Nirupa R. Ghai

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

Effects of Physical Activity and Sedentary Time on the Risk of Heart Failure

Background— Although the benefits of physical activity for risk of coronary heart disease are well established, less is known about its effects on heart failure (HF). The risk of prolonged sedentary behavior on HF is unknown. Methods and Results— The study cohort included 82 695 men aged ≥45 years from the California Men’s Health Study without prevalent HF who were followed up for 10 years. Physical activity, sedentary time, and behavioral covariates were obtained from questionnaires, and clinical covariates were determined from electronic medical records. Incident HF was identified through International Classification of Diseases, Ninth Revision codes recorded in electronic records. During a mean follow-up of 7.8 years (646 989 person-years), 3473 men were diagnosed with HF. Controlling for sedentary time, sociodemographics, hypertension, diabetes mellitus, unfavorable lipid levels, body mass index, smoking, and diet, the hazard ratio (95% confidence interval [CI]) of HF in the lowest physical activity category compared with those in the highest category was 1.52 (95% CI, 1.39–1.68). Those in the medium physical activity category were also at increased risk (hazard ratio, 1.17 [95% CI, 1.06–1.29]). Controlling for the same covariates and physical activity, the hazard ratio (95% CI) of HF in the highest sedentary category compared with the lowest was 1.34 (95% CI, 1.21–1.48). Medium sedentary time also conveyed risk (hazard ratio, 1.13 [95% CI, 1.04–1.24]). Results showed similar trends across white and Hispanic subgroups, body mass index categories, baseline hypertension status, and prevalent coronary heart disease. Conclusions— Both physical activity and sedentary time may be appropriate intervention targets for preventing HF.

A Large Multiethnic Genome-Wide Association Study of Prostate Cancer Identifies Novel Risk Variants and Substantial Ethnic Differences

UNLABELLED A genome-wide association study (GWAS) of prostate cancer in Kaiser Permanente health plan members (7,783 cases, 38,595 controls; 80.3% non-Hispanic white, 4.9% African-American, 7.0% East Asian, and 7.8% Latino) revealed a new independent risk indel rs4646284 at the previously identified locus 6q25.3 that replicated in PEGASUS (N = 7,539) and the Multiethnic Cohort (N = 4,679) with an overall P = 1.0 × 10(-19) (OR, 1.18). Across the 6q25.3 locus, rs4646284 exhibited the strongest association with expression of SLC22A1 (P = 1.3 × 10(-23)) and SLC22A3 (P = 3.2 × 10(-52)). At the known 19q13.33 locus, rs2659124 (P = 1.3 × 10(-13); OR, 1.18) nominally replicated in PEGASUS. A risk score of 105 known risk SNPs was strongly associated with prostate cancer (P < 1.0 × 10(-8)). Comparing the highest to lowest risk score deciles, the OR was 6.22 for non-Hispanic whites, 5.82 for Latinos, 3.77 for African-Americans, and 3.38 for East Asians. In non-Hispanic whites, the 105 risk SNPs explained approximately 7.6% of disease heritability. The entire GWAS array explained approximately 33.4% of heritability, with a 4.3-fold enrichment within DNaseI hypersensitivity sites (P = 0.004). SIGNIFICANCE Taken together, our findings of independent risk variants, ethnic variation in existing SNP replication, and remaining unexplained heritability have important implications for further clarifying the genetic risk of prostate cancer. Our findings also suggest that there may be much promise in evaluating understudied variation, such as indels and ethnically diverse populations.

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.

Longitudinal study of acculturation and BMI change among Asian American men.

BACKGROUND Cross-sectional studies examining the association between Western acculturation and BMI in Asians have been inconsistent, and studies on BMI change are lacking. OBJECTIVE This study examined the associations between indicators of acculturation (generational status, length of US residence, and age at immigration) and overweight (BMI ≥25kg/m(2)) as well as 5-year BMI changes in 7,073 Chinese, Japanese, Korean, Filipino, and Vietnamese men who lived in the US and were 44-71years old at baseline of the California Mens Health Study (2002-2003). METHODS Indicators of acculturation were reported at baseline. Repeated clinical measures of BMI were extracted from electronic health records (2005-2012). RESULTS Using generalized estimating equations we found that lower generational status, shorter duration of US residence and older age at immigration were inversely associated with being overweight. However, analysis of BMI curves using linear mixed models showed that shorter length of US residence and older age at immigration were associated with larger 5-year increases in BMI. CONCLUSIONS Asian immigrants who were less acculturated had larger BMI increases as they became more acculturated but had not achieved overweight status. Healthy weight interventions among Asians immigrants may be most effective when targeting weight maintenance early in the process of acculturation.

Racial/Ethnic Disparities in Colorectal Cancer Screening Across Healthcare Systems

INTRODUCTION Racial/ethnic disparities in colorectal cancer (CRC) screening and diagnostic testing present challenges to CRC prevention programs. Thus, it is important to understand how differences in CRC screening approaches between healthcare systems are associated with racial/ethnic disparities. METHODS This was a retrospective cohort study of patients aged 50-75 years who were members of the Population-based Research Optimizing Screening Through Personalized Regimens cohort from 2010 to 2012. Data on race/ethnicity, CRC screening, and diagnostic testing came from medical records. Data collection occurred in 2014 and analysis in 2015. Logistic regression models were used to calculate AORs and 95% CIs comparing completion of CRC screening between racial/ethnic groups. Analyses were stratified by healthcare system to assess differences between systems. RESULTS There were 1,746,714 participants across four healthcare systems. Compared with non-Hispanic whites (whites), odds of completing CRC screening were lower for non-Hispanic blacks (blacks) in healthcare systems with high screening rates (AOR=0.86, 95% CI=0.84, 0.88) but similar between blacks and whites in systems with lower screening rates (AOR=1.01, 95% CI=0.93, 1.09). Compared with whites, American Indian/Alaskan Natives had lower odds of completing CRC screening across all healthcare systems (AOR=0.76, 95% CI=0.72, 0.81). Hispanics had similar odds of CRC screening (AOR=0.99, 95% CI=0.98, 1.00) and Asian/Pacific Islanders had higher odds of CRC screening (AOR=1.16, 95% CI=1.15, 1.18) versus whites. CONCLUSIONS Racial/ethnic differences in CRC screening vary across healthcare systems, particularly for blacks, and may be more pronounced in systems with intensive CRC screening approaches.

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.

Genome-wide association study of prostate-specific antigen levels identifies novel loci independent of prostate cancer

Prostate-specific antigen (PSA) levels have been used for detection and surveillance of prostate cancer (PCa). However, factors other than PCa—such as genetics—can impact PSA. Here we present findings from a genome-wide association study (GWAS) of PSA in 28,503 Kaiser Permanente whites and 17,428 men from replication cohorts. We detect 40 genome-wide significant (P<5 × 10−8) single-nucleotide polymorphisms (SNPs): 19 novel, 15 previously identified for PSA (14 of which were also PCa-associated), and 6 previously identified for PCa only. Further analysis incorporating PCa cases suggests that at least half of the 40 SNPs are PSA-associated independent of PCa. The 40 SNPs explain 9.5% of PSA variation in non-Hispanic whites, and the remaining GWAS SNPs explain an additional 31.7%; this percentage is higher in younger men, supporting the genetic basis of PSA levels. These findings provide important information about genetic markers for PSA that may improve PCa screening, thereby reducing over-diagnosis and over-treatment.

Follow-Up of Abnormal Breast and Colorectal Cancer Screening by Race/Ethnicity

INTRODUCTION Timely follow-up of abnormal tests is critical to the effectiveness of cancer screening, but may vary by screening test, healthcare system, and sociodemographic group. METHODS Timely follow-up of abnormal mammogram and fecal occult blood testing or fecal immunochemical tests (FOBT/FIT) were compared by race/ethnicity using Population-Based Research Optimizing Screening through Personalized Regimens consortium data. Participants were women with an abnormal mammogram (aged 40-75 years) or FOBT/FIT (aged 50-75 years) in 2010-2012. Analyses were performed in 2015. Timely follow-up was defined as colonoscopy ≤3 months following positive FOBT/FIT; additional imaging or biopsy ≤3 months following Breast Imaging Reporting and Data System Category 0, 4, or 5 mammograms; or ≤9 months following Category 3 mammograms. Logistic regression was used to model receipt of timely follow-up adjusting for study site, age, year, insurance, and income. RESULTS Among 166,602 mammograms, 10.7% were abnormal; among 566,781 FOBT/FITs, 4.3% were abnormal. Nearly 96% of patients with abnormal mammograms received timely follow-up versus 68% with abnormal FOBT/FIT. There was greater variability in receipt of follow-up across healthcare systems for positive FOBT/FIT than for abnormal mammograms. For mammography, black women were less likely than whites to receive timely follow-up (91.8% vs 96.0%, OR=0.71, 95% CI=0.51, 0.97). For FOBT/FIT, Hispanics were more likely than whites to receive timely follow-up than whites (70.0% vs 67.6%, OR=1.12, 95% CI=1.04, 1.21). CONCLUSIONS Timely follow-up among women was more likely for abnormal mammograms than FOBT/FITs, with small variations in follow-up rates by race/ethnicity and larger variation across healthcare systems.

Recruitment results among families contacted for an obesity prevention intervention: the Obesity Prevention Tailored for Health Study

BackgroundOverweight and obesity are serious threats to health and increase healthcare utilization and costs. The Obesity Prevention Tailored for Health (OPT) study was designed to test the effectiveness of a family-based intervention targeting diet and physical activity. We describe the results of efforts to recruit parents and children enrolled in a large managed-care organization into the OPT study.MethodsParents with 10- to 12-year-old children were randomly selected from the membership of Kaiser Permanente Southern California, a large integrated health plan, and contacted between June 2010 and November 2011. We describe recruitment outcomes and compare characteristics of parents and children who did and did not participate. Information was collected from calls with parents and through the administrative and electronic medical records of the health plan.ResultsOf the 4,730 parents contacted, 16.1% expressed interest in participation (acceptors), 28.8% declined participation (refusers), 4.7% were ineligible, and, even after multiple attempts, we were unable to reach 50.4%. Slightly less than half of the acceptors (n = 361) were ultimately randomized to receive either the OPT program plus usual care or usual care alone (7.6% of all parents initially contacted). There were not any significant differences between acceptors who were or were not randomized. Overall, we found that acceptors were more likely to be female parents, have overweight/obese children, and higher utilization of outpatient visits by parents and children compared with refusers and those we were unable to reach. We found no differences in recruitment outcomes by body mass index or comorbidity score of the parents, level of physical activity of the parents and children, education of the parents, or household income.ConclusionsRecruiting parents and children into an obesity prevention program in a healthcare setting proved to be challenging and resource-intensive. Barriers and incentives for participation in obesity prevention programs need to be identified and addressed. Concern for the weight of their children may motivate parents to participate in family-based lifestyle interventions; however, the healthcare setting may be more relevant to weight-related treatment than to primary prevention.Trial registrationTrial Registration Number: ISRCTN06248443, 30 January 2014.