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Helicobacter and Cancer Collaborative Group
Background--The magnitude of the association between Helicobacter pylori and incidence of gastric cancer is unclear. H pylon infection and the circulating antibody response can be lost with development of cancer; thus retrospective studies are subject to bias resulting from classification of cases as H pylori negative when they were infected in the past.
Aims--To combine data from all case control studies nested within prospective cohorts to assess more reliably the relative risk of gastric cancer associated with H pylori infection. To investigate variation in relative risk by age, sex, cancer type and subsite, and interval between blood sampling and cancer diagnosis.
Methods--Studies were eligible if blood samples for H pylori serology were collected before diagnosis of gastric cancer in cases. Identified published studies and two unpublished studies were included. Individual subject data were obtained for each. Matched odds ratios (ORs) and 95% confidence intervals (95% CI) were calculated for the association between H pylori and gastric cancer.
Results--Twelve studies with 1228 gastric cancer cases were considered. The association with H pylon was restricted to non-cardia cancers (OR 3.0; 95% CI 2.3-3.8) and was stronger when blood samples for Hpylori serology were collected 10+ years before cancer diagnosis (5.9; 3.4-10.3). H pylon infection was not associated with an altered overall risk of cardia cancer (1.0; 0.7-1.4).
Conclusions--These results suggest that 5.9 is the best estimate of the relative risk of non-cardia cancer associated with H pylori infection and that H pylori does not increase the risk of cardia cancer. They also support the idea that when H pylori status is assessed close to cancer diagnosis, the magnitude of the non-cardia association may be underestimated.
Keywords: gastric cancer; Helicobacter pylori; cardia cancer; pooled analysis
There is substantial evidence that infection with the gastric bacterium Helicobacter pylori plays a role in the development of gastric cancer. [1,2] The magnitude of the risk of gastric cancer associated with infection is however unclear and there have been suggestions that this risk varies with sex, [3,4] age, [3,5] and the histological subtype of the cancer.  There is also evidence that the excess risk is restricted to cancer occurring at sites other than the gastric cardia. [4,5,7-9]
Many studies have been conducted in an attempt to address these issues. Retrospective case control studies are however limited by the fact that H pylori infection is, by necessity, assessed after the development of cancer in the cases. H pylori does not colonise areas of cancer, intestinal metaplasia, or atrophy and there is evidence that with the development of advanced gastric disease the organism can be lost from the stomach.  With loss of infection, the level of circulating anti-H pylon antibodies will fall so that patients with gastric cancer may be H pylori seronegative even though they have been infected in the past (TU Kosunen, personal communication).  This will not occur to the same extent in controls and, in the presence of such differential misclassification, estimates of the association between H pylori and gastric cancer will be biased downwards making the results of retrospective studies difficult to interpret.
This problem can be overcome by conducting case control studies nested within prospective cohorts where blood samples used for H pylon serology are collected before the development of cancer. In 1991, three such studies reported odds ratios (ORs) for the association between H pylori infection and the subsequent development of gastric cancer that ranged from 2.8 to 6.0. [4,5,12] "A number of other nested case control studies have since been published [7,13-18] and these have given less consistent results. Two possible reasons for this inconsistency are differing proportions of cardia and non-cardia cancers, and variable intervals between sample collection and cancer diagnosis with short intervals potentially leading to differential exposure misclassification of cases as may occur in retrospective studies. Initial support for this latter hypothesis comes from a pooled analysis of the data from the first three nested case control studies which suggested that higher ORs were seen when blood samples were collecte d more than 10 years before the diagnosis of cancer. 
Although there have been three previous meta-analyses of published data examining the association between H pylori infection and gastric cancer, [20-22] these have combined both prospective and retrospective studies and/or have been unable to separate cardia and non-cardia cancers. We have therefore conducted a collaborative reanalysis using individual subject data obtained from published and two unpublished prospective studies. By pooling these data we have been able to evaluate the magnitude of this relationship more precisely than previously and assess the relative risk in relevant subgroups.
The analysis was restricted to case control studies investigating the association between H pylori infection and gastric adenocarcinoma where samples for H pylori serology had been collected prior to the diagnosis of gastric cancer in the cases. Eligible studies were identified through a Medline search (1985-1999) and through contact with investigators in the area. By the end of 1999, 11 reports had been published from nine studies. [4-6,12-18,23] Results have since been published from a study in China  and two further studies have been conducted in Iceland (H Tulinius, personal communication) and Finland (TU Kosunen, personal communication). The investigators from all 12 studies agreed to provide their data for the present analysis. Results from an additional prospective study in Japan  have also been published recently but individual subject data from this study were not available at the time of the present analyses.
For each subject in their study, the investigators provided the following information (or information to allow calculation of the required variables): case or control status, sex, H pylori infection status (diagnosed by serology) and, for cases, age at diagnosis, site and histological type of the tumour (when available), and length of time between collection of the blood sample for H pylori serology and diagnosis of cancer. For some studies, additional information was available concerning cases who had gastric surgery prior to the development of the cancer. Identifiers for the matched sets were also obtained in order to preserve the original matching in the analyses. The matching variables were sex, age, and date of sample collection.
In two studies the controls were not matched to the cases. For the second Finnish study, controls greatly outnumbered cases and individual matched case control sets were created by dividing subjects into groups based on their age when the blood samples were collected (within a …