Evaluating health information technology's clinical effects.

In 2009 the federal government appropriated $34 billion in stimulus-related funding to promote the "meaningful use" of health information technology among Medicare and Medicaid providers and hospitals. One of the key elements of this technology is the adoption of computerized physician order entry (CPOE) systems for inpatient drug prescribing. The potential for CPOE to improve prescribing patterns and prevent adverse events is large, and as yet, unrealized. Amidst enthusiasm for the benefits of CPOE, providers and policymakers are becoming aware that CPOE could introduce new errors into the system and cannot simply be assumed to "work." This Issue Brief reports on the experience of one hospital system that used its CPOE to reduce the incidence of a serious drug interaction. This rigorous test of a specific CPOE intervention shows that an electronic alert system can be effective in changing prescribing, but may also have unintended consequences for patient safety.

Cancer incidence in The Health Improvement Network.

BACKGROUND: The utility of electronic medical record databases for clinical research relies on the validity and completeness of the recorded medical diagnoses. This study assessed whether the recorded incidence of cancer among patients in The Health Improvement Network (THIN) database is comparable to that expected in the UK based on national cancer registry data. METHODS: We examined incidence rates of any cancer other than non-melanoma skin cancer and the specific cancers colorectal, lung, pancreas, and lymphoma from 1992 to 2007. Indirect standardization was used to calculate standardized incidence ratios (SIR) using age- and sex-specific rates from the UK cancer registry for England and Wales for the corresponding years. RESULTS: Recording of the incidence of all cancers combined in THIN was very close to the expected rates from 2001 to 2007, that is, SIR within 10% of unity. Recording of the solid cancers was less than the expected based on cancer registry data, but with SIRs > 0.80 in 2007 for each cancer. Recording of lymphoma was close to the expected rate for the entire follow-up period. Time and experience with Vision software emerged as important factors in reported incidence rates for all cancers. CONCLUSIONS: For all cancers combined and for lymphoma the observed rates in THIN are very close to those reported in cancer registry data for the years 2001-2007. However, for solid cancers the observed rates in THIN are below those reported in cancer registry data. This may reflect the use of non-specific codes to record solid cancers.

Validity of The Health Improvement Network (THIN) for epidemiologic studies of hepatitis C virus infection.

PURPOSE: Before using computerized databases to study hepatitis C virus (HCV) epidemiology, the validity of the diagnosis must be assessed. We determined the accuracy of HCV diagnostic codes within The Health Improvement Network (THIN), an electronic database containing medical record data from general medical practices in the United Kingdom. METHODS: Patients with initial diagnostic codes for HCV infection and nonspecific viral hepatitis between 2000 and 2007 in the THIN database were identified. Questionnaires were mailed to general practitioners caring for a random sample of 150 of these patients (75 with an HCV code; 75 with a nonspecific viral hepatitis code) to collect information on HCV and other hepatitis diagnoses. We determined the positive predictive value of the database's HCV diagnostic codes and its ability to identify the date of a new HCV diagnosis. RESULTS: Usable surveys were returned for 146 (97%) patients. Among 74 patients with an HCV code and questionnaire data, HCV was confirmed in 64 (positive predictive value, 86%; 95%CI, 77-93%). In 40 (63%), the first recorded diagnosis in THIN was within 30 days of the date reported in the questionnaire (median difference, 11 days; interquartile range, 0-362 days). Among 72 patients with a nonspecific viral hepatitis code, 16 (22%) had HCV, but manual review of the database's electronic records correctly identified 12/16 (75%). CONCLUSIONS: In THIN, the HCV-specific diagnostic codes are highly predictive of HCV infection. After manual review, few patients with a nonspecific viral hepatitis code were misclassified as having HCV infection.

Pairwise combinations of estrogen metabolism genotypes in postmenopausal breast cancer etiology.

Estrogen exposures have been associated with breast cancer risk, and genes involved in estrogen metabolism have been reported to mediate that risk. Our goal was to better understand whether combinations of candidate estrogen metabolism genotypes are associated with breast cancer etiology. A population-based case-control study in three counties of the Philadelphia Metropolitan area was undertaken. We evaluated seven main effects and 21 first-order interactions in African Americans and European Americans for genotypes at COMT, CYP1A1, CYP1A2, CYP1B1, CYP3A4, SULT1A1, and SULT1E1 in 878 breast cancer cases and 1,409 matched random digit-dialed controls. In European Americans, we observed main effect associations of genotypes containing any CYP1A1*2C (odds ratio, 1.71; 95% confidence interval, 1.09-2.67) and breast cancer. No significant main effects were observed in African Americans. Three significant first-order interactions were observed. In European Americans, interactions between SULT1A1*2 and CYP1A1*2C genotypes (P(interaction) < 0.001) and between SULT1E1 and CYP1A2*1F genotypes were observed (P(interaction) = 0.006). In African Americans, an interaction between SULT1A1*2 and CYP1B1*4 was observed (P(interaction) = 0.041). We applied the false-positive report probability approach, which suggested that these associations were noteworthy; however, we cannot rule out the possibility that chance led to these associations. Pending future confirmation of these results, our data suggest that breast cancer etiology in both European American and African American postmenopausal women may involve the interaction of a gene responsible for the generation of catecholestrogens with a gene involved in estrogen and catecholestrogen sulfation.

Absence of cross-reactivity between sulfonamide antibiotics and sulfonamide nonantibiotics.

BACKGROUND: The safety of sulfonamide nonantibiotics is unclear in patients with prior allergic reactions to sulfonamide antibiotics. METHODS: We conducted a retrospective cohort study using the General Practice Research Database in the United Kingdom, examining the risk of allergic reactions within 30 days after the receipt of a sulfonamide nonantibiotic. Patients with evidence of prior hypersensitivity after the receipt of a sulfonamide antibiotic were compared with those without such evidence. Similar analyses were also performed with the use of penicillins instead of sulfonamides, to determine whether any risk was specific to sulfonamide cross-reactivity. RESULTS: Of 969 patients with an allergic reaction after a sulfonamide antibiotic, 96 (9.9 percent) had an allergic reaction after subsequently receiving a sulfonamide nonantibiotic. Of 19,257 who had no allergic reaction after a sulfonamide antibiotic, 315 (1.6 percent) had an allergic reaction after receiving a sulfonamide nonantibiotic (adjusted odds ratio, 2.8; 95 percent confidence interval, 2.1 to 3.7). However, the risk of allergic reactions was even greater after the receipt of a penicillin among patients with a prior hypersensitivity reaction to a sulfonamide antibiotic, as compared with patients with no such history (adjusted odds ratio, 3.9; 95 percent confidence interval, 3.5 to 4.3). Furthermore, among those with a prior hypersensitivity reaction after the receipt of a sulfonamide antibiotic, the risk of an allergic reaction after the subsequent receipt of a sulfonamide nonantibiotic was lower than the risk of an allergic reaction after the subsequent receipt of a penicillin (adjusted odds ratio, 0.7; 95 percent confidence interval, 0.5 to 0.9). Finally, the risk of an allergic reaction after the receipt of a sulfonamide nonantibiotic was lower among patients with a history of hypersensitivity to sulfonamide antibiotics than among patients with a history of hypersensitivity to penicillins (adjusted odds ratio, 0.6; 95 percent confidence interval, 0.5 to 0.8). CONCLUSIONS: There is an association between hypersensitivity after the receipt of sulfonamide antibiotics and a subsequent allergic reaction after the receipt of a sulfonamide nonantibiotic, but this association appears to be due to a predisposition to allergic reactions rather than to cross-reactivity with sulfonamide-based drugs.

Weight gain in the first week of life and overweight in adulthood: a cohort study of European American subjects fed infant formula.

BACKGROUND: Successful prevention of obesity and related cardiovascular risk factors requires a clear understanding of its determinants over the life course. Rapid infancy weight gain is associated with childhood obesity, whereas low infancy weight is associated with coronary heart disease. Our aim was to identify during which periods in infancy weight gain is associated with adult obesity. METHODS AND RESULTS: A cohort of European American formula-fed subjects, measured on 7 occasions during infancy as part of several infant formula studies, were contacted at age 20 to 32 years, when they reported usual adult weight and height. A life-course plot was used to identify critical periods of weight gain associated with adulthood overweight (body mass index > or =25 kg/m2). These associations were tested with logistic regressions. Data were available for 653 subjects (72% of eligible subjects). Approximately 32% of them were overweight adults. The period between birth and age 8 days was identified as potentially critical. After adjustment for important confounding factors, weight gain during the first week of life was associated with adulthood overweight status (OR for each 100-g increase 1.28, 95% CI 1.08 to 1.52), as was weight gain during the first 112 days of life (OR 1.04, 95% CI 1.01 to 1.08). Similar results were obtained after standardization with z scores from a reference population. CONCLUSIONS: In formula-fed infants, weight gain during the first week of life may be a critical determinant for the development of obesity several decades later. These results contribute to the understanding of chronic disease programming and suggest new approaches to obesity prevention.

Children with lower respiratory tract infections and serum 25-hydroxyvitamin D3 levels: A case-control study.

BACKGROUND: Pneumonia is the leading cause of death in children under age of 5 years worldwide. The role of vitamin D in respiratory infections including pneumonia is unclear; therefore, we aimed to determine if children with lower respiratory tract infections had low serum 25-hydroxyvitamin D3 . METHODS: We performed a case-control study of children ages 3-60 months from the Guatemala City metropolitan area, hospitalized with community-acquired pneumonia between September and December 2012. Controls were selected from the well-baby/care immunization clinics serving the population from which cases emerged. We analyzed serum 25-hydroxyvitamin D3 levels and conducted parental interviews to assess subject age, sex, race, feeding type, vitamin D supplementation, frequency of sun exposure, and maternal education. Height and weight were ascertained from medical records. Complete information was available for 70 (83%) of 84 eligible cases and 68 (60%) of 113 eligible controls. RESULTS: The median (IQR) serum 25-hydroxyvitamin D3 concentration for cases was 23.2 ng/ml (14.4-29.9) compared to 27.5 ng/ml (21.4-32.3) in controls (P = 0.006). Multiple regression analysis using an a priori cut-point for vitamin D of <20 ng/ml showed that children with lower respiratory tract infections were more likely to have low 25-hydroxyvitamin D3 levels than controls (adjusted odds ratio 2.4, 95% confidence interval 1.1-5.2, P = 0.02). CONCLUSIONS: Children with lower respiratory tract infections in Guatemala had low 25-hydroxyvitamin D3 levels. Pediatr Pulmonol. 2016;51:1080-1087. © 2016 Wiley Periodicals, Inc.

Statin Therapy and Risk of Acute Memory Impairment.

IMPORTANCE: Reports on the association between statins and memory impairment are inconsistent. OBJECTIVE: To assess whether statin users show acute decline in memory compared with nonusers and with users of nonstatin lipid-lowering drugs (LLDs). DESIGN, SETTING, AND PARTICIPANTS: Using The Health Improvement Network database during January 13, 1987, through December 16, 2013, a retrospective cohort study compared 482,543 statin users with 2 control groups: 482,543 matched nonusers of any LLDs and all 26,484 users of nonstatin LLDs. A case-crossover study of 68,028 patients with incident acute memory loss evaluated exposure to statins during the period immediately before the outcome vs 3 earlier periods. Analysis was conducted from July 7, 2013, through January 15, 2015. RESULTS: When compared with matched nonusers of any LLDs (using odds ratio [95% CI]), a strong association was present between first exposure to statins and incident acute memory loss diagnosed within 30 days immediately following exposure (fully adjusted, 4.40; 3.01-6.41). This association was not reproduced in the comparison of statins vs nonstatin LLDs (fully adjusted, 1.03; 0.63-1.66) but was also present when comparing nonstatin LLDs with matched nonuser controls (adjusted, 3.60; 1.34-9.70). The case-crossover analysis showed little association. CONCLUSIONS AND RELEVANCE: Both statin and nonstatin LLDs were strongly associated with acute memory loss in the first 30 days following exposure in users compared with nonusers but not when compared with each other. Thus, either all LLDs cause acute memory loss regardless of drug class or the association is the result of detection bias rather than a causal association.

Participants and refusers in a telephone interview about hormone replacement therapy were equally likely to be taking it.

OBJECTIVE: To address a major concern in pharmacoepidemiology studies related to whether the characteristics of responders are different from those who refuse to participate. STUDY DESIGN AND SETTING: We compared utilization of postmenopausal hormone replacement therapy (HRT) in women who agreed to participate in a telephone interview on HRT utilization and in women who refused to participate in the telephone interview. Information on HRT utilization among responders and refusers was independently available to us from a claims database (the Healthcare Management Alternatives, HMA, in Philadelphia), showing drugs dispensed to these patients. RESULTS: Out of a random sample of 213 women selected from the claims database whom we contacted, 154 (72.3%) women agreed to participate and 59 (32.7%) women refused. Among the 154 women who agreed to participate, 79 (51.3%, 95% CI: 43.1-59.4%) were shown by the database to have been dispensed an HRT during the 15-month period January 1995 through March 1996. Among the 59 women who refused to participate, 30 (50.8%, 95% CI: 37.5-64.1%) were shown by the database to have been dispensed an HRT during the same period. CONCLUSION: Thus, we have evidence that use of HRT was almost identical in responders and nonresponders.

An interview strategy was critical for obtaining valid information on the use of hormone replacement therapy.

OBJECTIVE: We compared telephone reports of hormone replacement therapy (HRT) use to claims for drugs dispensed. STUDY DESIGN AND SETTING: The study subjects included 106 women who were dispensed HRT and 107 who were not dispensed HRT. RESULTS: Recall of drug use overall was relatively good (65/79=82.3%, 95% confidence interval [CI] 73.9-90.7). Agreement between recall of drug name and the claims for dispensed drugs was lower (61/79=77.2%, 95% CI 68.0-86.5). Of 65 women reporting use of HRT in response to the indication prompt, nine (13.8%) could not identify the drug name using the drug list prompt, but all 65 women identified a drug using the photo prompt. Recall of start date of drug use was poor (29.2% agreement on month/year; 45.8% agreement within 1 month), and recall of end date of drug use was poorer yet (7.7% agreement on month/year; 21.5% agreement within 1 month). CONCLUSION: Recall of drug use and drug names is far better than recall of dates of use. Recall can be enhanced with lists of drug names and color photos, but even with memory prompts, recall remains imperfect. If drug use is the primary exposure of interest in a study, considerable effort is needed to collect it correctly. If not, then perhaps drug histories should be omitted.

Detecting pregnancy use of non-hormonal category X medications in electronic medical records.

OBJECTIVES: To determine whether a rule-based algorithm applied to an outpatient electronic medical record (EMR) can identify patients who are pregnant and prescribed medications proved to cause birth defects. DESIGN: A descriptive study using the University of Pennsylvania Health System outpatient EMR to simulate a prospective algorithm to identify exposures during pregnancy to category X medications, soon enough to intervene and potentially prevent the exposure. A subsequent post-hoc algorithm was also tested, working backwards from pregnancy endpoints, to search for possible exposures that should have been detected. MEASUREMENTS: Category X medications prescribed to pregnant patients. RESULTS: The alert simulation identified 2201 pregnancies with 16,969 pregnancy months (excluding abortions and ectopic pregnancies). Of these, 30 appeared to have an order for a non-hormone category X medication during pregnancy. However, none of the 30 'exposed pregnancies' were confirmed as true exposures in medical records review. The post-hoc algorithm identified 5841 pregnancies with 64 exposed pregnancies in 52,569 risk months, only one of which was a confirmed case. CONCLUSIONS: Category X medications may indeed be used in pregnancy, although rarely. However, most patients identified by the algorithm as exposed in pregnancy were not truly exposed. Therefore, implementing an electronic warning without evaluation would have inconvenienced prescribers, possibly hurting some patients (leading to non-use of needed drugs), with no benefit. These data demonstrate that computerized physician order entry interventions should be selected and evaluated carefully even before their use, using alert simulations such as that performed here, rather than just taken off the shelf and accepted as credible without formal evaluation.

Unintended effects of a computerized physician order entry nearly hard-stop alert to prevent a drug interaction: a randomized controlled trial.

BACKGROUND: The effectiveness of computerized physician order entry (CPOE) systems has been modest, largely because clinicians frequently override electronic alerts. METHODS: To evaluate the effectiveness of a nearly "hard stop" CPOE prescribing alert intended to reduce concomitant orders for warfarin and trimethoprim-sulfamethoxazole, a randomized clinical trial was conducted at 2 academic medical centers in Philadelphia, Pennsylvania. A total of 1981 clinicians were assigned to either an intervention group receiving a nearly hard stop alert or a control group receiving the standard practice. The study duration was August 9, 2006, through February 13, 2007. RESULTS: The proportion of desired responses (ie, not reordering the alert-triggering drug within 10 minutes of firing) was 57.2% (111 of 194 hard stop alerts) in the intervention group and 13.5% (20 of 148) in the control group (adjusted odds ratio, 0.12; 95% confidence interval, 0.045-0.33). However, the study was terminated early because of 4 unintended consequences identified among patients in the intervention group: a delay of treatment with trimethoprim-sulfamethoxazole in 2 patients and a delay of treatment with warfarin in another 2 patients. CONCLUSIONS: An electronic hard stop alert as part of an inpatient CPOE system seemed to be extremely effective in changing prescribing. However, this intervention precipitated clinically important treatment delays in 4 patients who needed immediate drug therapy. These results illustrate the importance of formal evaluation and monitoring for unintended consequences of programmatic interventions intended to improve prescribing habits. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00870298.

Randomized clinical trial of a customized electronic alert requiring an affirmative response compared to a control group receiving a commercial passive CPOE alert: NSAID--warfarin co-prescribing as a test case.

BACKGROUND: Studies that have looked at the effectiveness of computerized decision support systems to prevent drug-drug interactions have reported modest results because of low response by the providers to the automated alerts. OBJECTIVE: To evaluate, within an inpatient computerized physician order entry (CPOE) system, the incremental effectiveness of an alert that required a response from the provider, intended as a stronger intervention to prevent concurrent orders of warfarin and non-steroidal anti-inflammatory drugs (NSAIDs). DESIGN: Randomized clinical trial of 1963 clinicians assigned to either an intervention group receiving a customized electronic alert requiring affirmative response or a control group receiving a commercially available passive alert as part of the CPOE. The study duration was 2 August 2006 to 15 December 2007. MEASUREMENTS: Alert adherence was compared between study groups. RESULTS: The proportion of desired ordering responses (ie, not reordering the alert-triggering drug after firing) was lower in the intervention group (114/464 (25%) customized alerts issued) than in the control group (154/560 (28%) passive alerts firing). The adjusted OR of inappropriate ordering was 1.22 (95% CI 0.69 to 2.16). CONCLUSION: A customized CPOE alert that required a provider response had no effect in reducing concomitant prescribing of NSAIDs and warfarin beyond that of the commercially available passive alert received by the control group. New CPOE alerts cannot be assumed to be effective in improving prescribing, and need evaluation.

Impact of raloxifene or tamoxifen use on endometrial cancer risk: a population-based case-control study.

PURPOSE: Raloxifene reduces breast cancer risk in women with osteoporosis, and both tamoxifen and raloxifene prevent breast cancer in high-risk women. However, in vitro, raloxifene does not share the pro-estrogenic effects of tamoxifen on the endometrium. Randomized trials of these agents have provided limited information about endometrial cancer risk in the general population. We sought to compare endometrial cancer risks associated with raloxifene, tamoxifen, and nonusers of a selective estrogen receptor modulator (SERM) in the general population and characterize the endometrial tumors occurring in these groups. METHODS: We performed a case-control study of white and African American women age 50 to 79 years in the Philadelphia area. Patients were diagnosed with endometrial cancer between July 1999 and June 2002. Controls were identified through random-digit dialing. RESULTS: We analyzed 547 cases and 1,410 controls. Among cases, 3.3% had taken raloxifene; 6.2% had taken tamoxifen. Among controls, 6.6% had taken raloxifene; 2.4% had taken tamoxifen. After adjustment for other risk factors, the odds of endometrial cancer among raloxifene users was 50% that of nonusers (odds ratio [OR] = 0.50; 95% CI, 0.29 to 0.85), whereas tamoxifen users had three times the odds of developing endometrial cancer compared with raloxifene users (OR = 3.0; 95% CI, 1.3 to 6.9). Endometrial tumors in raloxifene users had a more favorable histologic profile and were predominantly International Federation of Gynecology and Obstetrics stage I and low grade. CONCLUSION: Raloxifene users had significantly lower odds of endometrial cancer compared with both tamoxifen users and SERM nonusers, suggesting a role for raloxifene in endometrial cancer prevention and individualization of SERM therapy.

Validation studies of the health improvement network (THIN) database for pharmacoepidemiology research.

BACKGROUND: The Health Improvement Network (THIN) is a new medical records database that contains records from general practices some of which have or continue to participate in the General Practice Research Database (GPRD) and others that never participated in GPRD. We sought to replicate in THIN well-established associations from the medical literature and to compare results from the GPRD practices to the non-GPRD practices within THIN. METHODS: Using THIN data from 1986-2003, we conducted case-control studies of associations between diseases (e.g., hypertension and stroke) and between diseases and drugs (e.g., aspirin and colon cancer). Conditional logistic regression was used to calculate odds ratios adjusted for potential confounders. Differences between GPRD and non-GPRD practices were assessed by testing for a statistical interaction by practice type in each outcome-exposure association. RESULTS: We observed the expected positive associations (p < 0.05) of stroke with hypertension and diabetes mellitus; of myocardial infarction with hypertension, hypercholesterolemia, obesity, and smoking; and of peptic ulcer disease with aspirin, NSAIDs, and potassium. We observed the expected negative associations (p < 0.05) of colorectal cancer with aspirin, NSAIDs, and cox-2 inhibitors. The expected protective effect of aspirin use for myocardial infarction was not observed. In all cases, the results obtained from the GPRD practices were similar to the results obtained from the non-GPRD practices, only being statistically different for the associations of myocardial infarction with diabetes and aspirin use. CONCLUSIONS: THIN data that are collected outside of the GPRD appear as valid as the data collected as part of the GPRD.

A retrospective case-control study of the use of hormone-related supplements and association with breast cancer.

Hormone-related supplements (HRS), many of which contain phytoestrogens, are widely used to manage menopausal symptoms, yet their relationship with breast cancer risk has generally not been evaluated. We evaluated whether use of HRS was associated with breast cancer risk, using a population-based case-control study in 3 counties of the Philadelphia metropolitan area consisting of 949 breast cancer cases and 1,524 controls. Use of HRS varied significantly by race, with African American women being more likely than European American women to use any herbal preparation (19.2% vs. 14.7%, p=0.003) as well as specific preparations including black cohosh (5.4% vs. 2.0%, p=0.003), ginseng (12.5% vs. 7.9%, p<0.001) and red clover (4.7% vs. 0.6%, p<0.001). Use of black cohosh had a significant breast cancer protective effect (adjusted odds ratio 0.39, 95% CI: 0.22-0.70). This association was similar among women who reported use of either black cohosh or Remifemin (an herbal preparation derived from black cohosh; adjusted odds ratio 0.47, 95% CI: 0.27-0.82). The literature reports that black cohosh may be effective in treating menopausal symptoms, and has antiestrogenic, antiproliferative and antioxidant properties. Additional confirmatory studies are required to determine whether black cohosh could be used to prevent breast cancer.

Case-control study of postmenopausal hormone replacement therapy and endometrial cancer.

This study evaluated recent inconsistent findings that adding progestins to postmenopausal estrogen replacement therapy protects against endometrial cancer. Using a population-based case-control study, the authors compared 511 endometrial cancer cases aged 50-79 years in the Philadelphia, Pennsylvania, region during 1999-2002 with 1,412 random-digit-dialing controls regarding postmenopausal hormone replacement therapy (HRT) use. Telephone interviews were performed with memory aids mailed in advance. An increased risk of endometrial cancer was observed among postmenopausal women using only unopposed estrogen for 3 or more years, compared with women who never used HRT (adjusted odds ratio = 3.4, 95% confidence interval (CI): 1.4, 8.3). Using combination HRT (of any duration) was associated with a substantial reduction in risk (odds ratio = 0.8, 95% CI: 0.6, 1.1). Comparing women using only combined estrogen and progestin for 3 or more years with women using only unopposed estrogen for 3 or more years, the authors found that the adjusted odds ratio was 0.2 (95% CI: 0.1, 0.6). Long-term use of unopposed estrogen is associated with increased risk for endometrial cancer, whereas combined estrogen plus progestin hormone therapy is not. Thus, if HRT is to be used in women with an intact uterus, this study confirms the benefit of adding progestins to the regimen.

Estrogen sulfation genes, hormone replacement therapy, and endometrial cancer risk.

BACKGROUND: Unopposed estrogen replacement therapy is associated with increased risk of endometrial cancer. To investigate the mechanism of this association, we evaluated whether risk of endometrial cancer was associated with the genotypes involved in steroid hormone metabolism and the duration of exogenous hormone use. METHODS: A population-based case-control study in nine counties of the Philadelphia metropolitan area was undertaken with 502 case patients with endometrial cancer and 1326 age- and race-matched control subjects. Data regarding exogenous hormone use were obtained by interview, and genotypes of the genes COMT, CYP1A1, CYP1A2, CYP1B1, CYP3A4, PGR, SULT1A1, SULT1E1, and UGT1A1 were obtained by polymerase chain reaction techniques. Conditional logistic regression was used to examine the relationship among genotype, hormone use, and endometrial cancer risk. RESULTS: Associations were observed between the risk of endometrial cancer and genotypes of the following steroid hormone metabolism genes: CYP1A1*2C (adjusted odds ratio [OR] = 1.68, 95% confidence interval [CI] = 1.08 to 2.61); SULT1A1*3 (adjusted OR = 0.51, 95% CI = 0.29 to 0.92); and the G --> A variant in the promoter of SULT1E1 at position -64 (adjusted OR = 1.45, 95% CI = 1.06 to 1.99). We observed a statistically significant interaction between estrogen replacement therapy use and SULT1A1*2 genotype: the SULT1A1*2 allele and long-term use of estrogen replacement therapy were associated with statistically significantly higher risk of endometrial cancer (adjusted OR = 3.85, 95% CI = 1.48 to 10.00) than that of the SULT1A1*2 allele and no estrogen replacement therapy use. CONCLUSIONS: Among women with long-term use of estrogen replacement therapy or combined hormone replacement therapy, the risk of endometrial cancer may be associated with functionally relevant genotypes that regulate steroid hormone sulfation.