rate of prolactin by the pigeon adenohypophysis decreased rapidly with time in vitro and closely resembled the performance of dead rat adenohypophysis. Necturus adenohypophysis showed a slight initial decrease in prolactin secretion rate, which then plateaued at a constantly low level. The effects of acid extracts of cerebral and hypothalamic tissues of Agelaius tricolor (blackbird) on prolactin secretion in vitro by Agelaius adenohypophysis were examined. The extract of cerebral tissue had no effect, but the hypothalamic extract increased prolactin secretion, indicating that the blackbird hypothalamus contains a stimulator of prolactin secretion. These results indicate that the neural mechanism which controls prolactin secretion in Columba and Agelaius is different from that which exists in rats and other laboratory mammals. No definite conclusions can be drawn regarding neural regulation of prolactin secretion in Necturus.
Thyroid‐gonad relationship in spotted munia, Uroloncha punctulata
Authors: Thapliyal J. P. , Pandha S. K.
Published: June 2005

Thyroidectomy of adult Spotted munia (Uroloncha punctulata) leads to the gonads remaining permanently in full breeding condition and is responsible for an early increase in testis size and activity in juvenile birds. These effects may be due to (i) general disturbances in metabolism or (ii) continuous secretion of gonadotropic hormones from the hypopyhsis or (iii) to both of these processes.
An investigation on the swimming reaction of the anemone Stomphia coccinea. I. Partial isolation of a reacting substance from the asteroid dermasterias imbricata
Authors: Ward Jack A.
Published: June 2005

Behaviorally the sea anemone, Stomphia coccinea, is an unusual actinarian compared to other members of the Actinaria. When the asteroid, Dermasterias imbricata, is brought into contact with Stomphia it responds by propelling itself through the water by a series of whip‐like swimming motions.

Tissue homogenates from the aboral surface of Dermasterias proved to be as effective as the entire animal. Homogenates from all other tissues gave negative results. The substance which causes the swimming response is dialyzable, thermostable, and from qualitative tests proved to be primarily carbohydrate. Acidic hydrolysis (HCL) of the polysaccharide revealed three definitive products. Enzymatic hydrolysis by hemicellulase yields the same compounds but caused a complete degradation of the substance. Chromatographic results showed that the compounds are probably products from an amino‐polysaccharide.