Lyle C. Gurrin

EXTENDING THE SIMPLE LINEAR REGRESSION MODEL TO ACCOUNT FOR CORRELATED RESPONSES: AN INTRODUCTION TO GENERALIZED ESTIMATING EQUATIONS AND MULTI-LEVEL MIXED MODELLING

Much of the research in epidemiology and clinical science is based upon longitudinal designs which involve repeated measurements of a variable of interest in each of a series of individuals. Such designs can be very powerful, both statistically and scientifically, because they enable one to study changes within individual subjects over time or under varied conditions. However, this power arises because the repeated measurements tend to be correlated with one another, and this must be taken into proper account at the time of analysis or misleading conclusions may result. Recent advances in statistical theory and in software development mean that studies based upon such designs can now be analysed more easily, in a valid yet flexible manner, using a variety of approaches which include the use of generalized estimating equations, and mixed models which incorporate random effects. This paper provides a particularly simple illustration of the use of these two approaches, taking as a practical example the analysis of a study which examined the response of portable peak expiratory flow meters to changes in true peak expiratory flow in 12 children with asthma. The paper takes the reader through the relevant practicalities of model fitting, interpretation and criticism and demonstrates that, in a simple case such as this, analyses based upon these model-based approaches produce reassuringly similar inferences to standard analyses based upon more conventional methods.

Iron-overload-related disease in HFE hereditary hemochromatosis.

BACKGROUND Most persons who are homozygous for C282Y, the HFE allele most commonly asssociated with hereditary hemochromatosis, have elevated levels of serum ferritin and transferrin saturation. Diseases related to iron overload develop in some C282Y homozygotes, but the extent of the risk is controversial. METHODS We assessed HFE mutations in 31,192 persons of northern European descent between the ages of 40 and 69 years who participated in the Melbourne Collaborative Cohort Study and were followed for an average of 12 years. In a random sample of 1438 subjects stratified according to HFE genotype, including all 203 C282Y homozygotes (of whom 108 were women and 95 were men), we obtained clinical and biochemical data, including two sets of iron measurements performed 12 years apart. Disease related to iron overload was defined as documented iron overload and one or more of the following conditions: cirrhosis, liver fibrosis, hepatocellular carcinoma, elevated aminotransferase levels, physician-diagnosed symptomatic hemochromatosis, and arthropathy of the second and third metacarpophalangeal joints. RESULTS The proportion of C282Y homozygotes with documented iron-overload-related disease was 28.4% (95% confidence interval [CI], 18.8 to 40.2) for men and 1.2% (95% CI, 0.03 to 6.5) for women. Only one non-C282Y homozygote (a compound heterozygote) had documented iron-overload-related disease. Male C282Y homozygotes with a serum ferritin level of 1000 mug per liter or more were more likely to report fatigue, use of arthritis medicine, and a history of liver disease than were men who had the wild-type gene. CONCLUSIONS In persons who are homozygous for the C282Y mutation, iron-overload-related disease developed in a substantial proportion of men but in a small proportion of women.

Prevalence of challenge-proven IgE-mediated food allergy using population-based sampling and predetermined challenge criteria in infants

BACKGROUND Several indicators suggest that food allergy in infants is common and possibly increasing. Few studies have used oral food challenge to measure this phenomenon at the population level. OBJECTIVE To measure the prevalence of common IgE-mediated childhood food allergies in a population-based sample of 12-month-old infants by using predetermined food challenge criteria to measure outcomes. METHODS A sampling frame was used to select recruitment areas to attain a representative population base. Recruitment occurred at childhood immunization sessions in Melbourne, Australia. Infants underwent skin prick testing, and those with any sensitization (wheal size ≥ 1 mm) to 1 or more foods (raw egg, peanut, sesame, shellfish, or cows milk) were invited to attend an allergy research clinic. Those who registered a wheal size ≥ 1 mm to raw egg, peanut, or sesame underwent oral food challenge. RESULTS Amongst 2848 infants (73% participation rate), the prevalence of any sensitization to peanut was 8.9% (95% CI, 7.9-10.0); raw egg white, 16.5% (95% CI, 15.1-17.9); sesame, 2.5% (95% CI, 2.0-3.1); cows milk, 5.6% (95% CI, 3.2-8.0); and shellfish, 0.9% (95% CI, 0.6-1.5). The prevalence of challenge-proven peanut allergy was 3.0% (95% CI, 2.4-3.8); raw egg allergy, 8.9% (95% CI, 7.8-10.0); and sesame allergy, 0.8% (95% CI, 0.5-1.1). Oral food challenges to cows milk and shellfish were not performed. Of those with raw egg allergy, 80.3% could tolerate baked egg. CONCLUSION More than 10% of 1-year-old infants had challenge-proven IgE-mediated food allergy to one of the common allergenic foods of infancy. The high prevalence of allergic disease in Australia requires further investigation and may be related to modifiable environmental factors.

Risk factors for female sexual dysfunction in the general population: exploring factors associated with low sexual function and sexual distress.

INTRODUCTION No previous population-based studies have used validated instruments to measure female sexual dysfunction (FSD) in Australian women across a broad age range. AIM To estimate prevalence and explore factors associated with the components of FSD. MAIN OUTCOME MEASURES Sexual Function Questionnaire measured low sexual function. Female Sexual Distress Scale measured sexual distress. Methods. Multivariate analysis of postal survey data from a random sample of 356 women aged 20-70 years. RESULTS Low desire was more likely to occur in women in relationships for 20-29 years (odds ratio 3.7, 95% confidence intervals 1.1-12.8) and less likely in women reporting greater satisfaction with their partner as a lover (0.3, 0.1-0.9) or who placed greater importance on sex (0.1, 0.03-0.3). Low genital arousal was more likely among women who were perimenopausal (4.4, 1.2-15.7), postmenopausal (5.3, 1.6-17.7), or depressed (2.5, 1.1-5.3), and was less likely in women taking hormone therapy (0.2, 0.04-0.7), more educated (0.5, 0.3-0.96), in their 30s (0.2, 0.1-0.7) or 40s (0.2, 0.1-0.7), or placed greater importance on sex (0.2, 0.05-0.5). Low orgasmic function was less likely in women who were in their 30s (0.3, 0.1-0.8) or who placed greater importance on sex (0.3, 0.1-0.7). Sexual distress was positively associated with depression (3.1, 1.2-7.8) and was inversely associated with better communication of sexual needs (0.2, 0.05-0.5). Results were adjusted for other covariates including age, psychological, socioeconomic, physiological, and relationship factors. CONCLUSIONS Relationship factors were more important to low desire than age or menopause, whereas physiological and psychological factors were more important to low genital arousal and low orgasmic function than relationship factors. Sexual distress was associated with both psychological and relationship factors.

Rapid decline in presentations of genital warts after the implementation of a national quadrivalent human papillomavirus vaccination programme for young women.

Objective: This study aimed to determine if the Australian human papillomavirus (HPV) vaccination programme has had a population impact on presentations of genital warts. Methods: Retrospective study comparing the proportion of new clients with genital warts attending Melbourne Sexual Health Centre (MSHC) from January 2004 to December 2008. Australia provided free quadrivalent HPV vaccine to 12–18-year-old girls in a school-based programme from April 2007, and to women 26 years and younger through general practices from July 2007. Results: 36 055 new clients attended MSHC between 2004 and 2008 and genital warts were diagnosed in 3826 (10.6%; 95% CI 10.3 to 10.9). The proportion of women under 28 years with warts diagnosed decreased by 25.1% (95% CI 30.5% to 19.3%) per quarter in 2008. Comparing this to a negligible increase of 1.8% (95% CI 0.2% to 3.4%) per quarter from the start of 2004 to the end of 2007 also in women under 28 years generates strong evidence of a difference in these two trends (p<0.001). There was no evidence of a difference in trend for the quarterly proportions before and after the end of 2007 for any other subgroup, and on only one occasion was there strong evidence of a trend different to zero, for heterosexual men in 2008 in whom the average quarterly change was a decrease of 5% (95% CI 0.5% to 9.4%; p = 0.031). Conclusions: The data suggest that a rapid and marked reduction in the incidence of genital warts among vaccinated women may be achievable through an HPV vaccination programme targeting women, and supports some benefit being conferred to heterosexual men.

Sexual Risk Factors and Bacterial Vaginosis: A Systematic Review and Meta-Analysis

We performed a systematic review and meta-analysis of the association between sexual risk factors and bacterial vaginosis (BV). Forty-three studies reported new or multiple sexual partners and condom use relative to prevalent, incident, or recurrent BV. The summary estimate of the relative risk for the association between BV new or multiple male partners was 1.6 (95% confidence interval, 1.5-1.8), between BV and any female partners was 2.0 (95% confidence interval, 1.7-2.3), and between BV and condom use was 0.8 (95% confidence interval, 0.8-0.9). This review is the first to summarize available observational data for BV. It shows that BV is significantly associated with sexual contact with new and multiple male and female partners and that decreasing the number of unprotected sexual encounters may reduce incident and recurrent infection. Investigation of sexual transmission of BV is limited by the absence of a clear microbiological etiology; however, we have shown that the epidemiological profile of BV is similar to that of established sexually transmitted infections.

Maternal cigarette smoking during pregnancy, low birth weight and subsequent blood pressure in early childhood

Given the widely acknowledged inverse relationship between birth weight and blood pressure, a raised blood pressure in the offspring of smoking mothers as compared to those whose mothers did not smoke, would be anticipated by virtue of the reduction in birth weight associated with smoking during pregnancy. The objective of the present study was to test the hypothesis that maternal cigarette smoking during pregnancy has an effect on blood pressure in childhood independent of its effect on birth weight. Data was obtained from a prospective cohort study of 1708 pregnant women and their singleton offspring, delivered live at term, in Perth, Western Australia, commenced at 16 weeks gestation with serial blood pressure measurements through early childhood. Statistically significant associations were found between maternal smoking during pregnancy and systolic blood pressure at age six, between birth weight and systolic blood pressure at ages three and six, and between maternal smoking during pregnancy and birth weight. The relationship between birth weight and blood pressure in early childhood differed significantly on the basis of maternal cigarette smoking or not during pregnancy. This differential relationship persisted after adjustment for the childs current weight and socio-economic status. We concluded that intra-uterine exposure to maternal cigarette smoking increased childrens blood pressure at age one through to age six. This was not wholly attributable to an effect on birth weight or confounding of the association between birth weight and subsequent blood pressure by the childs current weight or socio-economic factors. Furthermore, maternal smoking during pregnancy does not account for the acknowledged elevation in blood pressure associated with low birth weight. The present study is an exploration of a possible causal pathway underlying the birth weight/blood pressure association rather than simply a confirmation of such an association which has been detailed in many other papers.

Metachronous colorectal cancer risk for mismatch repair gene mutation carriers: the advantage of more extensive colon surgery

Background Surgical management of colon cancer for patients with Lynch syndrome who carry a mismatch repair (MMR) gene mutation is controversial. The decision to remove more or less of the colon involves the consideration of a relatively high risk of metachronous colorectal cancer (CRC) with the impact of more extensive surgery. Objective To estimate and compare the risks of metachronous CRC for patients with Lynch syndrome undergoing either segmental or extensive (subtotal or total) resection for first colon cancer. Design Risk of metachronous CRC was estimated for 382 MMR gene mutation carriers (172 MLH1, 167 MSH2, 23 MSH6 and 20 PMS2) from the Colon Cancer Family Registry, who had surgery for their first colon cancer, using retrospective cohort analysis. Age-dependent cumulative risks of metachronous CRC were calculated using the Kaplan–Meier method. Risk factors for metachronous CRC were assessed by a Cox proportional hazards regression. Results None of 50 subjects who had extensive colectomy was diagnosed with metachronous CRC (incidence rate 0.0; 95% CI 0.0 to 7.2 per 1000 person-years). Of 332 subjects who had segmental resections, 74 (22%) were diagnosed with metachronous CRC (incidence rate 23.6; 95% CI 18.8 to 29.7 per 1000 person-years). For those who had segmental resections, incidence was statistically higher than for those who had extensive surgery (P <0.001). Cumulative risk of metachronous CRC was 16% (95% CI 10% to 25%) at 10 years, 41% (95% CI 30% to 52%) at 20 years and 62% (95% CI 50% to 77%) at 30 years after segmental colectomy. Risk of metachronous CRC reduced by 31% (95% CI 12% to 46%; p=0.002) for every 10 cm of bowel removed. Conclusions Patients with Lynch syndrome with first colon cancer treated with more extensive colonic resection have a lower risk of metachronous CRC than those receiving less extensive surgery. This finding will better inform decision-making about the extent of primary surgical resection.

Increasing the accuracy of peanut allergy diagnosis by using Ara h 2

BACKGROUND Measurement of whole peanut-specific IgE (sIgE) is often used to confirm sensitization but does not reliably predict allergy. Ara h 2 is the dominant peanut allergen detected in 90% to 100% of patients with peanut allergy and could help improve diagnosis. OBJECTIVES We sought to determine whether Ara h 2 testing might improve the accuracy of diagnosing peanut allergy and therefore circumvent the need for an oral food challenge (OFC). METHODS Infants from the population-based HealthNuts study underwent skin prick tests to determine peanut sensitization and subsequently underwent a peanut OFC to confirm allergy status. In a stratified random sample of 200 infants (100 with peanut allergy and 100 with peanut tolerance), whole peanut sIgE and Ara h 2 sIgE levels were quantified by using fluorescence enzyme immunoassay. RESULTS By using the previously published 95% positive predictive value of 15 kU(A)/L for whole peanut sIgE, a corresponding specificity of 98% (95% CI, 93% to 100%) was found in this study cohort. At the equivalent specificity of 98%, the sensitivity of Ara h 2 sIgE is 60% (95% CI, 50% to 70%), correctly identifying 60% of subjects with true peanut allergy compared with only 26% correctly identified by using whole peanut sIgE. We report that when using a combined approach of plasma sIgE testing for whole peanut followed by Ara h 2 for the diagnosis of peanut allergy, the number of OFCs required is reduced by almost two thirds. CONCLUSION Ara h 2 plasma sIgE test levels provide higher diagnostic accuracy than whole peanut plasma sIgE levels and could be considered a new diagnostic tool to distinguish peanut allergy from peanut tolerance, which might reduce the need for an OFC.

Vitamin D insufficiency is associated with challenge-proven food allergy in infants

BACKGROUND Epidemiological evidence has shown that pediatric food allergy is more prevalent in regions further from the equator, suggesting that vitamin D insufficiency may play a role in this disease. OBJECTIVE To investigate the role of vitamin D status in infantile food allergy. METHODS A population sample of 5276 one-year-old infants underwent skin prick testing to peanut, egg, sesame, and cows milk or shrimp. All those with a detectable wheal and a random sample of participants with negative skin prick test results attended a hospital-based food challenge clinic. Blood samples were available for 577 infants (344 with challenge-proven food allergy, 74 sensitized but tolerant to food challenge, 159 negative on skin prick test and food challenge). Serum 25-hydroxyvitamin D levels were measured by using liquid chromatography tandem mass spectrometry. Associations between serum 25-hydroxyvitamin D and food allergy were examined by using multiple logistic regression, adjusting for potential risk and confounding factors. RESULTS Infants of Australian-born parents, but not of parents born overseas, with vitamin D insufficiency (≤50 nmol/L) were more likely to be peanut (adjusted odds ratio [aOR], 11.51; 95% CI, 2.01-65.79; P=.006) and/or egg (aOR, 3.79; 95% CI, 1.19-12.08; P=.025) allergic than were those with adequate vitamin D levels independent of eczema status. Among those with Australian-born parents, infants with vitamin D insufficiency were more likely to have multiple food allergies (≥2) rather than a single food allergy (aOR, 10.48; 95% CI, 1.60-68.61 vs aOR, 1.82; 95% CI, 0.38-8.77, respectively). CONCLUSIONS These results provide the first direct evidence that vitamin D sufficiency may be an important protective factor for food allergy in the first year of life.