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Thomas McKeown and RG Record were colleagues in Birmingham, England, from 1947 to 1977. During their first decade together, they laid the foundations of epidemiological research on malformations with a series of case-control studies of the commoner major defects. They found evidence of numerous trends of birth prevalence with variables such as season and year of birth, maternal age, birth rank, and socioeconomic status, suggesting that environmental factors played an important part in causation. The work that has led recently to the use of folate to reduce the risk of neural tube defects is among the lines of research that can be traced back to these case-control studies. McKeown and Record also initiated, in Birmingham, the first population-based register of malformations to be set up as an on-going activity. As well as paving the way for the international networks of registers that now exist, the Birmingham register has been used in a variety of cohort studies. This work has confirmed many of the case-control study findings and continues to yield new observations, including evidence that enteroviruses are involved in aetiology.

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STUDY OBJECTIVES: The aims were: (1) to compare the birth prevalence of malformations in different ethnic groups and (2) to explore the reasons for the ethnic variations found by examining birth prevalence in the offspring of matings between ethnic groups. DESIGN: Analysis of data from a register of malformations and register of births. SETTING: Birmingham, England. SUBJECTS: A total of 432,778 infants (including stillbirths) born in 1960-84. MAIN RESULTS: Significant differences (p < 0.01) between ethnic groups were exhibited by the birth prevalence of neural tube defects (NTD), cleft palate, cleft lip, oesophageal atresia/fistula, hypospadias, hip dislocation, clubfoot, polydactyly, and syndactyly. In the offspring of matings between parents of European and Caribbean origin, the birth prevalence of NTD, cleft lip, hypospadias, hip dislocation, polydactyly, and syndactyly seemed more likely to be influenced by the ethnicity of both parents than by that of the mother alone. The reverse was true for the birth prevalence of NTD in subjects with one parent of Irish origin and on of British. CONCLUSIONS: Genetic differences may be responsible for Europeans being at lower risk of polydactyly and at higher risk of NTD, cleft lip, hypospadias, hip dislocation, and syndactyly than Caribbeans. Variations in the intrauterine environment are more likely to account for NTD being more common in Irish than in British subjects.

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OBJECTIVES: To investigate the hypothesis that hydrocarbon exposure is a risk factor for chronic pancreatitis. METHODS: 102 cases of chronic pancreatitis and 204 age and sex matched referents were interviewed about their occupational histories, alcohol and cigarette consumption, and diet. Exposure to hydrocarbons was inferred from interview responses by four assessors who were blind to disease state, and these data were then summarised by a cumulative hydrocarbon exposure (CHE) score. RESULTS: After adjustment for alcohol, cigarettes, dietary antioxidants, and social class, odds ratios for low CHE scores were 1.20 (90% CI: 0.62-2.35) and 2.67 (90% CI: 1.22-5.87) for high scores. A test for trend with level of exposure among only those who had exposure scores > 0 gave p = 0.09. Analysis by type of hydrocarbon was limited to four exposures for each of which there were at least 20 exposed patients. The adjusted OR for paint solvents (any level) was 0.96 (90% CI: 0.48-1.93); for diesel exhaust fumes OR = 2.66 (90% CI: 1.05-6.73); for petrochemicals OR = 1.82 (90% CI: 0.80-4.11); and for chlorinated solvents OR = 1.49 (90% CI: 0.58-3.81). CONCLUSIONS: These results support the original hypothesis. Further studies are needed to confirm or refute the findings here and to clarify the types of hydrocarbon involved.

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A comparative study of the effects of combined oral contraceptives (OC) on coagulation and fibrinolytic variables using standardized laboratory technique and methodology has been performed in Dublin (Ireland), Salvador (Brazil), Santiago (Chile) and Singapore. Of 777 entrants to the study, 622 were randomly allocated to receive one of four different OC formulations. The remainder did not opt for OC. The progestogenic component was levonorgestrel (LNG) in three of the OC formulations and norethisterone acetate (NEA) in the fourth. Results for the three LNG user groups were pooled. The changes in haematological variables observed over 12 months in the LNG and NEA users were examined in relation to the changes seen in the women not on OC. Women in Salvador differed markedly from those in the other three centres, in showing no acceleration of the prothrombin time and no increase in either fibrin plate lysis or plasminogen following the use of OC. After adjusting the findings in OC users for those in non-users, significant differences in response between centres were also detected for activated partial thromboplastin time (accelerated only in Dublin and Santiago), factor VII activity (increased mainly in Salvador and Santiago) and fibrinogen (for which the most marked changes were an increase in Dublin and a decrease in Salvador). This variability between centres in the effects of OC on coagulation and fibrinolysis suggests that OC administration in different populations may not carry equal thrombotic risks.

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The completeness and accuracy of Hospital Activity Analysis (HAA) and Regional Cancer Registry (RCR) records were investigated in a series of 868 histologically reviewed cases in which primary ovarian neoplasms had been diagnosed according to one or more of seven data sources including HAA and RCR. All the women concerned were residents of Manchester and Salford who had presented in 1979-83 aged 15 years or more. The histological review confirmed the diagnosis of ovarian neoplasia in 829 of these women and excluded it in 39. Among the 829 confirmed cases, 333 were malignant or of borderline malignancy and therefore eligible for registration with the RCR, and 496 were benign. Only 611 (74%) of the 829 cases were listed as ovarian neoplasms or cysts in HAA records of hospital admissions from the study area during the study period, and the HAA diagnosis was incorrect in 40% of the 611 listed cases. Among the 333 borderline or malignant cases, only 241 (72%) appeared among the RCR's registrations of ovarian neoplasms for the study period and area. The RCR record of histological diagnosis was inaccurate in over 20% of these 241 registered cases, although most of the inaccuracies did not affect whether the neoplasm was classified as borderline or malignant. Five per cent of the cases listed as ovarian neoplasms in the HAA file and 15% of those listed as registrable ovarian neoplasms by the RCR should not have been so listed. The findings highlight the limitations of these routine health information systems, both as sources of cases for research and as National Health Service management tools.

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Published regional data show that the Standardized Mortality Ratio (SMR) for the northern half of England has recently increased from 113 to 115 per cent of the SMR for the south, and that the north is at least as disadvantaged in respect of morbidity and material deprivation and uses much less private medical care than the south. It is concluded that the north's share of National Health Service (NHS) resources should not be reduced, as it would be if recent proposals by the NHS Management Board were implemented; that a mortality index which gives different weights to deaths at different ages should possibly be used instead of the simple SMR to weight regional resource allocations for need; and that these allocations should also be weighted by some measure of the extent to which regional populations look to the NHS rather than to the private sector for hospital and specialist care.

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Relations between occupational history and the development of cancer of the lower urinary tract ("bladder cancer") were evaluated in Boston, Massachusetts, USA, Manchester, UK, and Nagoya, Japan. Population-based series of incident cases and controls were identified and interviewed in each area. The present analysis was limited to men and was based on 430 cases and 397 controls in Boston, 399 cases and 493 controls in Manchester, and 226 cases and 443 controls in Nagoya. In Boston, elevated risk of bladder cancer was associated with employment related to dyes (relative risk = 2 X 1; 90% confidence interval, 0 X 9-5 X 1), leather (1 X 7; 1 X 1-2 X 6), paint (1 X 5; 0 X 9-2 X 4), or organic chemicals (1 X 6; 1 X 1-2 X 5). In Manchester, elevated risk was associated with 0 X 9-3 X 6). No clear association was observed between occupation and risk in Nagoya. Elevations in risk related to occupation generally were stronger in men under 65 years of age compared to older men. Differences from place to place in associations between occupation and risk may be the result of differences in the exposures to hazardous agents that jobs with the same title involve.

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Knox's test for space-time interaction was applied to 922 cases of Hodgkin's disease which, according to the North Western Regional Cancer Registry, had presented in 1962-76 among the population of the region known before 1974 as the South East Lancashire Conurbation. In the series as a whole, there were statistically significant excesses of pairs of patients separated by time intervals of less than a year and distances of less than 1 km. Analysis by age and sex indicated that this clustering involved (a) a trio of young females and (b) pairs involving adults over 45 years old. No evidence was detected of any clustering by histological subtype or of any tendency for cases close in space to be separated by long time intervals of specific duration. These findings lend support to the idea that at least some cases of Hodgkin's disease may be induced by an infection or other environmental influence, but they do not suggest that such an infection has a long and specific incubation period.

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The effects of smoking cigarettes and other forms of tobacco on the development of cancer of the lower urinary tract (bladder cancer) were evaluated in Boston, Massachusetts, Manchester, United Kingdom and Nagoya, Japan. Population-based series of incident cases and controls were identified and interviewed in each area. The present analyses were based on 592 cases and 533 controls in Boston, 553 cases and 731 controls in Manchester, and 290 cases and 588 controls in Nagoya. Smokers of cigarettes had about twice the incidence of bladder cancer as nonsmokers. In men the strength of the association between cigarette smoking and bladder cancer was similar in the 3 study areas. The strength of the association varied somewhat from area to area among women. Bladder cancer risk increased with frequency of cigarette smoking and with deep inhaling. In Boston men who smoked 2 or more packs of cigarettes per day and inhaled deeply had nearly 7 times the risk of nonsmokers. Ex-smokers had a level of risk between that of current smokers and nonsmokers. However, there was no clear relationship between risk and age at which cigarette smoking began, time since discontinuation among ex-smokers and use of filters. Over-all, there was little difference in bladder cancer risk between men who had and who had not smoked pipes but pipe smoking did appear to be associated with risk among men who had never smoked cigarettes. Cigar smoking was unrelated to bladder cancer.

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Neonatal BCG vaccination has long been offered routinely to children born at St Mary's Hospital (SMH), Manchester, England, whereas the city's other obstetric hospitals have generally restricted this procedure to children of Asian origin and those with a family history of tuberculosis. Among children aged 0-14 years who had been born to Manchester residents in 1965-80, 65 presented with tuberculosis in 1975-80 whilst still resident in the city. The estimated incidence rate was less than half as high among all children born at SMH as among those not born there, largely because the rate for those born and vaccinated at SMH was less than one-quarter of that for those born elsewhere. Children with Bangladeshi, Indian, or Pakistani surnames also shared in the reduced risk associated with vaccination. These findings strongly support the effectiveness of neonatal BCG vaccination.

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Histologic characteristics of bladder cancer in Boston, USA, Manchester, UK, and Nagoya, Japan, were evaluated. In each of these areas broadly-based series of cases were assembled during a collaborative case-control study. The present analysis was based on 589 cases in Boston, 484 cases in Manchester, and 241 cases in Nagoya. A single pathologist reviewed a slide of the primary tumor without reference to identifying information or other data. The primary histologic type of nearly all tumors was transitional-cell, and there was little variation in the proportion of transitional-cell tumors among the study areas. Nor was there much variation in the distribution of histologic grade, the proportion of tumors showing submucosal invasion, or the proportion of tumors with a papillary surface. Age at diagnosis was strongly correlated with histologic grade. The proportion of grade III (most malignant) tumors was about twice as high among patients 80 years of age and over as among those aged less than 50. An apparent association between age and submucosal invasion was explained in large part by the relationships of histologic grade to submucosal invasion and to age. Other histologic features had only weak and inconsistent relations with age. None of the features evaluated showed consistent associations with history of cigarette-smoking or with sex.

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