Andrew J. Hall

Validation and validity of diagnoses in the General Practice Research Database: a systematic review

AIMS To investigate the range of methods used to validate diagnoses in the General Practice Research Database (GPRD), to summarize findings and to assess the quality of these validations. METHODS A systematic literature review was performed by searching PubMed and Embase for publications using GPRD data published between 1987 and April 2008. Additional publications were identified from conference proceedings, back issues of relevant journals, bibliographies of retrieved publications and relevant websites. Publications that reported attempts to validate disease diagnoses recorded in the GPRD were included. RESULTS We identified 212 publications, often validating more than one diagnosis. In total, 357 validations investigating 183 different diagnoses met our inclusion criteria. Of these, 303 (85%) utilized data from outside the GPRD to validate diagnoses. The remainder utilized only data recorded in the database. The median proportion of cases with a confirmed diagnosis was 89% (range 24–100%). Details of validation methods and results were often incomplete. CONCLUSIONS A number of methods have been used to assess validity. Overall, estimates of validity were high. However, the quality of reporting of the validations was often inadequate to permit a clear interpretation. Not all methods provided a quantitative estimate of validity and most methods considered only the positive predictive value of a set of diagnostic codes in a highly selected group of cases. We make recommendations for methodology and reporting to strengthen further the use of the GPRD in research.

Results of case-control study of leukaemia and lymphoma among young people near Sellafield nuclear plant in West Cumbria

OBJECTIVE--To examine whether the observed excess of childhood leukaemia and lymphoma near the Sellafield nuclear plant is associated with established risk factors or with factors related to the plant. DESIGN--A case-control study. SETTING--West Cumbria health district. SUBJECTS--52 Cases of leukaemia, 22 of non-Hodgkins lymphoma, and 23 of Hodgkins disease occurring in people born in the area and diagnosed there in 1950-85 under the age of 25 and 1001 controls matched for sex and date of birth taken from the same birth registers as the cases. MAIN OUTCOME MEASURES--Antenatal abdominal x ray examinations, viral infections, habit factors, proximity to and employment characteristics of parents at Sellafield. RESULTS--Expected associations with prenatal exposure to x rays were found, but little information was available on viral illnesses. Relative risks for leukaemia and non-Hodgkins lymphoma were higher in children born near Sellafield and in children of fathers employed at the plant, particularly those with high radiation dose recordings before their childs conception. For example, the relative risks compared with area controls were 0.17 (95% confidence interval 0.05 to 0.53) for being born further than 5 km from Sellafield 2.44 (1.04 to 5.71) for children of fathers employed at Sellafield at their conception, and 6.42 (1.57 to 26.3) for children of fathers receiving a total preconceptual ionising radiation dose of 100 mSv or more. Other factors, including exposure to x rays, maternal age, employment elsewhere, eating seafood, and playing on the beach did not explain these relationships. Focusing on Seascale, where the excess incidence has predominantly been reported, showed for the four out of five cases of leukaemia and one case of non-Hodgkins lymphoma whose fathers were employed at Sellafield and for whom dose information was obtained that the fathers of each case had higher radiation doses before their childs conception than all their matched control fathers; the father of the other Seascale case (non-Hodgkins lymphoma) was not employed at the plant. These results seem to explain statistically the geographical association. For Hodgkins disease neither geographical nor employment associations with Sellafield were found. CONCLUSIONS--The raised incidence of leukaemia, particularly, and non-Hodgkins lymphoma among children near Sellafield was associated with paternal employment and recorded external dose of whole body penetrating radiation during work at the plant before conception. The association can explain statistically the observed geographical excess. This result suggests an effect of ionising radiation on fathers that may be leukaemogenic in their offspring, though other, less likely, explanations are possible. There are important potential implications for radiobiology and for protection of radiation workers and their children.

Measles and atopy in Guinea-Bissau

BACKGROUND Epidemiological studies have led to speculation that infections in early childhood may prevent allergic sensitisation but evidence to support this hypothesis is lacking. We investigated whether measles infection protects against the development of atopy in children of Guinea-Bissau, West Africa. METHODS We conducted a historical cohort study in Bandim, a semi-rural district of Bissau, the capital of Guinea-Bissau. 395 young adults, first surveyed in 1978-80 aged 0-6 years, were followed up in 1994. Our analyses were restricted to 262 individuals still living in Bandim for whom a measles history, documented in childhood, was judged to be reliable. We defined atopy as skin-prick test positivity (> or = 3 mm weal) to one or more of seven allergens. FINDINGS 17 (12.8 percent) of 133 participants who had had measles infection were atopic compared with 33 (25.6 percent) of 129 of those who had been vaccinated and not had measles (odds ratio, adjusted for potential confounding variables 0.36 [95 percent CI 0.17-0.78], p=O.O1). Participants who had been breastfed for more than a year were less likely to have a positive skin test to housedust mite. After adjustment for breastfeeding and other variables, measles infection was associated with a large reduction in the risk of skin-prick test positivity to housedust mite (odds ratio for Dermatophagoides pteronyssinus 0.20 [0.05-0.81], p=0.02; D farinae 0.20 [0.06-0.71], p=0.01). INTERPRETATION Measles infection may prevent the development of atopy in African children.

What does epidemiology tell us about risk factors for herpes zoster

Reactivation of latent varicella zoster virus as herpes zoster is thought to result from waning of specific cell-mediated immunity, but little is known about its determinants in individuals with no underlying immunosuppression. We systematically reviewed studies of zoster epidemiology in adults and analysed data from a large morbidity study to identify factors that might be modulated to reduce the risk of zoster. Annual zoster incidence in population-based studies varied from 3.6-14.2/10(3) in the oldest individuals. Risk factors identified in analytical studies that could explain this variation included age, sex, ethnicity, genetic susceptibility, exogenous boosting of immunity from varicella contacts, underlying cell-mediated immune disorders, mechanical trauma, psychological stress, and immunotoxin exposure. Our review highlights the lack of information about risk factors for zoster. We suggest areas of research that could lead to interventions to limit the incidence of zoster. Such research might also help to identify risk factors for age-related immune decline.

Dietary aflatoxin exposure and impaired growth in young children from Benin and Togo: cross sectional study

Fetal and early childhood environment, including the nutritional status of the pregnant mother and the infant, are considered critical for growth and risk of disease in later life.1 Many people in developing countries are not only malnourished but also chronically exposed to high levels of toxic fungal metabolites (mycotoxins). One family of mycotoxins, the aflatoxins, are carcinogenic and immunotoxic and cause growth retardation in animals.2 Aflatoxins contaminate staple foods in West Africa, particularly maize and groundnuts, as a result of hot, humid storage conditions that promote fungal growth. High exposure to aflatoxins occurs throughout childhood in the region, 3 4 suggesting that growth and development could be critically affected. We assessed exposure to aflatoxins in relation to anthropometric measures in children in Benin and Togo. We studied 480 children (aged 9 months to 5 years) from 16 villages in four geographic zones (four in each zone): Sudan savannah, north Guinea savannah, south Guinea savannah, and coastal savannah. The Ministries for Health in Benin and Togo gave ethical …

Postweaning Exposure to Aflatoxin Results in Impaired Child Growth: A Longitudinal Study in Benin, West Africa

Aflatoxins are dietary contaminants that are hepatocarcinogenic and immunotoxic and cause growth retardation in animals, but there is little evidence concerning the latter two parameters in exposed human populations. Aflatoxin exposure of West African children is known to be high, so we conducted a longitudinal study over an 8-month period in Benin to assess the effects of exposure on growth. Two hundred children 16–37 months of age were recruited from four villages, two with high and two with low aflatoxin exposure (50 children per village). Serum aflatoxin–albumin (AF-alb) adducts, anthropometric parameters, information on food consumption, and various demographic data were measured at recruitment (February) and at two subsequent time points (June and October). Plasma levels of vitamin A and zinc were also measured. AF-alb adducts increased markedly between February and October in three of the four villages, with the largest increases in the villages with higher exposures. Children who were fully weaned at recruitment had higher AF-alb than did those still partially breast-fed (p < 0.0001); the major weaning food was a maize-based porridge. There was no association between AF-alb and micronutrient levels, suggesting that aflatoxin exposure was not accompanied by a general nutritional deficiency. There was, however, a strong negative correlation (p < 0.0001) between AF-alb and height increase over the 8-month follow-up after adjustment for age, sex, height at recruitment, socioeconomic status, village, and weaning status; the highest quartile of AF-alb was associated with a mean 1.7 cm reduction in growth over 8 months compared with the lowest quartile. This study emphasizes the association between aflatoxin and stunting, although the underlying mechanisms remain unclear. Aflatoxin exposure during the weaning period may be critical in terms of adverse health effects in West African children, and intervention measures to reduce exposure merit investigation.

Risk factors for multidrug resistant tuberculosis in Europe: a systematic review.

Background: The resurgence of tuberculosis (TB) in western countries has been attributed to the HIV epidemic, immigration, and drug resistance. Multidrug resistant tuberculosis (MDR-TB) is caused by the transmission of multidrug resistant Mycobacterium tuberculosis strains in new cases, or by the selection of single drug resistant strains induced by previous treatment. The aim of this report is to determine risk factors for MDR-TB in Europe. Methods: A systematic review was conducted of published reports of risk factors associated with MDR-TB in Europe. Meta-analysis, meta-regression, and sub-grouping were used to pool risk estimates of MDR-TB and to analyse associations with age, sex, immigrant status, HIV status, occurrence year, study design, and area of Europe. Results: Twenty nine papers were eligible for the review from 123 identified in the search. The pooled risk of MDR-TB was 10.23 times higher in previously treated than in never treated cases, with wide heterogeneity between studies. Study design and geographical area were associated with MDR-TB risk estimates in previously treated patients; the risk estimates were higher in cohort studies carried out in western Europe (RR 12.63; 95% CI 8.20 to 19.45) than in eastern Europe (RR 8.53; 95% CI 6.57 to 11.06). National estimates were possible for six countries. MDR-TB cases were more likely to be foreign born (odds ratio (OR) 2.46; 95% CI 1.86 to 3.24), younger than 65 years (OR 2.53; 95% CI 1.74 to 4.83), male (OR 1.38; 95% CI 1.16 to 1.65), and HIV positive (OR 3.52; 95% CI 2.48 to 5.01). Conclusions: Previous treatment was the strongest determinant of MDR-TB in Europe. Detailed study of the reasons for inadequate treatment could improve control strategies. The risk of MDR-TB in foreign born people needs to be re-evaluated, taking into account any previous treatment.

Risk of deep vein thrombosis and pulmonary embolism after acute infection in a community setting

BACKGROUND Acute infection increases the risk of arterial cardiovascular events, but effects on venous thromboembolic disease are less well established. Our aim was to investigate whether acute infections transiently increase the risk of venous thromboembolism. METHODS We used the self-controlled case-series method to study the risk of first deep vein thrombosis (DVT) (n=7278) and first pulmonary embolism (PE) (n=3755) after acute respiratory and urinary tract infections. Data were obtained from records from general practices who had registered patients with the UKs Health Improvement Network database between 1987 and 2004. FINDINGS The risks of DVT and PE were significantly raised, and were highest in the first two weeks, after urinary tract infection. The incidence ratio for DVT was 2.10 (95% CI 1.56-2.82), and that for PE 2.11 (1.38-3.23). The risk gradually fell over the subsequent months, returning to the baseline value after 1 year. The risk of DVT was also higher after respiratory tract infection, but possible diagnostic misclassification precluded a reliable estimate of the risk of PE after respiratory infection. INTERPRETATION Acute infections are associated with a transient increased risk of venous thromboembolic events in a community setting. Our results confirm that infection should be added to the list of precipitants for venous thromboembolism, and suggest a causal relation.

Contacts with varicella or with children and protection against herpes zoster in adults: a case-control study

BACKGROUND Whether exogenous exposure to varicella-zoster-virus protects individuals with latent varicella-zoster virus infection against herpes zoster by boosting immunity is not known. To test the hypothesis that contacts with children increase exposure to varicella-zoster virus and protect latently infected adults against zoster, we did a case-control study in south London, UK. METHODS From 22 general practices, we identified patients with recently diagnosed zoster, and control individuals with no history of zoster, matched to patients by age, sex, and practice. Participants were asked about contacts with people with varicella or zoster in the past 10 years, and social and occupational contacts with children as proxies for varicella contacts. Odds ratios were estimated with conditional logistic regression. FINDINGS Data from 244 patients and 485 controls were analysed. On multivariable analysis, protection associated with contacts with a few children in the household or via childcare seemed to be largely mediated by increased access to children outside the household. Social contacts with many children outside the household and occupational contacts with ill children were associated with graded protection against zoster, with less than a fifth the risk in the most heavily exposed groups compared with the least exposed. The strength of protection diminished after controlling for known varicella contacts; the latter remained significantly protective (odds ratio 0.29 [95% CI 0.10-0.84] for those with five contacts or more). INTERPRETATION Re-exposure to varicella-zoster virus via contact with children seems to protect latently infected individuals against zoster. Reduction of childhood varicella by vaccination might lead to increased incidence of adult zoster. Vaccination of the elderly (if effective) should be considered in countries with childhood varicella vaccination programmes.

Early BCG vaccination and reduction in atopy in Guinea-Bissau.

It has been proposed that certain viral and bacterial infections in early childhood may prevent allergic sensitization, by inducing Th1‐type immune responses. This has led to speculation that mycobacterial vaccines might, through their Th1‐stimulating properties, also protect against atopy.