Lee et al. BMC Cancer 2011, 11:20 http://www.biomedcentral.com/1471-2407/11/20 For site-specific cancers, the cohort by Libby et al [16] also provides evidence that CRC may be prevented by metformin; a retrospective cohort study of UK databases showed this for colorectal and pancreatic cancers [18]; and hospital-based case-control studies suggest this is so for hepatocellular in Italy [19] and pancreatic cancers in the US [7,8]. No information is available about these possibilities with regard to non-Caucasian ethnicity, especially where both T2DM prevalence is increasing and cancer patterns changing towards those in advanced economies, as in the Asia Pacific region [20-22]. Yet, there is little known about site-specific cancer in relation to metformin usage pattern (i.e., duration and dosage). Because the gastroen- terological cancer cluster is the major cause of cancer in Taiwan [23], we used representative National Health Insurance (NHI) datasets for Taiwan to form a cohort to assess total and gastroenterological (esophagus, sto- mach, CRC, liver and pancreas) cancers incidences in relation to metformin usage among T2DM. Methods Data sources Taiwan launched a single-payer NHI Program in 1995. As of 2007, 98.4% of Taiwan’s 22.96 million population was enrolled in this program. The NHI Research Data- base (NHIRD) derived from this system, subject to a double scrambling protocol is provided for research pur- poses. Based on the registration files and original claims data for reimbursement in the NHIRD, specific data subsets are constructed [24]. Cohort formation The Longitudinal Health Insurance Database 2000 (LHID2000) contains all the original claims data of 800,000 beneficiaries, randomly sampled from the year 2000 Registry for Beneficiaries of the NHIRD [24]. There are no significant differences in the gender or age distributions or in the average insured payroll-related amounts between the patients in the LHID2000 and the original NHIRD. We have studied the LHID2000 with antecedent data from 1st January 1996, which allowed us to exclude people with prevalent DM during the per- iod to 31st December 1999. To obtain incident T2DM subjects, we formed a cohort of 480,984 participants who were 20 years or older and were DM and cancer free on 1st January 2000 and non-use of DM medication from 1996-1999. The research was approved by the Institutional Review Board of the NHRI. Measurements T2DM ascertainment, grouping and index date T2DM patients were defined as those who had at least two DM records (A181, pre-ICD before 2000, or ICD-250) Page 2 of 10 within one year during 2000-2007, followed up for at least six months, and had no insulin at any time except for brief usage during a hospital admission. We categorized all cohort subjects into four groups. The first was the T2DM patients who used metformin (n = 12,005) during 2000-2007 with at least two pre- scriptions. The second was the T2DM patients who did not use metformin (n = 4,597) but had oral DM medica- tions except metformin, defined in the same way as metformin users. The third was the T2DM patients who did not use any oral anti-hyperglycemic medication (n = 8,643). The last was those subjects without any diagnosis of DM or use of DM medications during 2000-2007 (n = 417,844). The index date for a randomly-selected non-DM, cor- responded to that of a metformin user, with the same gender-and-age (born in the same year and month). Those selected were required to have been followed for at least 6 months and cancer-free during the first year after their index date in the same way as their metfor- min user counterpart. To summarize, the index date was the date of first prescription of metformin (metfor- min users), that for the first prescription of any other oral medications (non-metformin users), that of first diagnosis of DM (DM without medication) or the assigned date for the non-DM group. Due to different index date assignments of those DM patients who did not have medication, we limited the consideration of any effect of metformin use to those who had oral anti- hyperglycemic medications. Metformin usage Mean metformin dose was the cumulative dosage of all metformin prescriptions to the event or censored date divided by the cumulative duration from the index date to the last metformin prescription before event or cen- sored date or the end of 2007. Mean metformin dosage was expressed in daily 500 mg units. We treated ‘dura- tion’ as a time-dependent variable in modeling to avoid immortal time bias [25]. Cancer event ascertainment and cancer incidence density To consider an exposure (metformin) and outcome (cancer) relationship, incident cancer (A08-A14/ ICD140-208) cases were only valid if they occurred at least one year after the index date until 31st December 2007. We only considered the first cancer in the second year or beyond and when cancer diagnosis was recorded a second time within any year. To be cancer free, there was no record of cancer at anytime after the index date. Otherwise, cancer status was regarded as uncertain and the subject deleted from the study. Cancers studied were those at 5 specific gastrointestinal sites were esophagus (150/A090), gastric (151/A091), CRC (153- 154/A093-A094), hepatic (155/A095) and pancreatic (157/A096).