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S E Hodge

Publications and source records attributed to S E Hodge.

13 recordsLinked to original sources
PubMed1992

Adequacy of single-locus approximations for linkage analyses of oligogenic traits.

When a disease is controlled by two or more mendelian loci acting epistatically, it can be modeled in a linkage analysis as a single-locus mendelian disease with reduced penetrance. However, the reliability of such an approximation has not yet been demonstrated. This study evaluates the adequacy of such single-locus approximations, when the disease under investigation is determined by two loci, one of which is tightly linked to a genetic marker. A wide range of two-locus models were simulated, and analyzed under both the correct two-locus model and under a single-locus approximation to that model. In general, the single-locus approximations yielded lod scores very close to the correct ones, but estimates of theta tended to be upwardly biased. We conclude that a single-locus linkage analysis will, in general, provide an excellent approximation to a correct (two-locus) linkage analysis of epistatic two-locus diseases. This enables researchers to continue to use single-locus linkage analyses when two-locus disease transmission is a possibility, and it validates linkage findings already obtained under single-locus analysis, even if the disease under investigation proves ultimately to be governed by two mendelian loci. We also examine alternative methods for obtaining parameter estimates for the single-locus approximations, and we discuss both generalizations and limitations of our findings.

Chromosome Mapping↗
PubMed1992

Do bilineal pedigrees represent a problem for linkage analysis? Basic principles and simulation results for single-gene diseases with no heterogeneity.

Some investigators have expressed concern--especially for psychiatric disorders--that bilineal pedigrees should not be included in linkage studies. This study compares the "informativeness" of bilineal and unilineal families for a homogeneous single-gene disorder. Three approaches were used: (1) simulation studies of three-generation pedigrees, (2) calculation of expected lod scores (ELODs) in nuclear families, and (3) calculation of Fisher's information number I(theta) in nuclear families. The simulation studies in (1) permitted a realistic comparison between bilineal datasets and purely unilineal ones. The calculations in nuclear families in (2) and (3) then made it possible to analyze the sources of information loss in bilineal families. Overall, in datasets of five three-generation pedigrees each, the drop in mean maximum lod score was approximately 50% from purely unilineal datasets to extremely bilineal ones. In less-extreme bilineal datasets, which are closer to most real data than the extremely bilineal ones, the drops in lod score were very small--less than 10% in some, and practically zero in others. The details will vary, depending on size and structure of the pedigree, genetic model, true value of the recombination fraction, and informativeness of the marker. However, these results imply that the information loss due to bilineality is not necessarily very great. The nuclear-family calculations showed that for phase-known matings there is relatively little information loss in bilineal families, but for phase-unknown matings there the loss is much greater. In conclusion, for single-gene disorders with no genetic heterogeneity, whereas bilineal families can be less informative than comparable unilineal families, they are not so much less informative that they should automatically be discarded from linkage datasets. The implications of bilineal pedigrees for linkage studies of heterogeneous disorders are also discussed.

Computer Simulation↗
PubMed1992

Inter- and intrafamilial heterogeneity: effective sampling strategies and comparison of analysis methods.

Heterogeneity, both inter- and intrafamilial, represents a serious problem in linkage studies of common complex diseases. In this study we simulated different scenarios with families who phenotypically have identical diseases but who genotypically have two different forms of the disease (both forms genetic). We examined the proportion of families displaying intrafamilial heterogeneity, as a function of mode of inheritance, gene frequency, penetrance, and sampling strategies. Furthermore, we compared two different ways of analyzing linkage in these data sets: a two-locus (2L) analysis versus a one-locus (SL) analysis combined with an admixture test. Data were simulated with tight linkage between one disease locus and a marker locus; the other disease locus was not linked to a marker. Our findings are as follows: (1) In contrast to what has been proposed elsewhere to minimize heterogeneity, sampling only "high-density" pedigrees will increase the proportion of families with intrafamilial heterogeneity, especially when the two forms are relatively close in frequency. (2) When one form is dominant and one is recessive, this sampling strategy will greatly decrease the proportions of families with a recessive form and may therefore make it more difficult to detect linkage to the recessive form. (3) An SL analysis combined with an admixture test achieves about the same lod scores and estimate of the recombination fraction as does a 2L analysis. Also, a 2L analysis of a sample of families with intrafamilial heterogeneity does not perform significantly better than an SL analysis. (4) Bilineal pedigrees have little effect on the mean maximum lod score and mean maximum recombination fraction, and therefore there is little danger that including these families will lead to a false exclusion of linkage.

Computer Simulation↗
PubMed1992

Sensitivity of lod scores to changes in diagnostic status.

This paper investigates effects on lod scores when one individual in a data set changes diagnostic or recombinant status. First we examine the situation in which a single offspring in a nuclear family changes status. The nuclear-family situation, in addition to being of interest in its own right, also has general theoretical importance, since nuclear families are "transparent"; that is, one can track genetic events more precisely in nuclear families than in complex pedigrees. We demonstrate that in nuclear families log10 [(1-theta)/theta] gives an upper limit on the impact that a single offspring's change in status can have on the lod score at that recombination fraction (theta). These limits hold for a fully penetrant dominant condition and fully informative marker, in either phase-known or phase-unknown matings. Moreover, log10 [(1-theta)/theta] (where theta denotes the value of theta at which Zmax occurs) gives an upper limit on the impact of a single offspring's status change on the maximum lod score (Zmax). In extended pedigrees, in contrast to nuclear families, no comparable limit can be set on the impact of a single individual on the lod score. Complex pedigrees are subject to both stabilizing and destabilizing influences, and these are described. Finally, we describe a "sensitivity analysis," in which, after all linkage analysis is completed, every informative individual in the data set is changed, one at a time, to see the effect which each separate change has on the lod scores. The procedure includes identifying "critical individuals," i.e., those who would have the greatest impact on the lod scores, should their diagnostic status in fact change. To illustrate use of the sensitivity analysis, we apply it to the large bipolar pedigree reported by Egeland et al. and Kelsoe et al. We show that the changes in lod scores observed there, on the order of 1.1-1.2 per person, are not unusual. We recommend that investigators include a sensitivity analysis as a standard part of reporting the results of a linkage analysis.

Female↗
PubMed1990

Twin studies and the genetics of Parkinson's disease--a reappraisal.

Parkinson's disease (PD) has long been regarded as having a hereditary component. However, three recent twin studies have been interpreted as excluding any significant genetic component in the etiology of PD. In this article, we reexamine these twin studies and argue that such a conclusion is premature. We review statistical tests of twin concordance rates, including calculation of G, the coefficient of genetic determination. When variation in a trait is due entirely to genetic factors G = 1, and when variation in a trait is due entirely to nongenetic factors G = 0. We conclude that: (a) low monozygotic concordance rates can be compatible with substantial genetic contribution to etiology; (b) the PD twin study data give substantial optimal values of G (up to 0.78) but the very broad 95% confidence limits for G make it impossible for the twin study data to prove or disprove a substantial genetic component to the etiology of PD; and (c) changing clinical concepts of PD have undermined the assumptions underlying the methodology of the PD twin studies. We review three genetic models that are biologically plausible for PD and are compatible with the low twin concordance rates. Finally, we suggest that further family studies, including linkage studies, are needed to resolve this question.

Diseases in Twins↗
PubMed1990

A problem in identifying risk factors for disease using surrogate exposure variables that are under genetic control.

The use of a surrogate exposure variable to represent a complex of genetic and/or nongenetic factors is commonplace in epidemiologic studies. The authors present an hypothetical example in which a surrogate exposure results from underlying unknown genetic and nongenetic factors, yet only the genetic component predisposes to disease. The results demonstrate how risk may be incorrectly attributed to the nongenetic component of exposure and suggest a possible explanation for the identification of a risk factor in one case-control study in one population, but not in another study of the same disease conducted in a different population.

Case-Control Studies↗
PubMed1990

The probability of obtaining compatible blood from related directed donors.

Patients with alloantibodies may request directed blood donations from their relatives despite the lack of any scientific data suggesting that blood from these donors is safer. We have derived formulas that are applicable to any ethnic group for calculating the probability that a given class of relatives will have compatible blood for a given patient. These formulas apply to any non-X-linked blood group system (including the ABO and Rh systems) and are simple enough for routine blood bank use in advising patients as to how likely they are to obtain compatible donors. Use of these formulas may be helpful in counseling patients who may have difficulty in obtaining compatible directed donors because of antibodies or an unusual blood type. In general, the presence of an alloantibody should not automatically exclude a patient from utilizing directed donors. Moreover, for patients with antibodies to high-incidence antigens, directed donations from siblings may be the easiest way to obtain compatible blood.

Blood Donors↗
PubMed1979

A simple method to detect linkage for rare recessive diseases: an application to juvenile diabetes.

A simple procedure designed specifically to detect linkage for rare recessive diseases is described. The method uses information on identity by descent scores for a pair of sibs at a marker locus conditioned on the number of affected sibs in the pair. A procedure for estimating the recombination fraction is described, and a table facilitating the likelihood ratio test of linkage is provided. The method, when applied to a collection of multiplex families segregating for juvenile diabetes mellitus, suggests the possibility that this disease is linked to the HLA complex. The method is found to compare favorably to the maximum likelihood approach, for which the computer program LIPED gives a maximum lod score of 2.48 at a male and female recombination fraction of theta = 0.20.

Diabetes Mellitus, Type 1↗
PubMed1979

Is juvenile diabetes determined by a single gene closely linked to HLA?

The transmission behavior of insulin-dependent juvenile diabetes mellitus (JDM) has been studied with respect to its frequency in the relatives of JDM probands and its possible linkage to the HLA complex. Mathematical analysis shows that under a single locus hypothesis a very restricted range of incidence rates is possible in the full siblings of probands once the concordance rate in monozygotic (MZ) twins is specified. Specifically, for a given population prevalence of the disease, high concordance rates in MZ twins require high incidence rates in siblings, and low rates require low incidence rates, if a single locus model is th be valid. Moreover, if these rates do conform to a single locus model, then they give additional information about possible linkage between the purported JDM susceptibility gene and the HLA complex. By using observations on the identity by descent scores at the HLA locus of sibling pairs, both of whom are affected with JDM, it is shown that tight linkage of a disease susceptibility locus is possible only when the MZ twin and sibling incidence rates are low, whereas high rates support loose linkage. If the single locus model is rejected, then an alternative hypothesis, involving epistasis between a JDM susceptibility locus and genes in (or close to) the HLA complex can be suggested as a mechanism whereby JDM would appear to be linked to HLA within families while maintaining an association with HLA at the population level.

Diabetes Mellitus, Type 1↗
PubMed1978

A robust method for the detection of linkage in familial disease.

A nonparametric method for the detection of critical genes associated with familial disease was presented. The method involves the detection of deviations from expected identity by descent distributions at polymorphic marker loci for affected sib pairs. The method thus avoids the difficulties arising from incomplete penetrance, variable age of onset and other complications present in other forms of linkage analysis. The theoretical properties of method were worked out in detail for two important cases -- that of an incompletely penetrant recessive or incompletely penetrant dominant critical autosomal gene linked to a codominant marker locus. An easily implementable decision rule for the detection of linkage was proposed, and its operating characteristics for a variety of alternative hypothesis were obtained.

Genes, Dominant↗