Frequency of platelet-specific alloantigens in a Danish population

This study reports the first data on gene frequencies of platelet alloantigens HPA-1, HPA-2, HPA-3, HPA-4 and HPA-5 in a population of unrelated Danish blood donors using PCR-techniques. The observed gene frequencies fit the Hardy-Weinberg equilibrium, and the calculated phenotype frequencies are similar to those obtained in other Caucasian populations: HPA-la and -lb occur in 96.6% and 30.3% of 557 unrelated respectively. HPA-2a and -2b in 99.4% and 15.9% of 163 tested, HPA-3a and -3b in 88.3% and 63.2% of 163 tested, HPA-4a and -4b in 100% and 0% of 131 tested, and finally HPA-5a and -5b in 100% and 15.7% of 427 tested. It is a major technical improvement to use PCR techniques for genomic typing of HPA. Not only is it possible to perform HPA typings in severely thrombocytopenic patient and on amniotic fluid cells of the fetus of alloimunized mothers, but it must be expected that accuracy of the HPA typing will increase considerably, as has been the case with genomic HLA class II typing. Finally, use of PCR technique combined with allele-specific primers is suitable for accurate large scale typing of platelet donors, which may be useful in special clinical settings.     

An enquiry into the respiratory health effects on a rural community of a soil mound erected close to residential property

The health concerns of a rural community were investigated following the erection of a soil mound in close proximity to residential property. Retrospective comparisons were made of respiratory and non-respiratory consultations with general practitioners between the exposed population and a sociodemographically similar comparison population. A 2-year period was examined, 1 year before and 1 year after the mound was erected. In the 1-year period prior to erection of the mound, similar consultation rates for both respiratory and non-respiratory conditions were observed in both populations. In the 1-year period following erection of the mound, the exposed population was more likely to consult for respiratory conditions than the comparison population (OR=4.10, 95% CI 2.26-7.44). No differences were observed for non-respiratory conditions. We identified a significant increase in respiratory consultations in the exposed population following erection of the soil mound. Limitations associated with this type of study should be considered when interpreting the results.     

Adjusting for treatment effects in studies of quantitative traits: antihypertensive therapy and systolic blood pressure

A population-based study of a quantitative trait may be seriously compromised when the trait is subject to the effects of a treatment. For example, in a typical study of quantitative blood pressure (BP) 15 per cent or more of middle-aged subjects may take antihypertensive treatment. Without appropriate correction, this can lead to substantial shrinkage in the estimated effect of aetiological determinants of scientific interest and a marked reduction in statistical power. Correction relies upon imputation, in treated subjects, of the underlying BP from the observed BP having invoked one or more assumptions about the bioclinical setting. There is a range of different assumptions that may be made, and a number of different analytical models that may be used. In this paper, we motivate an approach based on a censored normal regression model and compare it with a range of other methods that are currently used or advocated. We compare these methods in simulated data sets and assess the estimation bias and the loss of power that ensue when treatment effects are not appropriately addressed. We also apply the same methods to real data and demonstrate a pattern of behaviour that is consistent with that in the simulation studies. Although all approaches to analysis are necessarily approximations, we conclude that two of the adjustment methods appear to perform well across a range of realistic settings. These are: (1) the addition of a sensible constant to the observed BP in treated subjects; and (2) the censored normal regression model. A third, non-parametric, method based on averaging ordered residuals may also be advocated in some settings. On the other hand, three approaches that are used relatively commonly are fundamentally flawed and should not be used at all. These are: (i) ignoring the problem altogether and analysing observed BP in treated subjects as if it was underlying BP; (ii) fitting a conventional regression model with treatment as a binary covariate; and (iii) excluding treated subjects from the analysis. Given that the more effective methods are straightforward to implement, there is no argument for undertaking a flawed analysis that wastes power and results in excessive bias.     

Carbonic anhydrase IX and the future of molecular markers in renal cell carcinoma

The use of carbonic anhydrase IX as a promising molecular marker in RCC is described by authors from Los Angeles, who discuss the promise that molecular markers hold to improve diagnosis, staging, treatment, surveillance and survival of patients with RCC. There is a whole range of new treatments being introduced in the management of metastatic renal cancer. The use of VEGF-targeted therapy has particular importance, especially as it has a strong genetically linked rationale for its potential success in this area. Authors from the USA show that substantial clinical activity has been reported in initial clinical trials. In prostate cancer, drugs targeting microtubules, such as taxanes, have already been introduced clinically, and their success has received widespread attention. A new group of drugs, the epothilones, have similar but not identical binding properties to microtubules, and authors from the USA describe how they have shown activity in hormone-refractory prostate cancer, and are moving to phase III testing.     

Effects of aging on cadmium and tubular dysfunction markers in urine from adult women in non-polluted areas

Objectives: The objectives of the present analyses were to examine if Cd and tubular dysfunction marker levels in urine show age-dependent changes among women who lived in areas with no known cadmium (Cd) pollution in Japan, and if the trends would be further modified by correction of analyte concentration in terms of urinary creatinine (CR or cr) or urine specific gravity (SG or sg). Methods: The results of urinalysis for Cd, ₁-microglobulin (₁-MG), ₂-microglobulin (₂-MG), and N-acetyl--D-glucosaminidase (NAG) concentrations together with CR and SG were cited from previously established databases. A majority of urine samples were collected in 2000–2002 from adult women (mostly at 40–60 years of age) in various areas in Japan, and the collection was supplemented by cases of 60-year-old women in 2003. In total, 11,090 never-smoking cases were subjected to statistical analysis. The values as observed (e.g., Cd_ob), together with after correction for CR (e.g., Cd_cr) or SG (e.g., Cd_sg), were examined by linear regression analysis after logarithmic conversion. Results: The geometric mean (GM) values for Cd were 1.10 g/l (as observed) or 1.32 g/g cr (after correction for creatinine concentration). No increases were found in the levels of ₁-MG, ₂-MG or NAG on a group basis, in agreement with the conditions that there was no known environmental pollution with Cd in the sampling areas. There were almost linear increases in logarithm of Cd, ₁-MG, ₂-MG and NAG concentrations as age advanced. As CR, and to a lesser extent SG, also decreases steadily throughout life (Ikeda et al. 2005; Moriguchi et al. 2005), the correction of the analyte concentrations for urine density induced substantial increases in the analyte values; i.e., the correction by CR and SG induced amplification of the increases by two- and 1.4-times, respectively, compared with the increase in non-corrected observed values. Conclusions: There were age-related increases in Cd and tubular dysfunction markers in urine among women in areas with no known Cd pollution. The increase was amplified two- or 1.4-times when CR or SG correction was applied, respectively. The observation suggests that care should be practiced in applying CR or SG correction, especially when evaluation of Cd exposure and resulting health effects is made among elderly populations.     

Accounting for haplotype uncertainty in matched association studies: a comparison of simple and flexible techniques

Population-based case-control studies measuring associations between haplotypes of single nucleotide polymorphisms (SNPs) are increasingly popular, in part because haplotypes of a few "tagging" SNPs may serve as surrogates for variation in relatively large sections of the genome. Due to current technological limitations, haplotypes in cases and controls must be inferred from unphased genotypic data. Using individual-specific inferred haplotypes as covariates in standard epidemiologic analyses (e.g., conditional logistic regression) is an attractive analysis strategy, as it allows adjustment for nongenetic covariates, provides omnibus and haplotype-specific tests of association, and can estimate haplotype and haplotype x environment interaction effects. In principle, some adjustment for the uncertainty in inferred haplotypes should be made. Via simulation, we compare the performance (bias and mean squared error of haplotype and haplotype x environment interaction effect estimates) of several analytic strategies using inferred haplotypes in the context of matched case-control data. These strategies include using only the most likely haplotype assignment, the expectation substitution approach described by Stram et al. ([2003b] Hum. Hered. 55:179-190) and others, and an improper version of multiple imputation. For relatively uncomplicated haplotype structures and moderate haplotype relative risks (/=5). An application to progesterone-receptor haplotypes and endometrial cancer further illustrates that the performance of all these methods depends on how well the observed haplotypes "tag" the unobserved causal variant.     

Practical population group assignment with selected informative markers: characteristics and properties of Bayesian clustering via STRUCTURE

Population stratification, which is caused by population genetic substructure (PGS), is a critical issue for the design and interpretation of genetic association studies. Methods to address this problem have been devised, but little is known at this point about practical genotyping requirements for resolving PGS based on different marker characteristics. In this report, we seek to (1) identify a small, practical marker set to differentiate African Americans (AAs) from European Americans (EAs), and (2) assess the impact of marker efficiency and sample size on clustering individuals into subgroups by the methods of STRUCTURE (Pritchard et al., [2000a] Genetics 155:945-959). A panel of 37 markers was genotyped for 865 individuals (640 EAs and 225 AAs) from the Northeastern United States. Among EAs, the assignment accuracy reached >99% using only the 4 most efficient markers. Among AAs, the assignment accuracy exceeded 95% when using the 6 most informative markers. Smaller sample size increased the variance in population differentiation, rather than degrading the results consistently. We conclude that the use of marker-efficiency measures for marker selection yielded a relatively small set of STR markers that were effective at differentiating EA and AA populations. The number of markers required is much lower than has been suggested in previous studies.     

Measuring the health of populations: the veil of ignorance approach

We report the results from two surveys designed to explore whether an application of Harsanyi's principle of choice form behind a veil of ignorance (VEI) can be used in order to measure the health of populations. This approach was tentatively recommended by Murray et al. (Bull. World Health Organ 2000; 78: 981-994; Summary Measures of population health: Concepts, Ethics, Measurement and Applications, WHO, 2002.) as an appropriate way of constructing summary measures of population health (SMPH) for comparative purposes. The operationalization of the VEI approach used in this paper was suggested by Nord (Summary Measures of Population Health: Concepts, Ethics, Measurement and Applications, WHO, 2002.). We test if VEI and person trade-off (PTO) methods generate similar quality-of-life weights. In addition, we compare VEI and PTO weights with individual utilities estimated by means of the conventional standard gamble (SG) and a variation of it we call double gamble. Finally, psychometric properties like feasibility, reliability, and consistency are examined. Our main findings are next: (1) VEI and PTO approaches generate very different weights; (2) it seems that differences between PTO and VEI are not due to the 'rule of rescue'; (3) the VEI resembled more a DG than a classical SG; (4) PTO, VEI, and DG exhibited good feasibility, reliability and consistency.     

Increasing socio-economic inequalities in life expectancy and QALYs in Sweden 1980-1997

The aim of this study was to estimate the change in socio-economic differences in life expectancy and in quality-adjusted life years (QALYs), for men and women at different ages, in Sweden 1980 to 1997. We used data from the Swedish Survey of Living Conditions (the ULF survey), which is linked to mortality data, to estimate the life expectancy in different socio-economic groups in 1980 and 1997 (n=100 868). Health state scores were obtained by mapping responses to selected ULF survey interview questions into the generic health-related quality of life measure EQ-5D, using the UK EQ-5D index tariff (n=34 447). For 20-year-old men the difference in life expectancy between the highest (higher non-manual) and the lowest socio-economic group (unskilled manual) was 2.11 years in 1980 and 3.79 years in 1997. The corresponding figures for 20-year-old women were 1.56 in 1980 and 2.15 in 1997. The difference in QALYs between the highest and the lowest socio-economic group increased from 5.76 QALYs in 1980 to 7.06 QALYs in 1997 for 20-year-old men, and from 4.14 QALYs in 1980 to 5.66 QALYs in 1997 for 20-year-old women. The widening socio-economic inequalities over time were more stable for men than for women. We conclude that our results suggest that the socio-economic inequality in health has increased between 1980 and 1997 in Sweden.