On analysis of path models by the multivariate normal model for pedigree analysis.
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Humans↗
Biomedical subjects
J L Hopper
Publications and source records attributed to J L Hopper.
A log-linear model for binary pedigree data.
A pedigree model for binary data, motivated by log-linear modelling, has been developed to examine evidence for familial aggregation in disease status. From an epidemiological point of view a convenient way to express disease concordance between a pair of relatives is in terms of the odds ratio. For a rare disease this is almost equivalent to the relative risk of one family member being affected given that the other is affected, and in extending this to pedigrees it is assumed that these relative risks are multiplicative. In applying the model to the breast cancer data, pedigrees on a rare disease ascertained through an affected proband, it has been shown that estimation of concordance is dependent critically on knowing the probability that a sampled individual is affected. Therefore known population estimates of prevalence or cumulative risk, and an appropriate ascertainment correction, need to be invoked for the model to give proper estimates of disease concordance. The model is flexible in that measured ancillary risk factors, including genetic marker information, can be incorporated into the analysis. Therefore in future studies this information should be collected on all individuals, not just those affected. Suggested statistics for examining a fitted model are presented.
Alanine Transaminase↗
Comparative double-blind trial of the effectiveness and antigenicity of semisynthetic human insulin and purified porcine insulin in newly treated diabetic subjects.
A double-blind comparative trial of the effectiveness and antigenicity of semisynthetic human insulin (Novo) and highly purified (Monocomponent) porcine insulin was performed over a 12 month period in 20 diabetic subjects newly treated with insulin. Human insulin was shown to be indistinguishable from porcine insulin of comparable purity with respect to plasma glucose and glycosylated hemoglobin levels and insulin dose requirements. Human insulin was no less antigenic than porcine insulin; significant IgG-associated insulin binding activity was detected in six of the ten patients in the human insulin treated group and four of the ten patients in the porcine insulin treated group. In all patients, the binding activity was of low capacity. No adverse reactions to human insulin were noted. It is concluded that semisynthetic human insulin, like purified porcine insulin, is safe and effective. Although there may be advantages for human insulin in the setting of insulin allergy, this study does not indicate that human insulin has advantages over purified porcine insulin with respect to elicitation of antibodies of the IgG class.
Adult↗
Treatment of reflux oesophagitis with a carbenoxolone/antacid/alginate preparation. A double-blind controlled trial.
Twenty-nine patients were treated with a carbenoxolone/antacid/alginate preparation (Pyrogastrone) and 30 with antacid/alginate alone four times each day for 8 weeks, in a double-blind study, to ascertain the value of carbenoxolone in the treatment of patients with endoscopically confirmed reflux oesophagitis. Symptom review every 2 weeks and endoscopic findings every 4 weeks were converted to a 6-point grading system to facilitate statistical comparison, using a stochastic model for predicting the rate of change in grades during treatment. Carbenoxolone-treated patients showed an 82% improvement in symptom grades over 8 weeks and improved 50% faster (P less than 0.01) than did control patients, who showed a 63% improvement. Endoscopic improvement was not significantly different in the first 4 weeks, although healing was better maintained in carbenoxolone-treated patients during the second 4 weeks (P less than 0.05). At the low doses used (5 X 20 mg daily) no significant side effects of carbenoxolone were encountered. Pyrogastrone should be considered as a therapeutic alternative in patients who fail to respond to routine management with antacids.
Adult↗
Twin concordance for a binary trait. II. Nested analysis of ever-smoking and ex-smoking traits and unnested analysis of a "committed-smoking" trait.
Twin concordance rates for a binary trait can provide information about causes of trait variation. However, if trait prevalence varies with age (or birth cohort) or between the sexes, trait concordance rates will be artificially inflated because of the matching within pairs of twins. Our previous paper showed how to minimize the effects of such confounding by using logistic regression to model trait prevalence as a function of age and sex and that the binary correlation coefficient was useful as a measure of concordance that can be adjusted for trait prevalence. This method is extended here to allow for nested analyses and is applied to the smoking habits of a sample of 3,807 pairs of adult twins. For monozygotic (MZ) twins, the correlation coefficients for the binary trait of "ever-smoking" (males: .50 +/- .04; females: .60 +/- .02) were significantly greater than for dizygotic (DZ) twins (males: .37 +/- .05; females: .31 +/- .04; unlike-sex pairs: .21 +/- .03). For "giving-up smoking," given that both twins were previously smokers, the correlations for MZ twins (males: .37 +/- .07; females: .29 +/- .05) were also greater than for DZ twins (males: .11 +/- .09; females: .26 +/- .08; unlike-sex pairs: .13 +/- .06), although the difference was not statistically significant for females. Current smokers who had been smoking for at least 10 years were arbitrarily defined as "committed-smokers." The binary trait of "committed-smoking" was more strongly correlated in MZ twins (males: .41 +/- .06; females: .41 +/- .04) than in DZ twins (males: .22 +/- .08; females: .18 +/- .05; unlike-sex pairs: .16 +/- .05). These observations suggest that as well as depending on socially determined environmental factors, smoking behavior is influenced by genetic factors and/or by environmental factors unique to the MZ twin environment, which are of particular importance as determinants of "committed-smoking." There is a need for further research to investigate the personal characteristics of "committed-smokers" and to seek intervention strategies that are more suited to the needs of individual smokers.
Adult↗
Glucose tolerance and mortality in diabetes mellitus in Maltese-born residents of Victoria.
In view of the recognized high prevalence of diabetes mellitus in Malta compared with Australia, 75 g oral glucose tolerance tests were performed on 396 Maltese-born residents of Melbourne. Eighteen (4.5%) were found to have diabetes mellitus and 19 (4.8%) were found to have impaired glucose tolerance by current criteria. Glucose tolerance was correlated with family history of diabetes, with age, with obesity and with parity in women, but not with length of residence in Australia. Analysis of statistical data of death certification showed that Maltese-born residents of Victoria had a higher age-specific mortality from both diabetes mellitus and ischaemic heart disease than did Victorian Italian-born residents or the total Victorian population. This was most marked in women. The results suggest that Maltese immigrants to Australia after years of residence, still run a higher risk of becoming affected with diabetes mellitus or ischaemic heart disease than the average for the Australian population. The relative importance of genetic and environmental factors involved in this difference should be the subject of continuing study in the future.
Adolescent↗
A genetic and environmental analysis of a twin family study of alcohol use, anxiety, and depression.
Alcohol consumption, anxiety, and depression were measured by questionnaire in 572 twin families ascertained from the Institute of Psychiatry (London) normal twin register, each family consisting of an adult twin pair, their parents, and siblings--a total of 1,742 individuals. A multivariate normal model for pedigree analysis was applied to each variable, with power transformations fitted to maximise the fit with distributional assumptions. The effect of shared twin environment was estimated by considering the measured cohabitation history of twin pairs. For log-transformed alcohol consumption, amongst current drinkers this effect was the same for MZ and DZ pairs but depended on the cohabitation status of pairs. For both anxiety and depression the effect was clearly not the same for MZ and DZ pairs. Therefore the basic assumption of the classical twin method appears to be invalid for all three traits. Estimates of heritability derived from these analyses were compared with those obtained (1) by applying the classical twin method to twin data only, and (2) by a pedigree analysis ignoring the effect of shared twin environment. For all variables there were considerable differences between estimates based on the three models. This study illustrates that data from twins and their relatives which includes information on cohabitation history might distinguish shared genes and shared environment as causes of familial aggregation. In these behavioral traits the effect of shared twin environment may depend on zygosity and play a major role in explaining familial aggregation in twin family data.
Adolescent↗
Genetic Analysis Workshop II: pedigree analysis of a binary trait without assuming an underlying liability.
A model for concordance in a binary measure that does not rely on the assumption of an underlying latent liability dichotomized about a threshold has been demonstrated for twin pairs [Hannah et al, 1983]. It is extended here to pedigrees of arbitrary structure by making an assumption that is, for small incidence rates, almost equivalent to postulating that relative risks are multiplicative. The model is applied to the workshop data to determine the extent to which the known structure of the simulated models can be recovered.
Alleles↗
Covariation between family members as a function of cohabitation history.
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Adolescent↗
Twin concordance for a binary trait. I. Statistical models illustrated with data on drinking status.
A flexible method based on maximum likelihood theory is introduced for the analysis of binary response data in twins. The method allows for explanatory variables such as age and sex, is free of the untestable distributional assumption of bivariate normality of liability, and makes more efficient use of the data available. The method is illustrated with preliminary data on drinking status in adult twins. Although there is some bias in the ascertainment of male dizygous twins, the results suggest that monozygous twins are more concordant than dizygous twins for drinking status.
Alcohol Drinking↗
The utility of a multivariate normal model for studying familial patterns in medical and psychiatric data.
Quantitative traits (such as blood pressure, height or anxiety level) are usually more similar in related than in unrelated individuals. A positive correlation between two family members indicates that there are common factors (genetic and/or environmental) which predispose to the trait values in this pair of individuals. A negative correlation can indicate that there is (environmental) competition or some other cause for negative interaction between the pair of relatives. Using a flexible method for the analysis of quantitative data measured over pedigrees, it is possible to estimate the magnitude of the correlations between family members as a function of both their genetic relationship and their cohabitation history. This computer-based method can distinguish the effects of shared genes from some of the effects of shared family environment, and can identify negative interactions between family members which are likely to be of particular interest in studies of behavioural and psychiatric traits. The utility of this method is illustrated with pedigree data on blood lead levels, blood pressure levels and psychological traits.
Adolescent↗
Extensions to multivariate normal models for pedigree analysis. II. Modeling the effect of shared environment in the analysis of variation in blood lead levels.
A multivariate normal model for pedigree analysis is applied to blood lead measurements from 617 individuals in 80 families in Melbourne, Australia, studied in 1977-1978. A new method is introduced for estimating time dependence of the family covariance matrix for blood lead levels; this time dependence can be interpreted as arising from the effects of common family environment on blood lead levels. Methods for the testing of assumptions and detection of outlying pedigrees and outlying individuals are applied. No correlation between blood lead levels of spouses was observed, but an effect of shared family environment was suggested by the difference between an estimated sibling correlation of about 0.5 for young sibling pairs living together and of about 0.1 for older siblings no longer living together. As there was no significant polygenic additive effect, the non-zero correlation between older siblings is more likely to be due to continuing effects of (environmental) factors shared in youth, rather than to a polygenic dominant effect. It is estimated that smoking 20 cigarettes per day is associated with an increase of about 12 per cent in blood lead level.
Adolescent↗
Assessing the heterogeneity of disease spread through a community.
Care needs to be exercised in attempts at obtaining a description of the spread of disease merely by fitting a mathematical model to infectious disease data and adjusting the model until it adequately fits the observed epidemic curve. It is always necessary to perform separate statistical tests of the underlying assumptions of an epidemic model before attempting to use such a model to obtain epidemiologically meaningful insights into the mechanism of disease spread. Methods for such tests are presented and illustrated with reference to epidemics of respiratory diseases that occurred on the island of Tristan da Cunha in the South Atlantic between 1964 and 1968.
Adolescent↗
Extensions to multivariate normal models for pedigree analysis.
Lange, Westlake & Spence (1976) used the assumption of multivariate normality to apply a likelihood method to the analysis of quantitative traits measured over pedigrees. We now introduce a test of the assumption of multivariate normality and methods for the detection of outlying families and outlying individuals. We also introduce a method for the estimation of effects of measured genetic markers as variance components, a flexible parameterization to estimate effects of shared family environment, and a method to allow for the ascertainment of pedigrees through probands. These innovations have been applied using numerical methods for maximization of the likelihood. Simulation studies and available theory suggest that the likelihood ratio criterion used in significance testing follows the expected asymptotic distribution with sample sizes encountered in typical applications.
Family↗
A random walk model for the analysis of the isoprenaline-stimulated proliferative response of the rat submaxillary gland.
In a series of papers, Hodgson, Radley and Koschel have studied the proliferative response of the rat submaxillary gland to the drug isoprenaline. They found that whereas the mitotic activity of the gland is normally very low, a single injection of isoprenaline will stimulate a wave of DNA synthesis and repeated administration at daily intervals, or longer, results in further waves of DNA synthesis. An explanation of these observations was proposed by Radley, Hodgson & Koschel (1976) who introduced the concept that administration of Isoprenaline resulted in a period of enhanced 'biochemical activity' of the cells. In this paper we present a stochastic model, based on a random walk model introduced by Hopper & Brockwell (1978), to represent quantitatively the concept of 'biochemical activity'. It is shown that the parameters of this model can be adjusted to fit the observed data. It is noted that the simpler Smith & Martin model (1973), which is a special case of our random walk model, can also be fitted to the data. However, there is experimental evidence that contradicts an assumption of the Smith & Martin model, but agrees with the predictions of our model. The random walk model also reveals that the different responses of the cell population to different injection schedules cannot be fully explained by changed in the cell population's biochemical activity distribution.
Animals↗
A stochastic model for cell populations with circadian rhythms.
A mathematical model for cell kinetics, based on a random walk, is developed. The model allows variations with time of the rates of passage of proliferating cells through the four phases of the mitotic cycle. Circadian variations in the mitotic and labelling indices of the Syrian hamster cheek pouch epithelium have previously been observed, and the random walk model has been used to simulate this phenomenon. Assuming that all basal cells are proliferative and that these cells leave the basal layer randomly throughout the mitotic cycle to become differentiated cells, it was found that the experimentally observed circadian rhythms of the mitotic and labelling indices could be reproduced in the model by postulating a circadian rhythm in the rate of passage of cells through the G1 and S phases only. Moreover, the growth activity of cells in both the G1 and S phases appears to reach a peak during the dark hours of the light-dark cycle, and to fall off rapidly in the early hours of daylight. The postulate of Møller, Larsen & Faber (1974) that injection of the animals with tritiated thymidine causes a shortening of the G2 phase duration has been qualitatively confirmed by using the random walk model to simulate the FLM and MI curves after injection with tritiated thymidine.
Animals↗
Australian NHMRC Twin Registry: a resource for pediatric research.
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Adolescent↗
Genetic correlates of menarcheal age: a multivariate twin study.
Multivariate genetic models were fitted to data from 44 pairs of MZ and 42 pairs of DZ twin girls on weight, height, and skeletal maturation at the age of menarche, in order to obtain information on genetic relationships of those measures with the age of menarche. The relationships of all three physical measures with this age were largely genetically controlled, but a genetic system controlling skeletal maturity was identified as the only genetic determinant of menarcheal age, independent of those systems of the two remaining physical measures. Heritabilities of all individual traits considered in the study were uniformly high. Possible links of genetic information with hormonal functions determining menarche are discussed.
Adolescent↗