Showing papers by "Clinical Trial Service Unit published in 1999"

Underestimation of Risk Associations Due to Regression Dilution in Long-term Follow-up of Prospective Studies

Abstract: In prospective studies, disease rates during follow-up are typically analyzed with respect to the values of factors measured during an initial baseline survey. However, because of "regression dilution," this generally tends to underestimate the real associations of disease rates with the "usual" levels of such risk factors during some particular exposure period. The "regression dilution ratio" describes the ratio of the steepness of the uncorrected association to that of the real association. To assess the relevance of the usual value of a risk factor during particular exposure periods (e.g., first, second, and third decades) to disease risks, regression dilution ratios can be derived by relating baseline measurements of the risk factor to replicate measurements from a reasonably representative sample of study participants after an interval equivalent to about the midpoint of each exposure period (e.g., at 5, 15, and 25 years, respectively). This report illustrates the impact of this time interval on the magnitude of the regression dilution ratios for blood pressure and blood cholesterol. The analyses were based on biennial remeasurements over 30 years for participants in the Framingham Study (Framingham, Massachusetts) and a 26-year resurvey for a sample of men in the Whitehall Study (London, England). They show that uncorrected associations of disease risk with baseline measurements underestimate the strength of the real associations with usual levels of these risk factors during the first decade of exposure by about one-third, the second decade by about one-half, and the third decade by about two-thirds. Hence, to correct appropriately for regression dilution, replicate measurements of such risk factors may be required at varying intervals after baseline for at least a sample of participants.

Risk factors for coronary heart disease and acute-phase proteins. A population-based study.

Abstract: AIMS: Circulating levels of C-reactive protein and serum amyloid A protein increase markedly, and albumin levels fall, during the acute-phase response to tissue injury, infection and inflammation. Some acute-phase proteins have been associated with increased risks of coronary heart disease in long-term prospective studies. The aim of the present study was to determine whether circulating concentrations of C-reactive protein, albumin and serum amyloid A protein are correlated with one another, standard vascular risk factors, markers of persistent infection, or indicators of socio-economic status. METHODS AND RESULTS: We report a cross-sectional study of 704 individuals without a history of coronary heart disease from five general practices in Bedfordshire, U.K. Plasma levels of C-reactive protein and serum amyloid A protein were strongly associated with each other (2 P<0.00001) and inversely related to levels of serum albumin (2 P<0.00001). There were highly significant associations of plasma C-reactive protein concentrations with cigarette smoking and obesity (2 P<0.00001 for each). Serum albumin levels were strongly associated with blood pressure (2 P<0.0001) and plasma lipids (2 P<0.001), and concentrations of serum amyloid A protein were strongly correlated with obesity (2 P<0.0001). CONCLUSION: Previously reported long-term prospective studies have found an increased risk of coronary heart disease of about 50% in people with raised baseline levels of plasma C-reactive protein or low albumin. The strong cross-sectional associations we have found between levels of these proteins with each other and with concentrations of serum amyloid A protein suggest that some underlying process related to inflammation is likely to be of relevance to the causation of disease. Further studies are needed to determine if the strong associations of plasma levels of C-reactive protein with cigarette smoking and obesity indicate that this particular protein can mediate some of the effects of those risk factors on coronary heart disease.

Helicobacter pylori infection and gastric cancer: systematic review of the epidemiological studies

Abstract: Background : The published epidemiological studies of chronic Helicobacter pylori infection and gastric cancer yield conflicting results, so there is uncertainty as to whether any material association exists and, if so, how strong it is Aim : To review these studies quantitatively Methods : A systematic review of sero-epidemiological studies published before 1998 of H pylori and gastric cancer, as identified by computer-assisted literature searches of relevant journals, reference lists and discussions with authors All relevant studies identified were included, subdivided by study design The following was abstracted from published reports: adjusted odds ratio (or, in prospective studies, the risk ratio) and confidence interval, study design, type of controls, mean age, mean duration of follow-up, assay methods, location of study, and degree of adjustment for confounders Results : The 34 retrospective studies included in total 3300 gastric cancers, but their controls were of uncertain validity The 10 ‘nested’ case–control comparisons in prospective studies included in total only 800 gastric cancers, and combined analysis of them yielded a risk ratio of 25 (95% CI: 19–34; 2P < 000001) for gastric cancer in people seropositive for H pylori antibodies Conclusions : The prospective studies suggest that gastric cancer is 2 or 3 times as common in those chronically infected by H pylori, but to help investigate causality, further observational studies are still needed, as are large-scale randomized trials of whether antibacterial regimens reduce the eventual incidence of gastric cancer

Coronary heart disease and iron status: meta-analyses of prospective studies.

Abstract: Background —Studies of iron status and coronary heart disease (CHD) have yielded conflicting results. In a systematic review (“meta-analysis”), we quantitatively assessed epidemiological associations reported in prospective studies. Methods and Results —Studies were identified by computer-assisted searches of the published literature, scanning of relevant reference lists, hand searching of relevant journals, and discussions with relevant authors. The following was abstracted: size and type of cohort, mean age, mean duration of follow-up, assay methods, degree of adjustment for confounders, and relationship of CHD risk to the baseline assay results. Twelve studies were identified, involving a total of 7800 CHD cases, with several reporting on >1 marker of iron status. For serum ferritin, with 570 CHD cases in 5 studies, comparison of individuals with baseline values ≥200 versus <200 μg/L yielded a combined risk ratio of 1.0 (95% CI, 0.8 to 1.3). For transferrin saturation, with 6194 CHD cases in 5 studies, comparison of individuals in the top third with those in the bottom third of the baseline measurements yielded a combined risk ratio of 0.9 (95% CI, 0.7 to 1.1). Comparisons of individuals in top and bottom thirds of baseline measurements also yielded nonsignificant risk ratios in combined analyses of studies involving total iron-binding capacity (combined risk ratio, 1.0; 95% CI, 0.7 to 1.5), serum iron (0.8; 95% CI, 0.7 to 1.0), and total dietary iron (0.8; 95% CI, 0.7 to 1.1). Conclusions —Published prospective studies do not provide good evidence to support the existence of strong epidemiological associations between iron status and CHD.

Tobacco--the growing epidemic.

Abstract: The largest study ever undertaken to examine the health effects of tobacco finds that there are already a million deaths a year from smoking in China, and it predicts large increases in mortality over the next few decades. This pattern is likely to be repeated in other developing countries.

Helicobacter pylori infection and early onset myocardial infarction: case-control and sibling pairs study

Abstract: Objectives: To examine the association between coronary heart disease and chronic Helicobacter pylori infection. Design: Case-control study of myocardial infarction at young ages and study of sibling pairs with one member affected and the other not. Setting: United Kingdom Participants: 1122 survivors of suspected acute myocardial infarction at ages 30-49 (mean age 44 years) and 1122 age and sex matched controls with no history of coronary heart disease; 510 age and sex matched pairs of siblings (mean age 59 years) in which one sibling had survived myocardial infarction and one had no history of coronary heart disease. Main outcome measures: Serological evidence of chronic infection with H pylori. Results: 472 (42%) of the 1122 cases with early onset myocardial infarction were seropositive for H pylori antibodies compared with 272 (24%) of the 1122 age and sex matched controls, giving an odds ratio of 2.28 (99% confidence interval 1.80 to 2.90). This odds ratio fell to 1.87 (1.42 to 2.47; P Conclusion: In the context of results from other relevant studies, these two studies suggest a moderate association between coronary heart disease and H pylori seropositivity that cannot be fully accounted for by other risk factors. But even if this association is causal and largely reversible by eradication of chronic infection, very large randomised trials would be needed to show this. Key messages Most previous studies of associations between chronic H pylori infection and coronary heart disease have been too small or prone to bias This case-control study found myocardial infarction was twice as common in people infected with H pylori as in those not infected Among sibling pairs, myocardial infarction was about a third more common in seropositive people than those who were seronegative These results support a weak association between H pylori infection and coronary heart disease

Chronic infection with Helicobacter pylori, Chlamydia pneumoniae, or cytomegalovirus: population based study of coronary heart disease

Abstract: OBJECTIVE—To study possible associations between coronary heart disease and serological evidence of persistent infection with Helicobacter pylori, Chlamydia pneumoniae, or cytomegalovirus. DESIGN—Population based, case-control study, nested within a randomised trial. SETTING—Five general practices in Bedfordshire, UK. INDIVIDUALS—288 patients with incident or prevalent coronary heart disease and 704 age and sex matched controls. RESULTS—High concentrations of serum IgG antibodies to H pylori were present in 54% of cases v 46% of controls, with corresponding results for C pneumoniae seropositivity (33% v 33%), and cytomegalovirus seropositivity (40% v 31%). After adjustments for age, sex, smoking, indicators of socioeconomic status, and standard risk factors, the odds ratios (95% confidence intervals) for coronary heart disease of seropositivity to these agents were: 1.28 (0.93 to 1.75) for H pylori, 0.95 (0.66 to 1.36) for C pneumoniae, and 1.40 (0.96 to 2.05) for cytomegalovirus. CONCLUSIONS—There is no good evidence of strong associations between coronary heart disease and serological markers of persistent infection with H pylori, C pneumoniae, or cytomegalovirus. To determine the existence of moderate associations between these agents and disease, however, larger scale studies will be needed that can keep residual confounders to a minimum. Keywords: ischaemic heart disease; Helicobacter pylori; Chlamydia pneumoniae; cytomegalovirus

Treatment‐related deaths during induction and first remission of acute myeloid leukaemia in children treated on the Tenth Medical Research Council Acute Myeloid Leukaemia Trial (MRC AML10)

Abstract: Between 1988 and 1995, 341 children with acute myeloid leukaemia (AML) were treated on the Medical Research Council Acute Myeloid Leukaemia Trial (MRC AML10). The 5-year overall survival was 57%, much improved on previous trials. However, there were 47 deaths (13.8%), 11 of which were associated with bone marrow transplantation (BMT). The treatment-related mortality was significant at 13.8%, but decreased in the latter half of the trial from 17.8% in 1998–91 to 9.6% in 1992–95 (P = 0.03%). The main causes of death were infection (65.9%), haemorrhage (19.1%) and cardiac failure (19.1%). Fungal infection was a significant problem, causing 23% of all infective deaths. Haemorrhage occurred early in treatment, in children with initial white cell counts >100 × 109/l (P = 0.001), and was more common in those with M4 and M5 morphology. Cardiac failure only occurred from the third course of chemotherapy onwards, with 78% (7/9) in conjunction with sepsis as a terminal event. Some deaths could be prevented by identifying those most at risk, and with prompt recognition and aggressive management of complications of treatment. Future options include the prophylactic use of antifungal agents, and the use of cardioprotectants or alternatives to conventional anthracyclines to decrease cardiac toxicity.

Severe adverse impact on sexual functioning and fertility of bone marrow transplantation, either allogeneic or autologous, compared with consolidation chemotherapy alone: analysis of the MRC AML 10 trial.

Abstract: BACKGROUND. Data relating to the impact of bone marrow transplantation (BMT) on sexual functioning are equivocal; some studies have shown no major impact whereas others demonstrate a significant adverse effect on sexual health in patients treated with BMT. Further clarification is required to facilitate treatment choices and follow-up management of patients.METHODS. A cross-sectional study of sexual health and infertility was conducted in 479 patients with acute myeloid leukemia (AML) in first complete remission (CR) who were entered into the UK MRC AML 10 trial comparing allogeneic BMT (Allo-BMT), autologous BMT (A-BMT), and intensive consolidation chemotherapy (CCT). Assessment was made by patient questionnaire via the treating centers for completion and returned directly to the coordinating center.RESULTS. Both Allo-BMT and A-BMT were observed to have severe, highly significant adverse effects on the patients' sexual health. Significantly more BMT patients than CCT patients reported a decrease in interest in sex (48% vs. 24%), sexual activity (53% vs. 35%), pleasure from sex (36% vs. 18%), and ability to have sex (38% vs. 18%) (P < 0.001 in each case). Hormonal disorders and infertility also were more common in BMT patients than in CCT patients. These differences were more apparent in women and remained after adjustment for age.CONCLUSIONS. These results indicate a need to consider quality of life parameters when reviewing treatment options and to instigate effective proactive management strategies for dealing with sexual health problems in leukemia survivors.

Outcome for children with relapsed acute myeloid leukaemia following initial therapy in the Medical Research Council (MRC) AML 10 trial. MRC Childhood Leukaemia Working Party.

Abstract: Between May 1988 and March 1995, 359 children with acute myeloid leukaemia (AML) were treated in the MRC AML 10 trial. Three risk groups were identified based on cytogenetics and response to treatment. One hundred and twenty-five children relapsed--103 in the bone marrow only, 12 in the bone marrow combined with other sites, and six had isolated extramedullary relapses (site was not known in four cases). Eighty-seven children received further combination chemotherapy, one all-trans retinoic acid for acute promyelocytic leukaemia, and one a matched unrelated donor allograft in relapse, and 61 achieved a second remission. One patient with no details on reinduction therapy also achieved second remission. Treatment in second remission varied--44 children received a BMT (22 autografts, 12 matched unrelated donor allografts, 10 family donor allografts), and 17 were treated with chemotherapy alone. The overall survival rate for all children (treated and untreated) was 24% at 3 years, with a disease-free survival of 44% for those achieving a second remission. Length of first remission was the most important factor affecting response rates--children with a first remission of less than 1 year fared poorly (second remission rate 36%, 3 year survival 11%), whereas those with longer first remissions had a higher response rate (second remission rate 75%, 3 year survival 49%, P < 0.0001).

No excess risk of cervical carcinoma among women seropositive for both HPV16 and HPV6/11

Abstract: Human papillomavirus (HPV) types 16 and 18 are the major risk factors for cervical carcinoma, whereas HPV types 6 and 11 cause benign genital lesions. We wanted to study the joint effect of simultaneous infections with the oncogenic and non-oncogenic HPV types on risk of subsequent development of cervical carcinoma. A cohort of 530,000 women who had donated blood samples to Nordic serum banks between 1973 and 1994 was followed up by linkage to national cancer registries. We identified 182 prospective cases with invasive cervical carcinoma and selected 538 matched controls at random. HPV 6, 11, 16, 18 and 33 seropositivity was used as a marker for the different HPV infections, and seropositivity for Chlamydia trachomatis and cotinine were used as markers for risk-taking sexual behavior and smoking respectively. The adjusted odds ratio (OR) of cervical squamous-cell carcinoma (SCC) was 2.2 for HPV6/11 among HPV16 seronegatives and 5.5 for HPV16 among HPV6/11 seronegatives. Assuming multiplicative joint effect, the expected OR for seropositivity to both HPV6/11 and HPV16 would have been 12, but the observed OR was 1.0. The antagonistic interaction was statistically significant (p = 0.001) and present also under deterministic considerations of possible misclassification bias. Antagonistic interactions were also detected for combinations of HPV16 and HPV18 and of HPV16 and HPV33. The results are in line with the concept that HPV-specific immunity protects against SCC and support primary prevention of SCC by vaccination against the HPVs.

Postcodes as useful markers of social class: population based study in 26 000 British households.

Abstract: # Postcodes as useful markers of social class: population based study in 26 000 British households {#article-title-2} Markers of poverty or of low social class are associated with many diseases and potential causes of disease, but medical studies often fail to record sufficient information on socioeconomic status.1 Postcodes of individuals are, however, often available in Britain, and commercial software exists that estimates household income from the postcode alone. We assessed how informative postcode income estimates are, either about reported household income or about other characteristics related to social class in a large, population based survey of British residents. The family resources survey involves personal interviews with members of private households in England, Scotland, and Wales selected by stratified clustered probability sample.2 During 1995-6, 26 445 (70%) of 37 712 eligible households gave answers to questions on socioeconomic characteristics. Reported weekly household income was taken as the sum of all sources of pretaxation income (excluding housing benefit) reported by household members. During 1985 to 1993 members of 11 million households, or about half of all households in Britain, provided information to a marketing company about annual income and gave a complete address that included a full postcode—that is, 6 or 7 characters. This information was used to produce commercial software that estimates household incomes from postcodes. After adjustments for regional variation and for inflation in reported income levels, the pretaxation incomes of at least six households were used to calculate a weighted average income for that postcode. When there were fewer than six responses, the income information was combined with the data for respondents with neighbouring postcodes until a reliable estimate could be made. Parts of this database are updated annually. We compared household income estimates obtained by FIND (a …

Patterns of care and survival for adolescents and young adults with acute leukaemia – a population-based study

Abstract: We report a population-based study of patterns of care and survival for people with acute leukaemia diagnosed at age 15–29 years during 1984–94 in regions of England and Wales covered by specialist leukaemia registries. There were 879 patients: 417 with acute lymphoblastic leukaemia (ALL) and 462 with acute myeloid leukaemia (AML). For ALL, actuarial survival rates were 43% at 5 years after diagnosis and 37% at 10 years. Survival improved significantly between 1984–88 and 1989–94 for those aged 15–19 at diagnosis. Patients entered in national clinical trials and those not entered had similar survival rates. Survival rates were similar at teaching and non-teaching hospitals and at hospitals treating different numbers of study patients per year. For AML, survival rates were 42% at 5 years after diagnosis and 39% at 10 years. Survival improved significantly between 1984–88 and 1989–94. Patients entered in the Medical Research Council AML10 trial had a higher survival rate than those who were in the earlier AML9 trial. Survival did not vary with category of hospital. We conclude that survival has improved for adolescents and young adults with acute leukaemia but that there is at present no evidence that centralized treatment results in a survival benefit for patients in this age group. © 1999 Cancer Research Campaign

Risk from tobacco and potentials for health gain

Abstract: Les preuves des effets nefastes de la consommation de tabac sur la sante se sont accumulees au cours des 200 dernieres annees, mais ont ete largement ignorees avant l'annee 1950, moment ou cinq etudes cas-controle ont associe le tabagisme au developpement du cancer du poumon. L'idee qu'il pourrait provoquer la maladie a ete accueillie avec scepticisme, et il a fallu pres de dix ans avant qu'elle ne soit generalement acceptee. Depuis lors, des preuves complementaires ont ete fournies par des etudes de cohorte et de plus des carcinogenes connus ont ete identifies dans les goudrons du tabac. Fumer la cigarette est actuellement associe de maniere positive avec quelques quarante causes de deces et negativement avec huit ou neuf. Un petit nombre de ces associations sont dues a des facteurs confondants, mais leur grande majorite traduit un effet de causalite. Dans certains cas, le fait de fumer la cigarette augmente de dix fois le risque de deces et dans l'ensemble double le risque annuel de deces pour tous les âges combines dans les deux sexes. La fumee de tabac environnementale a egalement un effet limite sur la sante des non-fumeurs, en particulier dans la petite enfance et dans l'enfance, mais aussi un certain degre, plus tard dans la vie. En 1990, dans les pays industrialises, environ un quart de tous les deces chez les hommes et un dixieme chez les femmes ont ete attribues au tabagisme, ce qui correspond a un total de 1,8 million de morts par an. L'on estime que d'ici 20 a 30 ans, le total augmentera jusqu'a 10 millions par annee dont 7 millions dans les pays en developpement, si les habitudes de fumer restent inchangees.

The Seascale cluster: a probable explanation.

Abstract: Seldom, if ever, can so few cases of disease have caused so much work and so much public concern for such a long time as the seven cases of leukaemia that occurred in young people under 25 years of age who lived in Seascale during the period 1955Ð1983. The expected number cannot be calculated precisely, but the excess under 10 years of age was about tenfold (five against 0.5 expected) and there can be no doubt that this ÔSeascale clusterÕ, as it has come to be called, constitutes a most unusual happening. The cluster was discovered by journalists from Yorkshire Television in 1983 in the course of enquiries into the mortality from cancer near Sellafield and was the subject of a television programme (Urquhart et al, 1984). It led to the appointment of a review committee under Sir Douglas Black, which advised the following year that there was sufficient evidence of an unusual incidence of disease to deserve intensive investigation of its cause (Black, 1984). Many studies have consequently been undertaken over the last 15 years, most of which have included non-HodgkinÕs lymphoma (NHL) with lymphoblastic leukaemia as, at young ages, there is no clear biological difference between them. The answer that the Black Committee sought has, however, proved elusive. Now with the most recent report by Dickinson and Parker in this issue (pp. 144Ð151) it may be thought that the answer has already been found. The occurrence of a cluster of cancers that are among those most easily produced by ionizing radiation in a village 3 km from Sellafield, the principal nuclear reprocessing plant in the UK, led many people to suspect that it was a direct effect of environmental pollution with radioactive waste and this was the first explanation considered by the Black Committee and the Committee on Medical Aspects of Radiation in the Environment (COMARE) that was set up by the Department of Health to oversee the recommended research and to review its findings. The idea was, however, quickly shown to be untenable (Black, 1984). For knowledge of the discharges from the plant showed that the doses that people were likely to have received were far too small to have caused such a large excess of cases, the maximum estimate of their likely effect being a 15% chance of producing one case (COMARE, 1986). This conclusion was later fortified by measurements of Pu and 137Cs in the bodies of exposed people, which showed that the models that had been used to estimate the doses people received had, for the most part, overestimated them (Popplewell et al, 1988; Stather et al, 1988). With the further information available 10 years later, COMARE (1996) concluded that the doses Seascale residents received that were attributable to discharges from Sellafield were less than 10% of their total dose and about 200 times too small to account for the observed excess of leukaemia and NHL. Alternative explanations consequently had to be considered and one was suggested by Gardner et al (1990) as a result of two studies. One was thought to show that an excess risk of leukaemia was seen only in children who were born in Seascale and not in those who went to school there but were born elsewhere (Gardner et al, 1987a, 1987b) and the other that the risk of the disease in West Cumbria was associated with the fathersÕ employment at Sellafield before the children were conceived (Gardner et al, 1990). The excess risk with the fatherÕs employment was not great (a relative risk of 1.97 based on nine cases), but the risk was greatest with the highest cumulative dose that the father had received (relative risk for 100 mSv or more 6.24, 95% confidence limits 1.51Ð25.76) and a significant doseÐresponse relationship was observed with the dose estimated to have been received in the 6 months immediately prior to the childÕs conception, when, for much of the time, the more radio-sensitive spermatids, relevant to the childÕs conception, would have been exposed. Gardner et alÕs (1990) idea was never attractive to radiobiologists who knew that no such effect had been observed in the children of the survivors of the Hiroshima and Nagasaki atomic explosions and that animal experiments did not support the idea that chronic low dose exposure would be much more hazardous than moderate doses given acutely and it was soon dispelled by the results of human studies elsewhere over the next few years. The evidence has been reviewed by Doll et al (1994), Little et al (1995) and COMARE (1996) and the conclusion reached that the hypothesis that irradiation of the testis caused any detectable risk of leukaemia in subsequent offspring could not be sustained. It did not accord with what was known of radiation genetics or of the hereditability of childhood leukaemia. It was not supported by the relationship observed between menÕs exposure to ionizing radiation and the risk of leukaemia in their offspring in the survivors of the atomic bomb explosions in Japan or in nuclear workers in Ontario, in Scotland, or in Cumbria other than in Seascale. It made no contribution to another cluster in young persons in Egremont, 7 km north of Sellafield (Wakeford and Parker, 1996) and could not account for the excess recorded near Dounreay in Scotland nor near two nuclear sites in the south of England, nor even for the whole of the cluster observed in Seascale, which as Kinlen (1993) showed was not limited to children born there. In these circumstances, it seemed that the association that was observed by Gardner et al (1990) between paternal irradiation and leukaemia in young people born and resident in the West Cumbrian Health District was most readily explained by chance, a conclusion that has subsequently been supported by the results of two large surveys of the risk of cancer in the offspring of nuclear workers, neither of which has provided any evidence for such an association outside the original confines of the Seascale cluster (Draper et al, 1997; Roman et al, 1999). What then can be the explanation for the occurrence of the Seascale cluster itself? To some statisticians, cognisant of the many clusters that, like the one in Seascale, had been defined post hoc

Is Helicobacter pylori a factor in coronary atherosclerosis

Abstract: A number of epidemiological studies have suggested associations between Helicobacter pylori seropositivity and coronary heart disease (2). High concentrations of immunoglobulin G antibody to H. pylori are fairly reliable indicators of chronic gastric infection, but the presence of antibodies in serum does not necessarily indicate persistent exposure of the coronary arteries to any type of insult. Although a number of pathological studies have reported the presence of Chlamydia pneumoniae DNA, antigens, or elementary bodies in diseased arterial specimens (3), there is little direct evidence available on the possible presence of H. pylori in the bloodstream or in vascular tissue. Hence, we investigated the presence of the H. pylori genome in buffy coat samples and in diseased arterial segments. We used a PCR that involved nested primers specific for the 16S rRNA gene of H. pylori, optimized to detect as little as 0.01 pg of genomic DNA (or about a dozen organisms) (6). DNA had been extracted from the buffy coat samples of 77 healthy individuals for a genetic study of myocardial infarction; 52 of these individuals were known to be strongly seropositive for immunoglobulin G antibodies to H. pylori, and 25 were chosen as seronegative controls. Samples of carotid atheroma were taken from another 39 individuals at carotid endarterectomy. DNA was extracted from the tissue by using a commercial kit (Puregene; Flowgen Ltd.) and analyzed by operators unaware of the tissue source. PCR products of samples appearing positive on gel electrophoresis were probed by Southern hybridization and autoradiographed for 1 week. Only 1 of the 77 buffy coat samples tested positive, and it belonged to a seropositive individual. Only 1 of the 39 atheromatous specimens collected at carotid surgery tested positive. A number of standard precautions were taken in the present study to protect against spurious results due to contamination, including the use of dedicated laboratory space, reagents, and instruments for pre- and post-PCR work and the testing of positive controls and negative controls in parallel with the test samples. Despite these precautions, the possibility of contamination in the two samples that tested positive for H. pylori DNA cannot be definitely excluded, nor can we exclude the possibility that a low-copy-number infection was actually present but undetected by our highly sensitive assay. Still, the present study adds to the sparse data that exists on H. pylori DNA in the bloodstream and in vascular tissue, being the first reported detection of H. pylori markers in human vascular tissue. It, however, does not support the likelihood of a high prevalence of the organism in buffy coat samples or in carotid atheroma. The only available report of H. pylori bacteremia involved positive blood cultures in a patient with gastric perforation due to malignancy (7), but in vitro studies suggest that any organisms penetrating beyond the gastric mucosa should be killed rapidly by complement proteins (5). Whereas a large number of studies have reported on the presence of markers of C. pneumoniae and cytomegalovirus in vascular lesions (2), there is only one previously reported study of H. pylori and atheroma (1). That study did not detect H. pylori DNA in any of the atherosclerotic plaques of 50 patients with abdominal aortic aneurysms, although about one-half of these samples tested positive for C. pneumoniae DNA (1). If H. pylori is relevant to the causation of vascular disease, it remains unclear how its effects are mediated. This suggests the need for further studies of coronary atheroma and comparisons of concentrations in plasma of vascular risk factors in seropositive and in seronegative individuals (4), as well as before and after H. pylori eradication treatment.

Use of hierarchical models for meta-analysis: experience in the metabolic ward studies of diet and blood cholesterol.

Abstract: Overviews that combine single effect estimates from published studies generally use a summary statistic approach where the effect of interest is first estimated within each study and then averaged across studies in an appropriately weighted manner. Combining multiple regression coefficients from publications is more problematic, particularly when there are differences in study design and inconsistent reporting of effect sizes and standard errors. This paper describes the use of a hierarchical model in such circumstances. Its use is illustrated in a meta-analysis of the metabolic ward studies that have investigated the effect of changes in intake of various dietary lipids on blood cholesterol. These studies all reported average blood cholesterol for groups of individuals who were studied on one or more diets. Thirty-one studies had randomized cross-over designs, 12 had matched parallel group designs, 12 had non-randomized Latin square designs and 16 had other uncontrolled designs. The hierarchical model allowed the different types of comparison (within-group between-diet, between matched group) that were made in the various studies to each contribute to the overall estimates in an appropriately weighted manner by distinguishing between-study variation, within-study between-matched-group variation and within-group between-diet variation. The hierarchical models do not require consistent specification of effect sizes and standard errors and hence have particular utility in combining results from published studies where the relationships between a dependent variable and two or more predictors have been investigated using heterogeneous methods of analysis.

Helicobacter pylori and gastric cancer: time for mega-trials?

Abstract: The first report of an association between chronic infection Helicobacter pylori, a spiral bacterium of the stomach, and gas cancer appeared in 1991 and in 1994 the International Agenc Research of Cancer declared H. pylori a human ‘carcinogen (IARC Working Group, 1994). Five years after that rep however, the causal role of H. pylori in gastric cancer remain controversial, with risk estimates ranging from ninefold (We and Forman, 1996) to no important association at all (Cresp Citarda, 1996). Recent quantitative reviews, by contrast, sug that H. pylori infection is likely to be only a moderate risk fact for gastric cancer (Danesh, 1999 a, 1999b). Reliable epidemiological evidence on H. pylori and gastric cancer is still relatively sparse. Although the number of c reported in prospective studies has increased by threefold 1994, there are now a total of only about 800 cases in ten pub prospective studies. A synthesis of these studies indicates th H. pylori is two or three times more common in people with gas cancer than in others (Figure 1). Doubts persist, however, abo extent to which inadequate adjustment for possible confoun factors, such as smoking and markers of poverty, and the pre tial publication of studies with more extreme results might have to exaggerated estimates. The biological plausibility of a ca association is suggested by strong correlations reported betwe H. pylori infection and putatively precancerous gastric lesions (suc atrophic gastritis and intestinal metaplasia) (Kuipers et al, 1 Sakaki et al, 1995) and by the production of lesions that rese human gastric cancer in Mongolian gerbils following long-te experimental infection (Watanabe et al, 1998). Even if a two threefold relative risk were established, however, it would explain the sharp variations in gastric cancer mortality betw populations (e.g. 20-fold higher in certain parts of China than in USA) (Peto, 1990) or between past and present (e.g. the fiv decrease in Scotland between 1950 and 1990) (Swerdlow 1998). Moreover, although H. pylori infects men and women abo equally and is strongly associated with duodenal ulceration, ga cancer is twice as common in men and may be inversely asso with duodenal ulceration (Howson et al, 1986; Hansson e 1996). Clearly, if H. pylori is a cause of gastric cancer, there m be some other major cause(s) of the disease. To assess the role of the infection in gastric cancer m precisely would require larger studies than hitherto, especial

Risk factors for coronary heart disease and persistent infection with Chlamydia pneumoniae or cytomegalovirus: a population-based study.

Abstract: BACKGROUND A large number of epidemiological and pathological studies have reported on associations between coronary heart disease and persistent infection with Chlamydia pneumoniae or cytomegalovirus, but relatively few have reported on possible relations between these infections and vascular risk factors. OBJECTIVE To determine whether serum concentrations of immunoglobulin G antibodies to C. pneumoniae or cytomegalovirus are correlated to standard vascular risk factors, markers of inflammation and indicators of socioeconomic status. METHODS We performed a cross-sectional sero-epidemiological study nested within a randomized trial involving five general practices in Bedfordshire, UK. We made measurements of a number of standard vascular risk factors, serum markers of systemic inflammation and other relevant characteristics in 704 individuals. RESULTS There were significant associations between C. pneumoniae immunoglobulin G levels and male sex and cigarette smoking (2P < 0.01 for each) and between cytomegalovirus immunoglobulin G levels and age (2P < 0.001). Other factors were not significantly associated with serum antibodies to either persistent infection. CONCLUSIONS Serological evidence of persistent infection with C. pneumoniae or cytomegalovirus in this population was not strongly associated with most standard vascular risk factors and other characteristics. The main implication is that such risk factors are not likely to be important confounders or mediators of the reported associations between coronary heart disease and these agents.

Postcodes as useful markers of income in 26,000 British households.

Abstract: We previously reported a validation study in 26 000 British residents, showing that postcodes were good indicators of a wide range of household characteristics related to socioeconomic status, including occupation, education, home ownership and access to various consumer goods. That report, however, was too brief to include details of the correlations between postcode estimates and reported household income in potentially relevant subgroups, and therefore it did not describe the data by the sex or age of the head of household, by the geographical region of residence, or by diVerent income levels. As such details might be relevant to epidemiologists and statisticians who use postcode estimates in population based studies, this report provides supplementary data.

Antiplatelet Therapy in Acute Cerebral Ischaemia

Abstract: To the Editor: The review by Bednar and Gross1 of antiplatelet therapy in acute cerebral ischemia mistakenly suggested that “only 1 study, the Multicentre Acute Stroke Trial–Italy (MAST-I), entered patients within 6 hours of the ictus.” The International Stroke Trial (IST) and the Chinese Acute Stroke Trial (CAST) randomized a total of 5629 patients within the first 6 hours,2 3 finding good evidence of benefit.2 3 4 Thus, antiplatelet therapy has already been evaluated in the acute phase of cerebral ischemia, and indeed, the number of patients randomized in aspirin trials within 6 hours is approximately the same as those randomized in all the trials of thrombolytic therapy for acute ischemic stroke. …