Novartis and Pfizer.

Accurately determining the distribution of rare variants is an important goal of human genetics, but resequencing of a sample large enough for this purpose has been unfeasible until now. Here, we applied Sanger sequencing of genomic PCR amplicons to resequence the diabetes-associated genes KCNJ11 and HHEX in 13,715 people (10,422 European Americans and 3,293 African Americans) and validated amplicons potentially harbouring rare variants using 454 pyrosequencing. We observed far more variation (expected variant-site count ∼578) than would have been predicted on the basis of earlier surveys, which could only capture the distribution of common variants. By comparison with earlier estimates based on common variants, our model shows a clear genetic signal of accelerating population growth, suggesting that humanity harbours a myriad of rare, deleterious variants, and that disease risk and the burden of disease in contemporary populations may be heavily influenced by the distribution of rare variants.

Rationale: Recent U.S. data suggest an increased risk of work-related asthma among health care workers, yet only a few specific determinants have been elucidated. Objectives: To evaluate associations of asthma prevalence with occupational exposures in a cross-sectional survey of health care professionals. Methods: A detailed questionnaire was mailed to a random sample (n ϭ 5,600) of all Texas physicians, nurses, respiratory therapists, and occupational therapists with active licenses in 2003. Information on asthma symptoms and nonoccupational asthma risk factors obtained from the questionnaire was linked to occupational exposures derived through an industry-specific job-exposure matrix. Measurements: There were two a priori defined outcomes: (1 ) physiciandiagnosed asthma with onset after entry into health care ("reported asthma") and (2 ) "bronchial hyperresponsiveness-related symptoms," defined through an 8-item symptom-based predictor. Conclusions:The contribution of occupational exposures to asthma in health care professionals is not trivial, meriting both implementation of appropriate controls and further study.

Background: Previous studies have described increased occurrence of asthma among healthcare workers, but to our knowledge there are no validated survey questionnaires with which to study this occupational group. Aims: To develop, validate, and refine a new survey instrument on asthma for use in epidemiological studies of healthcare workers. Methods: An initial draft questionnaire, designed by a multidisciplinary team, used previously validated questions where possible; the occupational exposure section was developed by updating health services specific chemical lists through hospital walk-through surveys and review of material safety data sheets. A cross-sectional validation study was conducted in 118 non-smoking subjects, who also underwent bronchial challenge testing, an interview with an industrial hygienist, and measurement of specific IgE antibodies to common aeroallergens. Results: The final version consisted of 43 main questions in four sections. Time to completion of the questionnaire ranged from 13 to 25 minutes. Test-retest reliability of asthma and allergy items ranged from 75% to 94%, and internal consistency for these items was excellent (Cronbach's a > 0.86). Against methacholine challenge, an eight item combination of asthma related symptoms had a sensitivity of 71% and specificity of 70%; against a physician diagnosis of asthma, this same combination showed a sensitivity of 79% and specificity of 98%. Agreement between self-reported exposures and industrial hygienist review was similar to previous studies and only moderate, indicating the need to incorporate more reliable methods of exposure assessment. Against the aerollergen panel, the best combinations of sensitivity and specificity were obtained for a history of allergies to dust, dust mite, and animals. Conclusions: Initial evaluation of this new questionnaire indicates good validity and reliability, and further field testing and cross-validation in a larger healthcare worker population is in progress. The need for development of more reliable occupational exposure assessment methods that go beyond self-report is underscored.

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