Haplotype tagging for the identification of common disease genes.

Genome-wide linkage disequilibrium (LD) mapping of common disease genes could be more powerful than linkage analysis if the appropriate density of polymorphic markers were known and if the genotyping effort and cost of producing such an LD map could be reduced. Although different metrics that measure the extent of LD have been evaluated, even the most recent studies have not placed significant emphasis on the most informative and cost-effective method of LD mapping-that based on haplotypes. We have scanned 135 kb of DNA from nine genes, genotyped 122 single-nucleotide polymorphisms (SNPs; approximately 184,000 genotypes) and determined the common haplotypes in a minimum of 384 European individuals for each gene. Here we show how knowledge of the common haplotypes and the SNPs that tag them can be used to (i) explain the often complex patterns of LD between adjacent markers, (ii) reduce genotyping significantly (in this case from 122 to 34 SNPs), (iii) scan the common variation of a gene sensitively and comprehensively and (iv) provide key fine-mapping data within regions of strong LD. Our results also indicate that, at least for the genes studied here, the current version of dbSNP would have been of limited utility for LD mapping because many common haplotypes could not be defined. A directed re-sequencing effort of the approximately 10% of the genome in or near genes in the major ethnic groups would aid the systematic evaluation of the common variant model of common disease.

Age related macular degeneration and sun exposure, iris colour, and skin sensitivity to sunlight.

BACKGROUND/AIM: It has been suggested that sun exposure may be a risk factor for age related macular degeneration (AMD) and that skin sensitivity to sunlight and iris colour could be confounding factors. The aim was to investigate this further in the white population. METHODS: 446 cases with end stage AMD were compared with 283 spouse controls. Data on sun exposure, places of residence, iris colour, subjective assessment of change in iris colour, hair colour at age 20, and skin sensitivity were obtained using a questionnaire. Iris colour was graded clinically by comparison with standard photographs. AMD was graded using stereoscopic colour fundus photographs as well as clinical examination and was defined as the presence of geographic atrophy or choroidal neovascularisation. All variables were included in a multiple logistic regression model including age, sex, and smoking. RESULTS: There was no association between AMD and sun exposure or related factors except for the suggestion of an association between sunburn prone skin type and geographic atrophy which reached borderline significance. CONCLUSIONS: No significant association between AMD and sun exposure, iris colour, change in iris colour, or hair colour was demonstrated.

Smoking and age related macular degeneration: the number of pack years of cigarette smoking is a major determinant of risk for both geographic atrophy and choroidal neovascularisation.

BACKGROUND/AIMS: There is evidence that smoking is a risk factor for age related macular degeneration (AMD). However, not all studies have demonstrated this association and several key questions about the role of smoking in AMD have still to be determined. The aim of this study was to further investigate this relation for both choroidal neovascularisation (CNV) and geographic atrophy (GA). METHODS: To investigate the relation between smoking and the risk of developing age related macular degeneration (AMD) in white people, 435 cases with end stage AMD were compared with 280 controls. All subjects had graded stereoscopic colour fundus photography and AMD was defined as the presence of GA or CNV. Smoking history was assessed using multiple parameters in a detailed questionnaire. RESULTS: Comparison of current and former smokers with non-smokers was consistent with smoking being a risk factor for AMD but did not reach statistical significance. There was a strong association between AMD and pack years of cigarette smoking (p = 0.002), the odds ratio increasing with the amount smoked; for subjects with more than 40 pack years of smoking the odds ratio was 2.75 (95% CI 1.22 to 6.20) compared with non-smokers. Both types of AMD showed a similar relation; smoking more than 40 pack years of cigarettes was associated with an odds ratio of 3.43 (95% CI 1.28 to 9.20) for GA and 2.49 (95% CI 1.06 to 5.82) for CNV. Stopping smoking was associated with reduced odds of AMD and the risk in those who had not smoked for over 20 years was comparable to non-smokers. The risk profile was similar for males and females. Passive smoking exposure was associated with an increased risk of AMD (OR 1.87; 95% CI 1.03 to 3.40) in non-smokers. CONCLUSIONS: The authors have demonstrated a strong association between the risk of both GA and CNV and pack years of cigarette smoking. This provides support for a causal relation between smoking and AMD. They also show an increased risk for AMD in non-smokers exposed to passive smoking. Stopping smoking appears to reduce the risk of developing AMD.

Statistical modeling of interlocus interactions in a complex disease: rejection of the multiplicative model of epistasis in type 1 diabetes.

In general, common diseases do not follow a Mendelian inheritance pattern. To identify disease mechanisms and etiology, their genetic dissection may be assisted by evaluation of linkage in mouse models of human disease. Statistical modeling of multiple-locus linkage data from the nonobese diabetic (NOD) mouse model of type 1 diabetes has previously provided evidence for epistasis between alleles of several Idd (insulin-dependent diabetes) loci. The construction of NOD congenic strains containing selected segments of the diabetes-resistant strain genome allows analysis of the joint effects of alleles of different loci in isolation, without the complication of other segregating Idd loci. In this article, we analyze data from congenic strains carrying two chromosome intervals (a double congenic strain) for two pairs of loci: Idd3 and Idd10 and Idd3 and Idd5. The joint action of both pairs is consistent with models of additivity on either the log odds of the penetrance, or the liability scale, rather than with the previously proposed multiplicative model of epistasis. For Idd3 and Idd5 we would also not reject a model of additivity on the penetrance scale, which might indicate a disease model mediated by more than one pathway leading to beta-cell destruction and development of diabetes. However, there has been confusion between different definitions of interaction or epistasis as used in the biological, statistical, epidemiological, and quantitative and human genetics fields. The degree to which statistical analyses can elucidate underlying biologic mechanisms may be limited and may require prior knowledge of the underlying etiology.

Spatial correlation in ecological analysis.

This paper presents a statistical approach, originally developed for mapping disease risk, to ecological regression analysis in the presence of spatial autocorrelated extra-Poisson variation. An insight into the effect of allowing for spatial autocorrelation on the relationship between disease rates and explanatory variables is given. Examples based on cancer frequency in Scotland and Sardinia are used to illustrate the interpretation of regression coefficient and further methodological issues.

Two cases of compartment syndrome in the intensive care unit.

Two cases of compartment syndrome in patients requiring Intensive Care are described. Problems surrounding the diagnosis and management of this condition are discussed.

Occurrence of cancer in Asians and non-Asians.

Cancer registration data for a defined geographical area, covering a seven year period, were modified to include the variable "Asian ethnic origin." The data were then used to test the hypothesis that a difference would be found between Asians and non-Asians in the pattern of cancer by site. Whereas the incidence of cancer of all sites appeared to be significantly lower in Asians (p less than 0.05), after taking account of this, and adjusting for the very different age distributions of the two populations, a highly significant difference (p less than 0.0005) was found between the two groups in the distribution of cancer between sites. Although, given the size and young age structure of the Asian population, absolute numbers of cases were small, a significant excess of Asian cases (compared with the expected) occurred for cancer of the tongue, oral cavity, pharynx, and oesophagus. For most sites there were fewer Asian cases than would be expected, particularly so for the stomach, testis, and skin. The results indicate the need for formal epidemiological study to test specific aetiological hypotheses which may account for these apparent differences.

The elderly in residential care: mortality in relation to functional capacity.

A census in which 4514 people aged 65 and over had been enumerated in all types of institutional care both within and outside the National Health Service in Leicestershire was taken as a starting point for the present investigation. This entire population was followed up for one year to determine its mortality experience. Mortality was described by three measures: (a) the proportion surviving for one year from the date of the census, (b) the standardised mortality ratio (using the population of Leicestershire in 1977 as a standard), and (c) using a life-table analysis, the percentage survival to specified time periods after admission to institutional care. We discuss the relationship of these indices to functional capacity, indicated by the ability to undertake basic activities of daily living (ADL), and to type of institution.

Inaccuracies in manometric central venous pressure measurement.

Manometric measurement of CVP was compared to electronic measurement in ten patients. Manometric measurement was found to give readings of up to 5 cmH2O greater than electronic, with a mean difference of 2.4 cmH2O. This was shown to be due to two factors. Firstly, a meniscus effect caused an error of 1.07 cmH2O in the manometers used. Secondly, an error attributed to the way mean values of CVP are commonly read from manometers caused a further over estimate of 1.33 cmH2O. In intensive care units, where it is important to recognise and treat small changes in CVP, the use of electronic transducers to measure CVP is recommended.

Asian mothers' risk factors for perinatal death--the same or different? A 10 year review of Leicestershire perinatal deaths.

A case-control study of all perinatal deaths in Leicestershire was established in 1976. By 1985 some 1342 singleton perinatal deaths had occurred. Perinatal mortality among patients of Asian origin was consistently higher than that among European women. Many of the sociomedical risk factors for perinatal death known at booking were common to both population groups. In this population of Asian women, however, low social class was not associated with perinatal risk and illegitimacy hardly ever occurred. In contrast, previous infertility among the Asian women was associated with risk of perinatal death, while no such association was found with European women. In 19% of perinatal deaths care was either inadequately provided or taken up. The case-control design in these circumstances provides a practicable way to evaluate causal factors and at the same time to provide information of value to educators and health service planners.

Transplants from living donors in the United Kingdom and Ireland: a centre survey.

A survey was carried out to determine for the first time the extent of transplantation from living donors in the United Kingdom and Republic of Ireland and the views of transplant surgeons regarding future developments. Questionnaires were sent to 32 transplant centres representing 18 health regions and covered their extent of experience of transplantation, sources of donors, ages of donors and recipients, outcome of transplantation, and views on expansion of living donor transplantation services. Replies received from 27 transplant centres representing 17 health regions gave data on more than 1200 transplants from living donors. Transplants from living donors accounted for 0-25% of the total experience of health regions. Two centres had abandoned living donor transplantation. Sixty per cent of transplant surgeons favoured expansion of the living donor programme to meet a shortage of kidneys from cadavers, and the remainder thought that existing programmes were optimal. Living donor transplantation promises to be an important factor in the future planning of health care resources.

Evaluating perinatal mortality rates: effects of referral and case mix.

OBJECTIVE: To evaluate perinatal mortality rates as a method of auditing obstetric and neonatal care after account had been taken of transfer between hospitals during pregnancy and case mix. DESIGN: Case-control study of perinatal deaths. SETTING: Leicestershire health district. SUBJECTS: 1179 singleton perinatal deaths and their selected live born controls among 114,362 singleton births to women whose place of residence was Leicestershire during 1978-87. MAIN OUTCOME MEASURE: Crude perinatal mortality rates and rates adjusted for case mix. RESULTS: An estimated 11,701 of the 28,750 women booked for delivery in general practitioner maternity units were transferred to consultant units during their pregnancy. These 11,701 women had a high perinatal mortality rate (16.8/1000 deliveries). Perinatal mortality rates by place of booking showed little difference between general practitioner units (8.8/1000) and consultant units (9.3-11.7/1000). Perinatal mortality rates by place of delivery, however, showed substantial differences between general practitioner units (3.3/1000) and consultant units (9.4-12.6/1000) because of the selective referral of high risk women from general practitioner units to consultant units. Adjustment for risk factors made little difference to the rates except when the subset of deaths due to immaturity was adjusted for birth weight. CONCLUSION: Perinatal mortality rates should be adjusted for case mix and referral patterns to get a meaningful result. Even when this is done it is difficult to compare the effectiveness of hospital units with perinatal mortality rates because of the increasingly small subset of perinatal deaths that are amenable to medical intervention.

Appropriate use of information on family history of disease in recruitment for linkage analysis studies.

When conducting genetic studies for complex traits, large samples are commonly required to detect any of the number of genes with relatively low effect thought to underly such traits. This is because, in contrast to monogenic diseases, complex traits typically result from a number of different genetic pathways (genetic heterogeneity) and any sample is likely to contain a considerable fraction of sporadic cases (phenocopies). Such samples are time-consuming and costly to recruit and analyse. Methods which might be used to decrease sample size include attempting to select families, with the aim of reducing genetic heterogeneity or phenocopy rate within the sample. Selecting cases with positive family history of disease should reduce the phenocopy rate, and this strategy has been employed in linkage studies of complex disease, although evaluations of such a strategy have been equivocal. This paper shows how identity by descent (IBD) distributions may be calculated for affected relative pairs recruited conditional on the affection status of a third relative. These distributions are then used to calculate expected power in affected sib and half-sib linkage studies when recruitment is conditional on family history of disease. We consider the proxy conditions of recruitment conditional on disease in an affected parent or third sibling with single-locus and additive multilocus genetic models. We show that while such selection strategies can reduce power if disease risk alleles are common and environmental heterogeneity low, under models more likely to underly common complex diseases power will generally be increased, and that this effect is greater as more loci are involved. Though the proxy cases studied are more extreme than a general strategy of asking potential recruits whether they have any family history of disease, these results suggest that conditional recruitment is more generally useful than previous studies have suggested.

A Monte Carlo method for Bayesian inference in frailty models.

Many analyses in epidemiological and prognostic studies and in studies of event history data require methods that allow for unobserved covariates or "frailties." Clayton and Cuzick (1985, Journal of the Royal Statistical Society, Series A 148, 82-117) proposed a generalization of the proportional hazards model that implemented such random effects, but the proof of the asymptotic properties of the method remains elusive, and practical experience suggests that the likelihoods may be markedly nonquadratic. This paper sets out a Bayesian representation of the model in the spirit of Kalbfleisch (1978, Journal of the Royal Statistical Society, Series B 40, 214-221) and discusses inference using Monte Carlo methods.

The Leicestershire Perinatal Mortality Study: a case study of multi-group discriminant analysis with complex sampling.

Case-control studies are usually analysed by two-group discriminant analysis or by a related method. However, in case-control studies of perinatal mortality the cases (perinatal deaths) are far from homogeneous, and it is likely that some risk factors are relevant only to certain subgroups of cases. This paper proposes a seven-category classification of perinatal deaths and reports an analysis using multi-group discriminant analysis. The problem is further complicated by non-random sampling of controls.

Multivariate parametric random effect regression models for fecundability studies.

Delay until conception is generally described by a mixture of geometric distributions. Weinberg and Gladen (1986, Biometrics 42, 547-560) proposed a regression generalization of the beta-geometric mixture model where covariates effects were expressed in terms of contrasts of marginal hazards. Scheike and Jensen (1997, Biometrics 53, 318-329) developed a frailty model for discrete event times data based on discrete-time analogues of Hougaard's results (1984, Biometrika 71, 75-83). This paper is on a generalization to a three-parameter family distribution and an extension to multivariate cases. The model allows the introduction of explanatory variables, including time-dependent variables at the subject-specific level, together with a choice from a flexible family of random effect distributions. This makes it possible, in the context of medically assisted conception, to include data sources with multiple pregnancies (or attempts at pregnancy) per couple.

The point accuracy of paediatric population registers.

The accurate identification of paediatric populations in primary health care is not being achieved. Fifteen per cent of the children were not at the address given for them on one or more of the three registers studied. Our calculations suggest that a further number of children in the community may appear on none of the three available registers.

Diagnostic plots for departures from proportional hazards in cohort study data.

The assumption of proportional hazards is routinely made in the analysis of cohort studies, whether a simple SMR calculation or a full survival analysis is used. In this paper, we introduce simple plots for checking the validity of the assumption. The plots are of two kinds. The first, which has been used previously for survival data, makes use of the fact that the individual integrated hazards are distributed as unit exponential varieties under proportional hazards, and involves plotting their estimates against expected exponential order statistics. The second displays the evolution of relative risk as a function of time, and in this case, a choice of time scale must be made for the plots. A score test for proportional hazards is also derived, and the methods are illustrated by data on cancer mortality among the employees of a South Wales nickel refinery.

The accuracy of age-sex registers, practice medical records and family practitioner committee registers.

This paper presents the results of a point prevalent evaluation of the comparative reliability and validity of age-sex registers, practice medical records and family practitioner committee (FPC) registers from five teaching practices. They all exhibited similar levels of acceptable accuracy for patient names, sex and age, but the distribution of wrong addresses varied greatly: practice medical records 3.9 per cent, age-sex registers 8.2 per cent and FPC registers 17.1 per cent. The presence of a patient entry in all three registers was associated with a high degree of probability (95.3 per cent) that this individual would be a bona fide practice patient. The register population inflation rates were FPC records 5.5 per cent, practice records 9.8 per cent and age-sex registers 10.6 per cent, but there were large variations between individual practices. A statistically significant contribution to inflation rates came from the age groups 0 to 1 and 21 to 40 (p<0.0005). The register population deflation rates were minimal. The significance of these findings is discussed and the need for practices to determine the accuracy of their individual age-sex registers is stressed. A convenient and economic method for so doing is suggested. We also suggest ways of making it easier to construct and use age-sex registers, since they can be a most versatile and useful aid to research in general practice.