Amy R. Marks

Variation of adenoma prevalence by age, sex, race, and colon location in a large population: implications for screening and quality programs.

BACKGROUND & AIMS Reliable community-based colorectal adenoma prevalence estimates are needed to inform colonoscopy quality standards and to estimate patient colorectal cancer risks; however, minimal data exist from populations with large numbers of diverse patients and examiners. METHODS We evaluated the prevalence of adenomas detected by sex, age, race/ethnicity, and colon location among 20,792 Kaiser Permanente Northern California members ≥50 years of age who received a screening colonoscopy examination (102 gastroenterologists, 2006-2008). RESULTS Prevalence of detected adenomas increased more rapidly with age in the proximal colon (adjusted odds ratio [OR], 2.39; 95% confidence interval [CI], 2.05-2.80; 70-74 vs 50-54 years) than in the distal colon (OR, 1.89; 95% CI, 1.63-2.19). Prevalence was higher among men vs women at all ages (OR, 1.77; 95% CI, 1.66-1.89), increasing in men from 25% to 39% at ≥70 years and in women from 15% at 50-54 years to 26% (P < .001). Proximal adenoma prevalence was higher among blacks than whites (OR, 1.26; 95% CI, 1.04-1.54), although total prevalence was similar, including persons <60 years old (OR, 1.17; 95% CI, 0.91-1.50). CONCLUSIONS Prevalence of detected adenomas increases substantially with age and is much higher in men; proximal adenomas are more common among blacks than whites, although the total prevalence and the prevalence for ages <60 years were similar by race. These demographic differences are such that current adenoma detection guidelines may not be valid, without adjustment, for comparing providers serving different populations. The variation in prevalence and location may also have implications for the effectiveness of screening methods in different demographic groups.

Fecal Immunochemical Test Program Performance Over 4 Rounds of Annual Screening: A Retrospective Cohort Study

Context The fecal immunochemical test is an effective way to screen for colorectal cancer, but we know more about how well it does the first time it is used and less about how well it does in later years with repeated testing. Contribution The researchers show that, after 4 years of repeated testing, patients continued to use the test and it continued to identify colorectal cancer. Caution This study did not measure whether identification of cancer changed outcomes. Implication The fecal immunochemical test is acceptable and effective for repeated testing. Colorectal cancer (CRC) is the second leading cause of cancer death in the United States (13), and screening with fecal occult blood tests (FOBTs) reduces CRC incidence and mortality (46). In randomized trials (711), annual or biennial guaiac-based FOBTs reduced CRC incidence by 17% to 20% and CRC mortality by 15% to 33%. Thus, the U.S. Preventive Services Task Force (4) and U.S. Multi-Society Task Force on Colorectal Cancer (12) recommend annual FOBT as an option for CRC screening for average-risk patients, defined as those aged 50 to 75 years with no history of CRC or adenoma, with no first-degree relatives with CRC, and who are not up to date with CRC screening according to other methods (that is, sigmoidoscopy within 5 years or colonoscopy within 10 years). Annual highly sensitive FOBTs are believed to be as effective as screening colonoscopy performed every 10 years if levels of adherence are high (13), although colonoscopy is recommended for those with a family history of CRC. Fecal blood tests are noninvasive and can be delivered by mail (14). In contrast to guaiac-based stool tests, fecal immunochemical test (FIT) screening can be done without dietary or medication restrictions, which allows it to achieve higher patient acceptance in organized CRC screening programs (15). This test also has higher detection rates for CRC and advanced adenomas than guaiac-based stool tests (1517). In a recent meta-analysis (18), the sensitivity of a single FIT application was 79% for CRC diagnosed within 2 years of testing; however, little is known about performance characteristics over several rounds of annual screening, particularly in community practice. The present study was conducted to evaluate FIT sensitivity for CRC and other performance characteristics over 4 rounds of annual testing in a U.S. community-based CRC screening program. Methods Study Population This retrospective longitudinal study was performed in a fixed cohort of Kaiser Permanente Northern California (KPNC) and Southern California (KPSC) health plan members. These integrated health care delivery organizations serve approximately 7 million persons in urban, suburban, and semirural regions throughout California. Kaiser Permanente health plan membership in California is diverse and similar in socioeconomic characteristics to the regions census demographics (1921). Study Oversight The study was approved by the institutional review boards of KPNC and KPSC, both of which waived the requirement for informed consent. The listed authors had sole responsibility for the study design, data collection, decision to submit the manuscript for publication, and drafting of the manuscript. This study was conducted within the National Cancer Institutefunded Population-based Research Optimizing Screening through Personalized Regimens (PROSPR) consortium, which conducts multisite, coordinated, transdisciplinary research to evaluate and improve cancer-screening processes. Organized CRC Screening Program The KPNC and KPSC initiated similar organized FIT screening programs between 2006 and 2008; the KPNC program has been described previously (14). Briefly, each year, the programs mail a FIT kit to eligible health plan members aged 50 to 75 years without a record of a colonoscopy within 10 years, sigmoidoscopy within 5 years, or fecal blood test within the prior year. The kit includes the FIT (OC FIT-CHEK; Polymedco), a standardized letter from the patients primary care provider, directions for completing and mailing the test, and a preprinted laboratory requisition order form. Outreach includes in-person, mail, secure e-mail, and telephone reminders as needed. The kits are returned by mail to regional laboratories and analyzed on or shortly after the return date using an OC-Sensor Diana automated system (Polymedco) with a cutoff level of 20 g of hemoglobin/g of buffer for a positive result. Patients with a positive FIT result are referred for follow-up colonoscopy. Study Eligibility Criteria and Participant Tracking The study cohort included CRC screening program participants aged 50 to 70 years on the date an initial kit was mailed to them in 2007 or 2008. Patients were excluded if they had been enrolled in the health plan for less than 1 year before the round 1 FIT mail date (to allow for the recording of prior out-of-system endoscopy procedures). They were also excluded if they were mailed a kit but subsequently had sigmoidoscopy or colonoscopy, were diagnosed with CRC, died, or terminated membership in the health plan before returning the initial FIT or within 1 year after their round 1 mail date if no FIT was returned. A total of 670841 health plan members was mailed the initial kit in 2007 or 2008 and met the study eligibility criteria; 323349 (48.2%) returned a FIT within 1 year after the mail date (Figure). The analytic cohort comprised these round 1 participants who were tracked from their baseline mail date (cohort entry) through up to 4 rounds of testing for mail dates; result dates; results (positive or negative); whether follow-up colonoscopy was performed within 1 year after a positive FIT result; and diagnoses of adenoma, adenoma with advanced histology, and CRC. Cohort members were followed for CRC through the follow-up screening rounds, even if they subsequently became ineligible for screening because of sigmoidoscopy or colonoscopy. Patients were censored at the time of CRC diagnosis, death, or termination of membership in the health plan if they did not rejoin. Figure. Study flow diagram.* The figure includes 1192 patients with CRC who were screened by FIT the year before diagnosis. Further, there were 118 additional patients with CRC diagnosed more than 1 y beyond the FIT screening date and 101 additional patients diagnosed with CRC who either crossed over to endoscopy in subsequent rounds or terminated health plan membership but then rejoined. CRC = colorectal cancer; FIT = fecal immunochemical test. * Shading indicates where patients were censored or became ineligible for subsequent FIT screening. Patients were eligible for the initial FIT mailing if they were aged 50 to 70 y and had 1 y of membership. See Methods section for exclusions. Number censored because of CRC and includes patients with CRC diagnosed within 1 y after their FIT result. Defining Annual Screening Episodes For each patient, the initial kit mail date in 2007 or 2008 was the anchor date for round 1 and for each subsequent round of testing. However, because subsequent mailing dates varied each round, mail dates within 3 months before to 12 months after each subsequent rounds anchor date were counted as having been distributed during that specific round. For example, a patient with a round 1 mail date of 15 March 2007 had subsequent anchor dates of 15 March for rounds 2 through 4 (2008, 2009, and 2010, respectively). If their next FIT was mailed on 15 January 2008, the test was considered to be distributed in round 2 because the second mail date occurred within 3 months of the round 2 anchor date. The FIT results recorded within 1 year of each mail date, and colonoscopies performed and adenomas or CRC diagnosed within 1 year after FIT results, were considered part of a single screening episode for the round when the FIT was distributed. Among round 1 participants, FITs with no recorded mail dates returned in rounds 2 through 4 were assumed to be distributed through in-reach methods (such as a clinic visit) and were counted in the follow-up round returned. In general, the first result per patient was counted in any given round. The earliest possible date of cohort entry (first mail date) was 1 January 2007, and the last possible date of follow-up was 31 December 2013 (12 months after the last possible FIT result date of 31 December 2012). Data Sources The FIT-related dates and results were obtained from the CRC screening program and laboratory databases for each region, respectively. Endoscopy procedures were identified using Current Procedural Terminology codes (22). Adenoma diagnoses used Systematized Nomenclature of Medicine codes. Prior validation studies have confirmed high levels of sensitivity and accuracy for capture of colonoscopy examinations and assignment of adenoma status (23). Colorectal adenocarcinomas and disease stage were obtained from the KPNC and KPSC cancer registries, which report to the SEER (Surveillance, Epidemiology, and End Results) registry. Cancer databases capture more than 98% of cancer diagnoses within the KPNC and KPSC populations. Advanced-stage cancer was defined as stage III (regional disease with spread to regional lymph nodes only) or stage IV (distant metastasis) according to the American Joint Committee on Cancer staging system; for patients who did not have such staging, advanced-stage cancer was defined as code 3 (disease in the regional lymph nodes), code 4 (regional disease with direct extension and spread to regional lymph nodes), or code 7 (distant metastasis) according to the SEER Program Coding and Staging Manual 2013 (24). Data Analysis The following performance characteristics were calculated for each round of screening and overall: 1) participation (percentage of eligible patients who were distributed and completed a FIT within 1 year of their mailing date), 2) FIT positivity (percentage of participants who completed FITs and had positive results), 3) follow-up colonoscopy (per

Population-Representative Incidence of Drug-Induced Acute Liver Failure Based on an Analysis of an Integrated Health Care System

BACKGROUND & AIMS Medications are a major cause of acute liver failure (ALF) in the United States, but no population-based studies have evaluated the incidence of ALF from drug-induced liver injury. We aimed to determine the incidence and outcomes of drug-induced ALF in an integrated health care system that approximates a population-based cohort. METHODS We performed a retrospective cohort study using data from the Kaiser Permanente Northern California (KPNC) health care system between January 1, 2004, and December 31, 2010. We included all KPNC members age 18 years and older with 6 months or more of membership and hospitalization for potential ALF. The primary outcome was drug-induced ALF (defined as coagulopathy and hepatic encephalopathy without underlying chronic liver disease), determined by hepatologists who reviewed medical records of all KPNC members with inpatient diagnostic and laboratory criteria suggesting potential ALF. RESULTS Among 5,484,224 KPNC members between 2004 and 2010, 669 had inpatient diagnostic and laboratory criteria indicating potential ALF. After medical record review, 62 (9.3%) were categorized as having definite or possible ALF, and 32 (51.6%) had a drug-induced etiology (27 definite, 5 possible). Acetaminophen was implicated in 18 events (56.3%), dietary/herbal supplements in 6 events (18.8%), antimicrobials in 2 events (6.3%), and miscellaneous medications in 6 events (18.8%). One patient with acetaminophen-induced ALF died (5.6%; 0.06 events/1,000,000 person-years) compared with 3 patients with non-acetaminophen-induced ALF (21.4%; 0.18/1,000,000 person-years). Overall, 6 patients (18.8%) underwent liver transplantation, and 22 patients (68.8%) were discharged without transplantation. The incidence rates of any definite drug-induced ALF and acetaminophen-induced ALF were 1.61 events/1,000,000 person-years (95% confidence interval, 1.06-2.35) and 1.02 events/1,000,000 person-years (95% confidence interval, 0.59-1.63), respectively. CONCLUSIONS Drug-induced ALF is uncommon, but over-the-counter products and dietary/herbal supplements are its most common causes.

Association Between Time to Colonoscopy After a Positive Fecal Test Result and Risk of Colorectal Cancer and Cancer Stage at Diagnosis

Importance The fecal immunochemical test (FIT) is commonly used for colorectal cancer screening and positive test results require follow-up colonoscopy. However, follow-up intervals vary, which may result in neoplastic progression. Objective To evaluate time to colonoscopy after a positive FIT result and its association with risk of colorectal cancer and advanced-stage disease at diagnosis. Design, Setting, and Participants Retrospective cohort study (January 1, 2010-December 31, 2014) within Kaiser Permanente Northern and Southern California. Participants were 70 124 patients aged 50 through 70 years eligible for colorectal cancer screening with a positive FIT result who had a follow-up colonoscopy. Exposures Time (days) to colonoscopy after a positive FIT result. Main Outcomes and Measures Risk of any colorectal cancer and advanced-stage disease (defined as stage III and IV cancer). Odds ratios (ORs) and 95% CIs were adjusted for patient demographics and baseline risk factors. Results Of the 70 124 patients with positive FIT results (median age, 61 years [IQR, 55-67 years]; men, 52.7%), there were 2191 cases of any colorectal cancer and 601 cases of advanced-stage disease diagnosed. Compared with colonoscopy follow-up within 8 to 30 days (n = 27 176), there were no significant differences between follow-up at 2 months (n = 24 644), 3 months (n = 8666), 4 to 6 months (n = 5251), or 7 to 9 months (n = 1335) for risk of any colorectal cancer (cases per 1000 patients: 8-30 days, 30; 2 months, 28; 3 months, 31; 4-6 months, 31; and 7-9 months, 43) or advanced-stage disease (cases per 1000 patients: 8-30 days, 8; 2 months, 7; 3 months, 7; 4-6 months, 9; and 7-9 months, 13). Risks were significantly higher for examinations at 10 to 12 months (n = 748) for any colorectal cancer (OR, 1.48 [95% CI, 1.05-2.08]; 49 cases per 1000 patients) and advanced-stage disease (OR, 1.97 [95% CI, 1.14-3.42]; 19 cases per 1000 patients) and more than 12 months (n = 747) for any colorectal cancer (OR, 2.25 [95% CI, 1.89-2.68]; 76 cases per 1000 patients) and advanced-stage disease (OR, 3.22 [95% CI, 2.44-4.25]; 31 cases per 1000 patients). Conclusions and Relevance Among patients with a positive fecal immunochemical test result, compared with follow-up colonoscopy at 8 to 30 days, follow-up after 10 months was associated with a higher risk of colorectal cancer and more advanced-stage disease at the time of diagnosis. Further research is needed to assess whether this relationship is causal.

Oral Azole Antifungal Medications and Risk of Acute Liver Injury, Overall and by Chronic Liver Disease Status

BACKGROUND Reports on associations between azole antifungal medications and acute liver injury are inconsistent and have not been based on liver-related laboratory tests. We evaluated incidence rates of acute liver injury associated with oral azole antifungals. METHODS We conducted a cohort study among Kaiser Permanente Northern California members who initiated an oral azole antifungal in an outpatient setting during 2004-2010. We determined development of: (1) liver aminotransferases >200 U/L, (2) severe acute liver injury (coagulopathy with hyperbilirubinemia), and (3) acute liver failure. We calculated incidence rates of endpoints. Cox regression was used to determine whether chronic liver disease was a risk factor for outcomes. RESULTS Among 195,334 azole initiators (178,879 fluconazole; 14,296 ketoconazole; 1653 itraconazole; 478 voriconazole; 28 posaconazole), incidence rates (events/1000 person-years [95% confidence intervals (CIs)]) of liver aminotransferases >200 U/L were similarly low with fluconazole (13.0 [11.4-14.6]), ketoconazole (19.3 [13.8-26.3]), and itraconazole (24.5 [10.6-48.2]). Rates were higher with voriconazole (181.9 [112.6-278.0]) and posaconazole (191.1 [23.1-690.4]), but comparable. Severe acute liver injury was uncommon with fluconazole (2.0 [1.4-2.7]), ketoconazole (2.9 [1.1-6.3]), and itraconazole (0.0 [0.0-11.2]), but more frequent with voriconazole (16.7 [2.0-60.2]) and posaconazole (93.4 [2.4-520.6]). One patient developed acute liver failure due to ketoconazole. Pre-existing chronic liver disease increased risks of aminotransferases >200 U/L (hazard ratio 4.68 [95% CI, 3.68-5.94]) and severe acute liver injury (hazard ratio 5.62 [95% CI, 2.56-12.35]). CONCLUSIONS Rates of acute liver injury were similarly low for fluconazole, ketoconazole, and itraconazole. Events were more common among voriconazole and posaconazole users but were comparable. Pre-existing chronic liver disease increased risk of azole-induced liver injury.

Risk of Acute Liver Failure in Patients With Drug-Induced Liver Injury: Evaluation of Hy's Law and a New Prognostic Model.

BACKGROUND & AIMS Few studies have evaluated the ability of laboratory tests to predict risk of acute liver failure (ALF) among patients with drug-induced liver injury (DILI). We aimed to develop a highly sensitive model to identify DILI patients at increased risk of ALF. We compared its performance with that of Hys Law, which predicts severity of DILI based on levels of alanine aminotransferase or aspartate aminotransferase and total bilirubin, and validated the model in a separate sample. METHODS We conducted a retrospective cohort study of 15,353 Kaiser Permanente Northern California members diagnosed with DILI from 2004 through 2010, liver aminotransferase levels above the upper limit of normal, and no pre-existing liver disease. Thirty ALF events were confirmed by medical record review. Logistic regression was used to develop prognostic models for ALF based on laboratory results measured at DILI diagnosis. External validation was performed in a sample of 76 patients with DILI at the University of Pennsylvania. RESULTS Hys Law identified patients that developed ALF with a high level of specificity (0.92) and negative predictive value (0.99), but low level of sensitivity (0.68) and positive predictive value (0.02). The model we developed, comprising data on platelet count and total bilirubin level, identified patients with ALF with a C statistic of 0.87 (95% confidence interval [CI], 0.76-0.96) and enabled calculation of a risk score (Drug-Induced Liver Toxicity ALF Score). We found a cut-off score that identified patients at high risk patients for ALF with a sensitivity value of 0.91 (95% CI, 0.71-0.99) and a specificity value of 0.76 (95% CI, 0.75-0.77). This cut-off score identified patients at high risk for ALF with a high level of sensitivity (0.89; 95% CI, 0.52-1.00) in the validation analysis. CONCLUSIONS Hys Law identifies patients with DILI at high risk for ALF with low sensitivity but high specificity. We developed a model (the Drug-Induced Liver Toxicity ALF Score) based on platelet count and total bilirubin level that identifies patients at increased risk for ALF with high sensitivity.

Adjusting for Patient Demographics has Minimal Effects on Rates of Adenoma Detection in a Large, Community-Based Setting

BACKGROUND & AIMS Reliable estimates of adenoma detection rates (ADRs) are needed to inform colonoscopy quality standards, yet little is known about the contributions of patient demographics to variation in ADRs. We evaluated the effects of adjusting for patient age, race/ethnicity, and family history of colorectal cancer on variations in ADRs and the relative rank order of physicians. METHODS In a retrospective cohort study, we collected data from Kaiser Permanente Northern California members who were ≥ 50 years old who received colonoscopies from 2006 through 2008. We evaluated ADRs (before and after adjustment for age, sex, race/ethnicity, and family history of colorectal cancer) for 102 endoscopists who performed 108,662 total colonoscopies and 20,792 screening colonoscopies. Adenomas were identified from the pathology database, and cancers were detected by using the Kaiser Permanente Northern California cancer registry. RESULTS About two-thirds of examiners had unadjusted ADRs for screening exams that met gastroenterology society guidelines (>25% for men and >15% for women), although rates of detection varied widely (7.7%-61.5% for male patients and 1.7%-45.6% for female patients). Adjusting for case mix reduced the variation in detection rates (from 8-fold to 3-fold for male patients and from 27-fold to 5-fold for female patients), but the median change in physician order by detection rate was just 2 ranks, and few physicians changed quartiles of detection. For example, only 3 of 102 endoscopists moved into and 3 out of the lowest quartile of ADR. CONCLUSIONS In a community-based setting, most endoscopists met the ADR standards, although there was wide variation in ADRs, which was similar to that reported from academic and referral settings. Case-mix adjustment reduced variability but had only small effects on differences in ADRs between physicians, and only a small percentage of physicians changed quartiles of detection. Adjustments to ADRs are therefore likely only needed in settings in which physicians have very different patient demographics, such as in sex or age. Moderate differences in patient demographics between physicians are unlikely to substantially change rates of adenoma detection.

Validity of diagnostic codes and laboratory tests of liver dysfunction to identify acute liver failure events

Identification of acute liver failure (ALF) is important for post‐marketing surveillance of medications, but the validity of using ICD‐9 diagnoses and laboratory data to identify these events within electronic health records is unknown. We examined positive predictive values (PPVs) of hospital ICD‐9 diagnoses and laboratory tests of liver dysfunction for identifying ALF within a large, community‐based integrated care organization.

METFORMIN USE AND RISK OF COLORECTAL ADENOMA AFTER POLYPECTOMY IN PATIENTS WITH TYPE 2 DIABETES MELLITUS

Background: Existing literature suggests that metformin, the most commonly used biguanide, may lower colorectal cancer risk. Because most colorectal cancers originate in precancerous adenomas, we examined whether metformin use lowered colorectal adenoma risk after polypectomy in patients with type-2 diabetes. Methods: Retrospective cohort study of 40- to 89-year-old Kaiser Permanente Northern California patients who had type 2 diabetes, and ≥1 adenoma detected at baseline colonoscopy during 2000 to 2009 and a repeat colonoscopy 1 to 10 years from baseline adenoma diagnosis through 2012. Cox models evaluated the association between metformin use during follow-up and subsequent adenoma diagnoses, controlling for age, race/ethnicity, sex, body mass index, and repeat examination indication. Results: Study included 2,412 patients followed for a median of 4.5 years; cumulatively, 1,117 (46%) patients had ≥1 adenoma at repeat colonoscopy. Compared with patients not receiving diabetes medications (n = 1,578), metformin-only use (n = 457) was associated with lower adenoma recurrence risk [adjusted HR, 0.76; 95% confidence interval (CI), 0.65–0.89], and the association was stronger with increasing total metformin dose [quartile (Q) 1: HR, 0.90; 95% CI, 0.72–1.12; Q2: HR, 0.89; 95% CI, 0.70–1.12; Q3: HR, 0.80; 95% CI, 0.63–1.01; Q4: HR, 0.50; 95% CI, 0.42–0.60, Ptrend < 0.001]. Findings were unchanged in sensitivity analyses, including evaluating only outcomes during the 3- to 10-year period from baseline. Conclusion: Our study suggests a potential benefit of metformin use in lowering the risk of subsequent adenomas after polypectomy in patients with type 2 diabetes. Impact: Metformin may lower colorectal cancer risk by reducing the formation of precancerous lesions, reinforcing the potential additional benefits of its use. Cancer Epidemiol Biomarkers Prev; 24(11); 1692–8. ©2015 AACR.

Endoscopist fatigue estimates and colonoscopic adenoma detection in a large community-based setting

BACKGROUND AND AIMS Endoscopist fatigue may impact colonoscopy quality, but prior studies conflict, and minimal data exist from community-based practices where most colonoscopies are performed. METHODS Within a large, community-based integrated healthcare system, we evaluated the associations among 4 measures of endoscopist fatigue and colonoscopic adenoma detection from 2010 to 2013. Fatigue measures included afternoon versus morning colonoscopy and the number of GI procedures performed before a given colonoscopy, including consideration of prior procedure complexity. Analyses were adjusted for potential confounders using multivariate logistic regression. RESULTS We identified 126 gastroenterologists who performed 259,064 total GI procedures (median, 6 per day; range, 1-24), including 76,445 screening and surveillance colonoscopies. Compared with morning examinations, colonoscopies in the afternoon were not associated with lower adenoma detection for screening examinations, surveillance examinations, or their combination (OR for combination, .99; 95% CI, .96-1.03). The number of procedures performed before a given colonoscopy, with or without consideration of prior procedure complexity, was also not inversely associated with adenoma detection (OR for adenoma detection for colonoscopies in the fourth quartile of fatigue based on the number of prior procedures performed vs colonoscopies performed as the first procedure of the day, .99; 95% CI, .94-1.04). CONCLUSIONS In a large community-based setting, adenoma detection for screening and surveillance colonoscopies were not associated with either time of day or the number of prior procedures performed by the endoscopist, within the range of procedure volumes evaluated. The lack of association persisted after accounting for prior procedure complexity.