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Joshua Demb,1,2 Tomi Akinyemiju,3 Isabel Allen,1 Tracy Onega,4 Robert A Hiatt,1 Dejana Braithwaite2 1Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA; 2Department of Oncology, Georgetown University School of Medicine, Washington, DC, USA; 3Department of Epidemiology, University of Kentucky, Lexington, KY, USA; 4Department of Biomedical Data Science, Geisel School of Medicine at Dartmouth, Hanover, NH, USA Background: The extent to which screening mammography (SM) recommendations in older women incorporate life expectancy factors is not well established. Objective: The objective of this review was to evaluate evidence on SM utilization in older women by life expectancy factors. Data sources: We searched Medline, Embase and Web of Science from January 1991 to March 2016. Study selection: We included studies examining SM utilization in women ages ≥65 years that measured life expectancy using comorbidity, functional limitations or health or prognostic status. Data extraction and synthesis: ORs and 95% CIs were extracted and grouped by life expectancy category. Findings were aggregated into pooled ORs and 95% CIs and meta-analyzed by life expectancy category. Main outcomes and measures: The primary outcome was SM utilization within the last 5 years. Life expectancy factors included number of comorbidities, Charlson Comorbidity Index (CCI), activities of daily living, instrumental activities of daily living, self-reported health status and 5-year prognostic indices. Results: Of 2,606 potential titles, we identified 25 meeting the inclusion criteria (comorbidity: eight studies, functional status: 11 studies and health/prognostic status: 13 studies). Women with higher CCI scores had decreased SM utilization (pooled OR: 0.75, 95% CI: 0.67–0.85), but increased absolute number of comorbidities were weakly associated with increased SM utilization (pooled OR: 1.17, 95% CI: 1.00–1.36). Women with more functional limitations had lower SM use odds than women with no limitations (pooled OR: 0.72, 95% CI: 0.62–0.83). Screening utilization odds were lower among women with poor vs excellent health (pooled OR: 0.85, 95% CI: 0.74–0.96). Conclusion: Greater CCI score, functional limitations and lower perceived health were associated with decreased SM use, whereas higher absolute number of comorbidities was associated with increased SM use. SM guidelines should consider these factors to improve assessments of potential benefits and harms in older women. Keywords: screening mammography, comorbidity, functional limitations, health status, meta-analysis

Dejana Braithwaite,1 Joshua Demb,1 Louise M Henderson2 1Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, 2Department of Radiology, University of North Carolina, Chapel Hill, NC, USA Abstract: Breast cancer is a major cause of cancer-related deaths among older women, aged 65 years or older. Screening mammography has been shown to be effective in reducing breast cancer mortality in women aged 50–74 years but not among those aged 75 years or older. Given the large heterogeneity in comorbidity status and life expectancy among older women, controversy remains over screening mammography in this population. Diminished life expectancy with aging may decrease the potential screening benefit and increase the risk of harms. In this review, we summarize the evidence on screening mammography utilization, performance, and outcomes and highlight evidence gaps. Optimizing the screening strategy will involve separating older women who will benefit from screening from those who will not benefit by using information on comorbidity status and life expectancy. This review has identified areas related to screening mammography in older women that warrant additional research, including the need to evaluate emerging screening technologies, such as tomosynthesis among older women and precision cancer screening. In the absence of randomized controlled trials, the benefits and harms of continued screening mammography in older women need to be estimated using both population-based cohort data and simulation models. Keywords: aging, breast cancer, precision cancer screening

Our aim was to examine the association between fatal colorectal cancer (CRC) and time to colonoscopy among individuals who underwent diagnostic colonoscopy after abnormal stool blood test (SBT) in a cohort of United States Veterans. Methods: We performed a cohort study of Veterans aged 50-75 years, with an abnormal SBT using the Veterans Health Administration's (VA) national electronic health record data during the years 1999 and 2010. Colonoscopy receipt was ascertained using current procedural terminology codes after abnormal SBT. The study outcome, CRC death, was defined through National Death Index cause-specific mortality data. We followed patients through CRC-related death, other death, or until December 31, 2015. Multivariable Cox proportional hazards modeling was used to generate CRC-specific mortality hazard ratios (HRs) and 95% confidence intervals (CI) for 3-month colonoscopy intervals, with 3-6 months as the reference. Models were adjusted for age, sex, race/ethnicity, smoking, diabetes, body mass index, and Charlson Comorbidity Index. Results: We included 222,004 patients with abnormal SBTs; the average age was 63 with a standard deviation of 7.2 years, 97% were male, 72% were Non-Hispanic White and 20% were Black. Of the 222,004 patients, 69% completed diagnostic colonoscopy within 12 months of abnormal SBT, 4% were diagnosed with CRC, and 1% died of CRC specific death. Compared to patients with a colonoscopy at 3-6 months (standard of care), CRC-related mortality risk was significantly higher for patients with colonoscopies at 0-3 months (HR = 1.29; 95% CI, 1.14-1.47), 18-21 months (HR = 1.57; 95% CI, 1.19-2.06), and 21-24 months (HR = 1.46; 95% CI, 1.07-1.97). No significant increase in mortality risk was shown for 6-9 month, 9-12 month, 12-15 month, 15-18 months, and 24+ month intervals. Conclusion: Time to colonoscopy plays a significant role in CRC death after abnormal SBT. Compared to a colonoscopy performed during a 3-6-month window, a colonoscopy performed outside of the 15-month window had a higher risk for mortality. Given the impact of timely diagnostic colonoscopy on CRC mortality, development of interventions to increase timely diagnostic follow-up after abnormal SBT are essential to CRC outcome improvement. [ABSTRACT FROM AUTHOR]

Obesity, a growing pandemic in Western societies, significantly impacts metabolic health and contributes to visual disorders. While the systemic consequences of obesity, such as chronic inflammation and insulin resistance, are well-studied in adults, its early-life effects on retinal health remain underexplored. Using a maternal Western Diet (WD) exposure model, we investigated the developmental impact of early-life metabolic disturbances on retinal and cognitive function. Our findings reveal that WD exposure from gestation to early adulthood accelerates the onset of features resembling diabetic retinopathy, including increased retinal vascularization, inflammation, and compromised blood-retina barrier integrity, observed within just four months. Females exhibited heightened vulnerability, showing pronounced ocular defects such as anophthalmia, microphthalmia, and congenital cataracts. These results underscore a critical developmental window during which metabolic disruptions predispose to sex-specific retinal and neurovascular pathologies. This work bridges the link between pediatric and adult obesity, highlighting the urgent need for early interventions to mitigate long-term visual impairments that could further impair recognition memory.

Importance: Rates of early-onset (before 50 years of age) colorectal cancer (EOCRC) are increasing, with notable differences across racial and ethnic groups. Limited data are available on EOCRC-related mortality differences when disaggregating racial and ethnic groups., Objective: To investigate racial and ethnic differences in EOCRC mortality, including disaggregation of Asian American populations separately, including Native Hawaiian or Other Pacific Islander populations and specific Asian American groups, and to quantify the contribution of clinical and sociodemographic factors accounting for these differences., Design, Setting, and Participants: This population-based cohort study included California Cancer Registry data for individuals aged 18 to 49 years with EOCRC between January 1, 2000, to December 31, 2019. Median follow-up was 4.2 (IQR, 1.6-10.0) years. The data analysis was conducted between July 1, 2021, and September 30, 2024., Exposure: Race and ethnicity defined as Asian American (and 7 disaggregated subgroups), Hispanic, Native Hawaiian or Other Pacific Islander, non-Hispanic American Indian or Alaska Native, non-Hispanic Black, and non-Hispanic White., Main Outcomes and Measures: Cox proportional hazards regression models were used to measure association between race and ethnicity and CRC mortality risk, yielding adjusted hazard ratios (AHRs) and 95% CIs. Associations of sociodemographic, health system, and clinical factors with differences in mortality by racial and ethnic minority group were assessed using sequential modeling., Results: There were 22 834 individuals diagnosed with EOCRC between 2000 and 2019 (12 215 [53.5%] male; median age, 44 [IQR, 39-47] years). Racial and ethnic identity included 3544 (15.5%) Asian American, 6889 (30.2%) Hispanic, 135 (0.6%) Native Hawaiian or Other Pacific Islander, 125 (0.5%) non-Hispanic American Indian or Alaska Native, 1668 (7.3%) non-Hispanic Black, and 10 473 (45.9%) non-Hispanic White individuals. Compared with non-Hispanic White individuals, higher EOCRC mortality was found for Native Hawaiian or Other Pacific Islander (AHR, 1.34; 95% CI, 1.01-1.76) and non-Hispanic Black (AHR, 1.18; 95% CI, 1.07-1.29) individuals. Disaggregation of Asian American ethnic groups revealed notable heterogeneity, but no single group had increased EOCRC mortality risk after full adjustment for covariates. For Hispanic individuals, there was higher EOCRC mortality (AHR, 1.15 [95% CI, 1.08-1.22]) with the base model (adjustment for age, sex, and tumor characteristics), but the association disappeared once neighborhood socioeconomic status was added to the base model (AHR, 1.00 [95% CI, 0.94-1.06]). Similarly, there was higher EOCRC mortality among Southeast Asian individuals with the base model (AHR, 1.17 [95% CI, 1.03-1.34], but that association disappeared with the addition of insurance status to the model (AHR, 1.10 [95% CI, 0.96-1.25])., Conclusions and Relevance: In this cohort study, racial and ethnic disparities in EOCRC mortality were evident, with the highest burden among Native Hawaiian or Other Pacific Islander and non-Hispanic Black individuals. These results provide evidence of the role of social determinants of health in explaining these differences.

Introduction: Non-Hispanic Black (NHB) Americans have a higher incidence of colorectal cancer (CRC) and worse survival than non-Hispanic white (NHW) Americans, but the relative contributions of biological versus access to care remain poorly characterized. This study used two nationwide cohorts in different healthcare contexts to study health system effects on this disparity., Methods: We used data from the Surveillance, Epidemiology, and End Results (SEER) registry as well as the United States Veterans Health Administration (VA) to identify adults diagnosed with colorectal cancer between 2010 and 2020 who identified as non-Hispanic Black (NHB) or non-Hispanic white (NHW). Stratified survival analyses were performed using a primary endpoint of overall survival, and sensitivity analyses were performed using cancer-specific survival., Results: We identified 263,893 CRC patients in the SEER registry (36,662 (14%) NHB; 226,271 (86%) NHW) and 24,375 VA patients (4,860 (20%) NHB; 19,515 (80%) NHW). In the SEER registry, NHB patients had worse OS than NHW patients: median OS of 57 months (95% confidence interval (CI) 55-58) versus 72 months (95% CI 71-73) (hazard ratio (HR) 1.14, 95% CI 1.12-1.15, p  = 0.001). In contrast, VA NHB median OS was 65 months (95% CI 62-69) versus NHW 69 months (95% CI 97-71) (HR 1.02, 95% CI 0.98-1.07, p  = 0.375). There was significant interaction in the SEER registry between race and Medicare age eligibility ( p  < 0.001); NHB race had more effect in patients <65 years old (HR 1.44, 95% CI 1.39-1.49, p < 0.001) than in those ≥65 (HR 1.13, 95% CI 1.11-1.15, p < 0.001). In the VA, age stratification was not significant ( p  = 0.21)., Discussion: Racial disparities in CRC survival in the general US population are significantly attenuated in Medicare-aged patients. This pattern is not present in the VA, suggesting that access to care may be an important component of racial disparities in this disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Riviere, Morgan, Deshler, Demb, Mehtsun, Martinez, Gupta, Banegas, Murphy and Rose.)

Importance: Early-onset colorectal cancer (EOCRC), defined as a diagnosis at younger than age 50 years, is increasing, and so-called red flag signs and symptoms among these individuals are often missed, leading to diagnostic delays. Improved recognition of presenting signs and symptoms associated with EOCRC could facilitate more timely diagnosis and impact clinical outcomes., Objective: To report the frequency of presenting red flag signs and symptoms among individuals with EOCRC, to examine their association with EOCRC risk, and to measure variation in time to diagnosis from sign or symptom presentation., Data Sources: PubMed/MEDLINE, Embase, CINAHL, and Web of Science were searched from database inception through May 2023., Study Selection: Studies that reported on sign and symptom presentation or time from sign and symptom presentation to diagnosis for patients younger than age 50 years diagnosed with nonhereditary CRC were included., Data Extraction and Synthesis: Data extraction and quality assessment were performed independently in duplicate for all included studies using Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guidelines. Joanna Briggs Institute Critical Appraisal tools were used to measure risk of bias. Data on frequency of signs and symptoms were pooled using a random-effects model., Main Outcomes and Measures: Outcomes of interest were pooled proportions of signs and symptoms in patients with EOCRC, estimates for association of signs and symptoms with EOCRC risk, and time from sign or symptom presentation to EOCRC diagnosis., Results: Of the 12 859 unique articles initially retrieved, 81 studies with 24 908 126 patients younger than 50 years were included. The most common presenting signs and symptoms, reported by 78 included studies, were hematochezia (pooled prevalence, 45% [95% CI, 40%-50%]), abdominal pain (pooled prevalence, 40% [95% CI, 35%-45%]), and altered bowel habits (pooled prevalence, 27% [95% CI, 22%-33%]). Hematochezia (estimate range, 5.2-54.0), abdominal pain (estimate range, 1.3-6.0), and anemia (estimate range, 2.1-10.8) were associated with higher EOCRC likelihood. Time from signs and symptoms presentation to EOCRC diagnosis was a mean (range) of 6.4 (1.8-13.7) months (23 studies) and a median (range) of 4 (2.0-8.7) months (16 studies)., Conclusions and Relevance: In this systematic review and meta-analysis of patients with EOCRC, nearly half of individuals presented with hematochezia and abdominal pain and one-quarter with altered bowel habits. Hematochezia was associated with at least 5-fold increased EOCRC risk. Delays in diagnosis of 4 to 6 months were common. These findings highlight the need to identify concerning EOCRC signs and symptoms and complete timely diagnostic workup, particularly for individuals without an alternative diagnosis or sign or symptom resolution.

Importance: To date, the diagnostic test completion rate and the time to diagnostic endoscopy or colonoscopy among adults with iron-deficiency anemia (IDA) and/or hematochezia have not been well characterized., Objective: To evaluate the diagnostic test completion rate and the time to diagnostic testing among veterans younger than 50 years with IDA and/or hematochezia., Design, Setting, and Participants: This cohort study was conducted within the Veterans Health Administration between October 1, 1999, and December 31, 2019, among US veterans aged 18 to 49 years from 2 separate cohorts: those with a diagnosis of IDA (n = 59 169) and those with a diagnosis of hematochezia (n = 189 185). Statistical analysis was conducted from August 2021 to August 2023., Exposures: Diagnostic testing factors included age, sex, race and ethnicity, Veterans Health Administration geographic region, and hemoglobin test value (IDA cohort only)., Main Outcomes and Measures: Primary outcomes of diagnostic testing were (1) bidirectional endoscopy after diagnosis of IDA and (2) colonoscopy or sigmoidoscopy after diagnosis of hematochezia. The association between diagnostic testing factors and diagnostic test completion was examined using Poisson models., Results: There were 59 169 veterans with a diagnosis of IDA (mean [SD] age, 40.7 [7.1] years; 30 502 men [51.6%]), 189 185 veterans with a diagnosis of hematochezia (mean [SD] age, 39.4 [7.6] years; 163 690 men [86.5%]), and 2287 veterans with IDA and hematochezia (mean [SD] age, 41.6 [6.9] years; 1856 men [81.2%]). The cumulative 2-year diagnostic workup completion rate was 22% (95% CI, 22%-22%) among veterans with IDA and 40% (95% CI, 40%-40%) among veterans with hematochezia. Veterans with IDA were mostly aged 40 to 49 years (37 719 [63.7%]) and disproportionately Black (24 480 [41.4%]). Women with IDA (rate ratio [RR], 0.42; 95% CI, 0.40-0.43) had a lower likelihood of diagnostic test completion compared with men with IDA. Black (RR, 0.65; 95% CI, 0.62-0.68) and Hispanic (RR, 0.88; 95% CI, 0.82-0.94) veterans with IDA were less likely to receive diagnostic testing compared with White veterans with IDA. Veterans with hematochezia were mostly White (105 341 [55.7%]). Among veterans with hematochezia, those aged 30 to 49 years were more likely to receive diagnostic testing than adults younger than 30 years of age (age 30-39 years: RR, 1.15; 95% CI, 1.12-1.18; age 40-49 years: RR, 1.36; 95% CI, 1.33-1.40). Hispanic veterans with hematochezia were less likely to receive diagnostic testing compared with White veterans with hematochezia (RR, 0.96; 95% CI, 0.93-0.98)., Conclusions and Relevance: In the cohorts of veterans younger than 50 years with IDA and/or hematochezia, the diagnostic test completion rate was low. Follow-up was less likely among female, Black, and Hispanic veterans with IDA and Hispanic veterans with hematochezia. Optimizing timely follow-up across social and demographic groups may contribute to improving colorectal cancer outcomes and mitigate disparities.

Background and Aims: There are limited contemporary population-based data on Helicobacter pylori epidemiology and outcomes in the United States. Our primary aim was to create a validated cohort of veterans with H pylori testing or treatment using Veterans Health Administration data., Methods: Using Veterans Health Administration structured and unstructured data, we developed and validated 4 algorithms for H pylori infection (3 algorithms) and treatment status (1 algorithm). During the development phase, we iteratively modified each algorithm based on a manual review of random sets of electronic health records (reference standard). The a priori validation goal was to achieve a one-sided 95% confidence lower bound (LB) for positive predictive value (PPV) and/or negative predictive value (NPV) >90%. We applied the Bonferroni correction when both PPV and NPV were relevant., Results: For H pylori infection, we achieved 99.0% PPV (LB = 94.6%) and 100% NPV (LB = 96.4%) for discriminating H pylori positive vs negative status using structured (ie, laboratory tests) and 95% PPV (LB = 90.3%) and 97.9% NPV (LB = 93.9%) using unstructured (ie, histopathology reports) data. Diagnostic codes achieved 98% PPV (LB = 93.0%) for H pylori diagnosis. The treatment algorithm was composed of multiple antimicrobial combinations and overall achieved ≥98% PPV (LB = 93.0%) for H pylori treatment, except for amoxicillin/levofloxacin (PPV<60%). Application of these algorithms yielded nearly 1.2 million veterans with H pylori testing and/or treatment between 1999 and 2018., Conclusion: We assembled a validated national cohort of veterans who were tested or treated for H pylori infection. This cohort can be used for evaluating H pylori epidemiology and treatment patterns, as well as complications of chronic infection.

Background: Prompt detection of colorectal cancer (CRC) among individuals younger than age 50 years (early-onset CRC) is a clinical priority because of its alarming rise., Methods: We conducted a matched case-control study of 5075 incident early-onset CRC among US commercial insurance beneficiaries (113 million adults aged 18-64 years) with 2 or more years of continuous enrollment (2006-2015) to identify red-flag signs and symptoms between 3 months to 2 years before the index date among 17 prespecified signs and symptoms. We assessed diagnostic intervals according to the presence of these signs and symptoms before and within 3 months of diagnosis., Results: Between 3 months and 2 years before the index date, 4 red-flag signs and symptoms (abdominal pain, rectal bleeding, diarrhea, and iron deficiency anemia) were associated with an increased risk of early-onset CRC, with odds ratios (ORs) ranging from 1.34 to 5.13. Having 1, 2, or at least 3 of these signs and symptoms were associated with a 1.94-fold (95% confidence interval [CI] = 1.76 to 2.14), 3.59-fold (95% CI = 2.89 to 4.44), and 6.52-fold (95% CI = 3.78 to 11.23) risk (Ptrend < .001), respectively, with stronger associations for younger ages (Pinteraction < .001) and rectal cancer (Pheterogenity = .012). The number of different signs and symptoms was predictive of early-onset CRC beginning 18 months before diagnosis. Approximately 19.3% of patients had their first sign or symptom occur between 3 months and 2 years before diagnosis (median diagnostic interval = 8.7 months), and approximately 49.3% had the first sign or symptom within 3 months of diagnosis (median diagnostic interval = 0.53 month)., Conclusions: Early recognition of red-flag signs and symptoms (abdominal pain, rectal bleeding, diarrhea, and iron-deficiency anemia) may improve early detection and timely diagnosis of early-onset CRC., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background and Aims: Postpolypectomy risk stratification for subsequent metachronous advanced neoplasia (MAN) is imprecise and does not account for colonoscopist adenoma detection rate (ADR). Our aim was to assess association of ADR with MAN and create a prediction model for postpolypectomy risk stratification incorporating ADR and other factors., Methods: We conducted a retrospective cohort study of individuals with baseline polypectomy and subsequent surveillance colonoscopy from 2004 to 2016 within the U.S. Department of Veterans Affairs (VA). Clinical factors, polyp findings, and baseline colonoscopist ADR were considered for the model. Model performance (sensitivity, specificity, and area under the curve) for identifying individuals with MAN was compared with 2020 U.S. Multi-Society Task Force on Colorectal Cancer (USMSTF) surveillance recommendations., Results: A total of 30,897 individuals were randomly assigned 2:1 into independent model training and validation sets. Increasing age, male sex, diabetes, current smoking, adenoma number, polyp location, adenoma ≥10 mm or with tubulovillous/villous features, and decreasing colonoscopist ADR were independently associated with MAN. A range of 1.48- to 1.66-fold increased risk for MAN was observed for ADR in the lowest 3 quintiles (ADR <19.7%-39.3%) vs the highest quintile (ADR >47.0%). When the final model selected based on the training set was applied to the validation set, improved sensitivity and specificity over 2020 USMSTF risk stratification were achieved (P = .001), with an area under the curve of 0.62 (95% confidence interval, 0.60-0.64)., Conclusions: Colonoscopist ADR is associated with MAN. Combining clinical factors and ADR for risk stratification has potential to improve postpolypectomy risk stratification. Improving ADR is likely to improve postpolypectomy outcomes., (Published by Elsevier Inc.)

Background and Aims: Traditional serrated adenomas (TSAs) may confer increased risk for colorectal cancer (CRC). Our objective with this study was to examine clinical characteristics and long-term outcomes associated with TSA diagnosis., Methods: We conducted a retrospective cohort study of U.S. Veterans ≥18 years of age with ≥1 TSA between 1999 and 2018. Baseline characteristics, colonoscopy findings, and diagnosis of incident and fatal CRC were abstracted. Advanced neoplasia was defined by CRC or adenoma with high-grade dysplasia, villous histology, or size ≥1 cm. Follow-up was through CRC diagnosis, death, or end of study (December 31, 2018)., Results: A total of 853 Veterans with a baseline TSA were identified; 74% were ≥60 years of age, 96% were men, 14% were Black, and 73% were non-Hispanic White. About 64% were current or former smokers. Over 2044 total person-years at follow-up, there were 11 incident CRC cases and 1 CRC death. Cumulative CRC incidence was 1.34% (95% confidence interval [CI], 0.67%-2.68%), and cumulative CRC death was 0.12% (95% CI, 0.00%-0.35%). Among the subset of 378 TSA patients with ≥1 surveillance colonoscopy, 65.1% had high-risk neoplasia on follow-up. CRC incidence among TSA patients was significantly higher than in a comparison cohort of patients with normal baseline colonoscopy at baseline (hazard ratio, 3.70; 95% CI, 1.63-8.41) and similar to a comparison cohort with baseline conventional advanced adenoma (hazard ratio, 0.86; 95% CI, 0.45-1.64)., Conclusion: Individuals with TSA have substantial risk for CRC based on their cumulative CRC incidence, as well as significant risk of developing other high-risk neoplasia at follow-up surveillance colonoscopy. These data underscore importance of current recommendations for close colonoscopy surveillance after TSA diagnosis., (Published by Elsevier Inc.)

Purpose: Standardized approaches for rigorous validation of phenotyping from large-scale electronic health record (EHR) data have not been widely reported. We proposed a methodologically rigorous and efficient approach to guide such validation, including strategies for sampling cases and controls, determining sample sizes, estimating algorithm performance, and terminating the validation process, hereafter referred to as the San Diego Approach to Variable Validation (SDAVV)., Methods: We propose sample size formulae which should be used prior to chart review, based on pre-specified critical lower bounds for positive predictive value (PPV) and negative predictive value (NPV). We also propose a stepwise strategy for iterative algorithm development/validation cycles, updating sample sizes for data abstraction until both PPV and NPV achieve target performance., Results: We applied the SDAVV to a Department of Veterans Affairs study in which we created two phenotyping algorithms, one for distinguishing normal colonoscopy cases from abnormal colonoscopy controls and one for identifying aspirin exposure. Estimated PPV and NPV both reached 0.970 with a 95% confidence lower bound of 0.915, estimated sensitivity was 0.963 and specificity was 0.975 for identifying normal colonoscopy cases. The phenotyping algorithm for identifying aspirin exposure reached a PPV of 0.990 (a 95% lower bound of 0.950), an NPV of 0.980 (a 95% lower bound of 0.930), and sensitivity and specificity were 0.960 and 1.000., Conclusions: A structured approach for prospectively developing and validating phenotyping algorithms from large-scale EHR data can be successfully implemented, and should be considered to improve the quality of "big data" research., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Importance: Although screening decreases incidence of and mortality from colorectal cancer (CRC), screening rates are low. Health-promoting financial incentives may increase uptake of cancer screening., Objective: To evaluate the relative and absolute benefit associated with adding financial incentives to the uptake of CRC screening., Data Sources: PubMed, Cochrane Central Register of Controlled Trials, and Web of Science were searched from inception to July 31, 2020. Keywords and Medical Subject Headings terms were used to identify published studies on the topic. The search strategy identified 835 studies., Study Selection: Randomized clinical trials (RCTs) were selected that involved adults older than 50 years who were eligible for CRC screening, who received either various forms of financial incentives along with mailed outreach or no financial incentives but mailed outreach and reminders alone, and who reported screening completion by using recommended tests at different time points. Observational or nonrandomized studies and a few RCTs were excluded., Data Extraction and Synthesis: The review was reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA). Data were abstracted and risk of bias was assessed by 2 independent reviewers. Random-effects meta-analysis was conducted, heterogeneity was examined through subgroup analysis and metaregression, and quality of evidence was appraised., Main Outcomes and Measures: The primary outcome was CRC screening completion within 12 months of receiving the intervention., Results: A total of 8 RCTs that were conducted in the United States and reported between January 1, 2014, and December 31, 2020, were included. The trials involved 110 644 participants, of whom 53 444 (48.3%) were randomized to the intervention group (received financial incentives) and 57 200 (51.7%) were randomized to the control group (received no financial incentives). Participants were predominantly male, with 59 113 men (53.4%). Low-quality evidence (rated down for risk of bias and heterogeneity) suggested that adding financial incentives may be associated with a small benefit of increasing CRC screening vs no financial incentives (odds ratio [OR], 1.25; 95% CI, 1.05-1.49). With mailed outreach having a 30% estimated CRC screening completion rate, adding financial incentives may increase the rate to 33.5% (95% CI, 30.8%-36.2%). On metaregression, the magnitude of benefit decreased as the proportion of participants with low income and/or from racial/ethnic minority groups increased. No significant differences were observed by type of behavioral economic intervention (fixed amount: OR, 1.26 [95% CI, 1.05-1.52] vs lottery: OR, 1.06 [95% CI, 0.80-1.40]; P = .32), amount of incentive (≤$5: OR, 1.09 [95% CI, 1.01-1.18] vs >$5: OR, 1.25 [95% CI, 1.02-1.54]; P = .22), or screening modality (stool-based test: OR, 1.14 [95% CI, 0.92-1.41] vs colonoscopy: OR, 1.63 [95% CI, 1.01-2.64]; P = .18)., Conclusions and Relevance: Adding financial incentives appeared to be associated with a small benefit of increasing CRC screening uptake, with marginal benefits in underserved populations with adverse social determinants of health. Alternative approaches to enhancing CRC screening uptake are warranted.

Importance: Breast density is associated with breast cancer risk in women aged 40 to 65 years, but there is limited evidence of its association with risk of breast cancer among women aged 65 years or older., Objective: To compare the association between breast density and risk of invasive breast cancer among women aged 65 to 74 years vs women aged 75 years or older and to evaluate whether the association is modified by body mass index (BMI)., Design, Setting, and Participants: This prospective cohort study used data from the Breast Cancer Surveillance Consortium from January 1, 1996, to December 31, 2012, for US women aged 65 years or older who underwent screening mammography. Data were analyzed from January 1, 2018, to December 31, 2020., Exposures: Breast Imaging Reporting and Data System breast density category, age, and BMI., Main Outcomes and Measures: The 5-year cumulative incidence of invasive breast cancer by level of breast density (almost entirely fat, scattered fibroglandular densities, or heterogeneous or extreme density) and age (65-74 vs ≥75 years) was calculated using weighted means. Cox proportional hazards models were fit to estimate the association of breast density with invasive breast cancer risk. The likelihood ratio test was used to test the interaction between BMI and breast density., Results: A total of 221 714 screening mammograms from 193 787 women were included in the study; a total of 38% of the study population was aged 75 years or older. Of the mammograms, most were from women aged 65 to 74 years (64.6%) and non-Hispanic White individuals (81.4%). The 5-year cumulative incidence of invasive breast cancer increased in association with increasing breast density among women aged 65 to 74 years (almost entirely fatty breasts: 11.3 per 1000 women [95% CI, 10.4-12.5 per 1000 women]; scattered fibroglandular densities: 17.2 per 1000 women [95% CI, 16.1-17.9 per 1000 women]; extremely or heterogeneously dense breasts: 23.7 per 1000 women [95% CI, 22.4-25.3 per 1000 women]) and among those aged 75 years or older (fatty breasts: 13.5 per 1000 women [95% CI, 11.6-15.5]; scattered fibroglandular densities: 18.4 per 1000 women [95% CI, 17.0-19.5 per 1000 women]; extremely or heterogeneously dense breasts: 22.5 per 1000 women [95% CI, 20.2-24.2 per 1000 women]). Extreme or heterogeneous breast density was associated with increased risk of breast cancer compared with scattered fibroglandular breast density in both age categories (65-74 years: hazard ratio [HR], 1.39 [95% CI, 1.28-1.50]; ≥75 years: HR, 1.23 [95% CI, 1.10-1.37]). Women with almost entirely fatty breasts had a decrease of approximately 30% (range, 27%-34%) in the risk of invasive breast cancer compared with women with scattered fibroglandular breast density (65-74 years: HR, 0.66 [95% CI, 0.58-0.75]; ≥75 years: HR, 0.73; 95% CI, 0.62-0.86). Associations between breast density and breast cancer risk were not significantly modified by BMI (for age 65-74 years: likelihood ratio test, 2.67; df, 2; P = .26; for age ≥75 years, 2.06; df, 2; P = .36)., Conclusions and Relevance: The findings suggest that breast density is associated with increased risk of invasive breast cancer among women aged 65 years or older. Breast density and life expectancy should be considered together when discussing the potential benefits vs harms of continued screening mammography in this population.

Background: Previous reports suggested risk of death and breast cancer varied by comorbidity and age in older women undergoing mammography. However, impacts of functional limitations remain unclear., Methods: We used data from 238,849 women in the Breast Cancer Surveillance Consortium-Medicare linked database (1999-2015) who had screening mammogram at ages 66-94 years. We estimated risk of breast cancer, breast cancer death, and non-breast cancer death by function-related indicator (FRI) which incorporated 16 claims-based items and was categorized as an ordinal variable (0, 1, and 2+). Fine and Gray proportional sub-distribution hazards models were applied with breast cancer and death treated as competing events. Risk estimates by FRI scores were adjusted by age and NCI comorbidity index separately and stratified by these factors., Results: Overall, 9,252 women were diagnosed with breast cancer, 406 died of breast cancer, and 41,640 died from non-breast cancer causes. The 10-year age-adjusted invasive breast cancer risk slightly decreased with FRI score [FRI = 0: 4.0%, 95% confidence interval (CI) = 3.8-4.1; FRI = 1: 3.9%, 95% CI = 3.7-4.2; FRI ≥ 2: 3.5%, 95% CI = 3.1-3.9). Risk of non-breast cancer death increased with FRI score (FRI = 0: 18.8%, 95% CI = 18.5-19.1; FRI = 1: 24.4%, 95% CI = 23.9-25.0; FRI ≥ 2: 39.8%, 95% CI = 38.8-40.9]. Risk of breast cancer death was low with minimal differences across FRI scores. NCI comorbidity index-adjusted models and stratified analyses yielded similar patterns., Conclusions: Risk of non-breast cancer death substantially increases with FRI score, whereas risk of breast cancer death is low regardless of functional status., Impact: Older women with functional limitations should be informed that they may not benefit from screening mammography., (©2021 American Association for Cancer Research.)

Background and Aims: The optimal time interval for diagnostic colonoscopy completion after an abnormal stool-based colorectal cancer (CRC) screening test is uncertain. We examined the association between time to colonoscopy and CRC outcomes among individuals who underwent diagnostic colonoscopy after abnormal stool-based screening., Methods: We performed a retrospective cohort study of veterans age 50 to 75 years with an abnormal fecal occult blood test (FOBT) or fecal immunochemical test (FIT) between 1999 and 2010. We used multivariable Cox proportional hazards to generate CRC-specific incidence and mortality hazard ratios (HRs) and 95% confidence intervals (CI) for 3-month colonoscopy intervals, with 1 to 3 months as the reference group. Association of time to colonoscopy with late-stage CRC diagnosis was also examined., Results: Our cohort included 204,733 patients. Mean age was 61 years (SD 6.9). Compared with patients who received a colonoscopy at 1 to 3 months, there was an increased CRC risk for patients who received a colonoscopy at 13 to 15 months (HR 1.13; 95% CI 1.00-1.27), 16 to 18 months (HR 1.25; 95% CI 1.10-1.43), 19 to 21 months (HR 1.28; 95% CI: 1.11-1.48), and 22 to 24 months (HR 1.26; 95% CI 1.07-1.47). Compared with patients who received a colonoscopy at 1 to 3 months, mortality risk was higher in groups who received a colonoscopy at 19 to 21 months (HR 1.52; 95% CI 1.51-1.99) and 22 to 24 months (HR 1.39; 95% CI 1.03-1.88). Odds for late-stage CRC increased at 16 months., Conclusions: Increased time to colonoscopy is associated with higher risk of CRC incidence, death, and late-stage CRC after abnormal FIT/FOBT. Interventions to improve CRC outcomes should emphasize diagnostic follow-up within 1 year of an abnormal FIT/FOBT result., (Published by Elsevier Inc.)

Background & Aims: The incidence and mortality of early-onset colorectal cancer (CRC) are increasing. Adenoma detection, removal, and subsequent endoscopic surveillance might modify risk of CRC diagnosed before age 50 years (early-onset CRC). We conducted a systematic review of young-onset adenoma (YOA) prevalence, associated risk factors, and rate of metachronous advanced neoplasia after YOA diagnosis., Methods: We performed a systematic search of multiple electronic databases through February 12, 2019 and identified studies of individuals 18 to 49 years old that reported prevalence of adenoma, risk factors for adenoma, and/or risk for metachronous advanced neoplasia. Summary estimates were derived using random effects meta-analysis, when feasible., Results: The pooled overall prevalence of YOA was 9.0% (95% CI, 7.1%-11.4%), based on 24 studies comprising 23,142 individuals. On subgroup analysis, the pooled prevalence of YOA from autopsy studies was 3.9% (95% CI, 1.9%-7.6%), whereas the prevalence from colonoscopy studies was 10.7% (95% CI, 8.5%-13.5). Only advancing age was identified as a consistent risk factor for YOA, based on 4 studies comprising 78,880 individuals. Pooled rate of metachronous advanced neoplasia after baseline YOA diagnosis was 6.0% (95% CI, 4.1%-8.6%), based on 3 studies comprising 1493 individuals undergoing follow-up colonoscopy, with only 1 CRC case reported. Overall, few studies reported metachronous advanced neoplasia and no studies evaluated whether routine surveillance colonoscopy decreases risk of CRC., Conclusions: In a systematic review, we estimated the prevalence of YOA to be 9% and to increase with age. Risk for metachronous advanced neoplasia after YOA diagnosis is estimated to be 6%. More research is needed to understand the prevalence, risk factors, and risk of CRC associated with YOA., (Published by Elsevier Inc.)

Rising trends in the incidence and mortality of early-onset colorectal cancer (CRC) in those who are younger than 50 years have been well established. These trends have spurred intense investigation focused on elucidating the epidemiology and characteristics of early-onset CRC, as well as on identifying strategies for early detection and prevention. In this review, we provide a contemporary update on early-onset CRC with a particular focus on epidemiology, molecular characterization, red flag signs and symptoms, and screening for early-onset CRC., (Copyright © 2021 AGA Institute. All rights reserved.)

Background & Aims: Colorectal cancer (CRC) incidence and mortality are increasing among persons younger than 50 years old in the United States, but risk factors associated with early-onset CRC (EOCRC) have not been widely studied., Methods: We conducted a case-control study of US veterans 18 to 49 years old who underwent colonoscopy examinations from 1999 through 2014. EOCRC cases were identified from a national cancer registry; veterans who were free of CRC at their baseline colonoscopy through 3 years of follow-up were identified as controls. We collected data on age, sex, race/ethnicity, body weight, body mass index (BMI), diabetes, smoking status, and aspirin use. Multivariate-adjusted EOCRC odds were estimated for each factor, with corresponding 95% confidence interval (CI) values., Results: Our final analysis included 651 EOCRC cases and 67,416 controls. Median age was 45.3 years, and 82.3% were male. Higher proportions of cases were older, male, current smokers, nonaspirin users, and had lower BMIs, compared with controls (P < .05). In adjusted analyses, increasing age and male sex were significantly associated with increased risk of EOCRC, whereas aspirin use and being overweight or obese (relative to normal BMI) were significantly associated with decreased odds of EOCRC. In post hoc analyses, weight loss of 5 kg or more within the 5-year period preceding colonoscopy was associated with higher odds of EOCRC (odds ratio 2.23; 95% CI 1.76-2.83)., Conclusions: In a case-control study of veterans, we found increasing age and male sex to be significantly associated with increased risk of EOCRC, and aspirin use to be significantly associated with decreased risk; these factors also affect risk for CRC onset after age 50. Weight loss may be an early clinical sign of EOCRC. More intense efforts are required to identify the factors that cause EOCRC and signs that can be used to identify individuals at highest risk., (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Potential benefits of screening mammography among women ages 75 years and older remain unclear., Methods: We evaluated 10-year cumulative incidence of breast cancer and death from breast cancer and other causes by Charlson Comorbidity Index (CCI) and age in the Medicare-linked Breast Cancer Surveillance Consortium (1999-2010) cohort of 222 088 women with no less than 1 screening mammogram between ages 66 and 94 years., Results: During median follow-up of 107 months, 7583 were diagnosed with invasive breast cancer and 1742 with ductal carcinoma in situ; 471 died from breast cancer and 42 229 from other causes. The 10-year cumulative incidence of invasive breast cancer did not change with increasing CCI but decreased slightly with age: ages 66-74 years (CCI0 = 4.0% [95% CI = 3.9% to 4.2%] vs CCI  ≥ 2 = 3.9% [95% CI = 3.5% to 4.3%]); ages 75-84 years (CCI0 = 3.7% [95% CI = 3.5% to 3.9%] vs CCI  ≥ 2 = 3.4% [95% CI = 2.9% to 3.9%]); and ages 85-94 years (CCI0 = 2.7% [95% CI = 2.3% to 3.1%] vs CCI  ≥ 2 = 2.1% [95% CI = 1.3% to 3.0%]). The 10-year cumulative incidence of other-cause death increased with increasing CCI and age: ages 66-74 years (CCI0 = 10.4% [95% CI = 10.3 to 10.7%] vs CCI ≥ 2 = 43.4% [95% CI = 42.2% to 44.4%]), ages 75-84 years (CCI0 = 29.8% [95% CI = 29.3% to 30.2%] vs CCI ≥ 2 = 61.7% [95% CI = 60.2% to 63.3%]), and ages 85 to 94 years (CCI0 = 60.3% [95% CI = 59.1% to 61.5%] vs CCI  ≥ 2 = 84.8% [95% CI = 82.5% to 86.9%]). The 10-year cumulative incidence of breast cancer death was small and did not vary by age: ages 66-74 years = 0.2% (95% CI = 0.2% to 0.3%), ages 75-84 years = 0.29% (95% CI = 0.25% to 0.34%), and ages 85 to 94 years = 0.3% (95% CI = 0.2% to 0.4%)., Conclusions: Cumulative incidence of other-cause death was many times higher than breast cancer incidence and death, depending on comorbidity and age. Hence, older women with increased comorbidity may experience diminished benefit from continued screening., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction: Metformin may be associated with reduced colorectal cancer (CRC) risk, but findings from previous studies have been inconsistent and had insufficient sample sizes to examine whether the association differs by anatomic site. This study examined whether metformin was associated with reduced CRC risk, both overall and stratified by anatomic site, in a large sample of persons with diabetes who underwent colonoscopy., Methods: We performed a case-control study of US Veterans with prevalent diabetes who underwent colonoscopy between 1999 and 2014 using Department of Veterans Affairs electronic health record data. Cases were defined by presence of CRC at colonoscopy, while controls had normal colonoscopy. The primary exposure was metformin use at time of colonoscopy (yes/no). Association of metformin exposure with CRC (further stratified by proximal, distal, or rectal subsite) was examined using multivariable and multinomial logistic regression and summarized by odds ratios (ORs) with 95% confidence intervals (CIs)., Results: We included 6,650 CRC patients and 454,507 normal colonoscopy patients. CRC cases were older and had lower metformin exposure. Metformin was associated with 8% relative reduction in CRC odds (OR: 0.92, 95% CI: 0.87-0.96). By subsite, metformin was associated with a 14% statistically significant reduced rectal cancer odds (OR: 0.86, 95% CI: 0.78-0.94) but no reduced distal or proximal cancer odds., Discussion: Metformin was associated with reduced CRC odds-particularly rectal cancer-in a large sample of persons with diabetes undergoing colonoscopy.

Objective: To conduct an anatomic site-specific case-control study of candidate colorectal cancer (CRC) risk factors., Design: Case-control study of US veterans with >1 colonoscopy during 1999-2011. Cases had cancer registry-identified CRC at colonoscopy, while controls were CRC free at colonoscopy and within 3 years of colonoscopy. Primary outcome was CRC, stratified by anatomic site: proximal, distal, or rectal. Candidate risk factors included age, sex, race/ethnicity, body mass index, height, diabetes, smoking status, and aspirin exposure summarised by adjusted ORs and 95% CIs., Results: 21 744 CRC cases (n=7017 rectal; n=7039 distal; n=7688 proximal) and 612 646 controls were included. Males had significantly higher odds relative to females for rectal cancer (OR=2.84, 95% CI 2.25 to 3.58) than distal cancer (OR=1.84, 95% CI 1.50 to 2.24). Relative to whites, blacks had significantly lower rectal cancer odds (OR=0.88, 95% CI 0.82 to 0.95), but increased distal (OR=1.27, 95% CI 1.19 to 1.37) and proximal odds (OR=1.62, 95% CI 1.52 to 1.72). Diabetes prevalence was more strongly associated with proximal (OR=1.29, 95% CI 1.22 to 1.36) than distal (OR=1.15, 95% CI 1.08 to 1.22) or rectal cancer (OR=1.12, 95% CI 1.06 to 1.19). Current smoking was more strongly associated with rectal cancer (OR=1.81, 95% CI 1.68 to 1.95) than proximal cancer (OR=1.53, 95% CI 1.43 to 1.65) or distal cancer (OR=1.46, 95% CI 1.35 to 1.57) compared with never smoking. Aspirin use was significantly more strongly associated with reduced rectal cancer odds (OR=0.71, 95% CI 0.67 to 0.76) than distal (OR=0.85, 95% CI 0.81 to 0.90) or proximal (OR=0.91, 95% CI 0.86 to 0.95)., Conclusion: Candidate CRC risk factor associations vary significantly by anatomic site. Accounting for site may enable better insights into CRC pathogenesis and cancer control strategies., Competing Interests: Competing interests: None declared.

Objectives: We conducted a systematic review of the literature relating early life socioeconomic position (SEP) to breast cancer incidence and mortality from a critical period and life-course trajectory perspective., Methods: PubMed, EMBASE and Web of Science were searched to identify cohort studies that evaluated the impact of early life SEP indicators on the incidence and/or mortality from breast cancer in adulthood., Results: Nine distinct studies evaluated the relationship between early life SEP and breast cancer between 1990 and 2016. Five reports assessed breast cancer incidence and five assessed breast cancer mortality as outcomes; one study assessed both incidence and mortality. While lower early life SEP was associated with reduced breast cancer incidence and increased breast cancer mortality in the US, studies conducted in Europe were unable to establish a consistent association., Conclusions: We found moderate support for the association between early life SEP and incidence and mortality from breast cancer. The impact of early life SEP on breast cancer incidence and mortality appeared to vary between countries. We urge further investigation of the role of lifelong SEP trajectories in breast cancer outcomes.

Background: Approximately half of new invasive breast cancer cases diagnosed each year in the United States occur among women aged 65 years and older. The increasing life expectancy coupled with the attendant rise in breast cancer incidence and elimination of out-of-pocket expenses for screening mammography as a result of the Affordable Care Act could lead to higher utilization rates of screening mammography. Although research indicates that life expectancy should be a strong consideration when making screening decisions among older women, the extent to which screening mammography utilization is tailored to comorbidity and life expectancy is not well established., Methods/design: To identify relevant studies, a systematic search of the literature will be conducted using PubMed and EMBASE between January 1, 1991, and March 1, 2016. Additional studies will be found through citation review or by contacting experts in the field. The inclusion criteria will be any study design comprised of women aged 65 and older, assessing women's comorbidity, functional impairments, and/or health status, and reporting outcome measures that addressed mammography utilization within the last 1-5 years. For each study, two authors will independently abstract data regarding study eligibility and outcomes to determine relevance. Quantitative results will be extracted from text and tables, choosing preferably those adjusted for important confounders., Discussion: The review will provide evidence on the impact of comorbidity, functional limitations, and health status on screening mammography utilization in older women and inform decision aids in this area., Systematic Review Registration: PROSPERO CRD42016032661.

We perceive motion when presented with spatiotemporal changes in contrast (second-order cue). This requires linear signals to be rectified and then summed in temporal order to compute direction. Although both operations have been attributed to cortex, rectification might occur in retina, prior to the ganglion cell. Here we show that the Y ganglion cell does indeed respond to spatiotemporal contrast modulations of a second-order motion stimulus. Responses in an OFF ganglion cell are caused by an EPSP/IPSP sequence evoked from within the dendritic field; in ON cells inhibition is indirect. Inhibitory effects, which are blocked by tetrodotoxin, clamp the response near resting potential thus preventing saturation. Apparently the computation for second-order motion can be initiated by Y cells and completed by cortical cells that sum outputs of multiple Y cells in a directionally selective manner.

The receptive field of the Y-ganglion cell comprises two excitatory mechanisms: one integrates linearly over a narrow field, and the other integrates nonlinearly over a wide field. The linear mechanism has been attributed to input from bipolar cells, and the nonlinear mechanism has been attributed to input from a class of amacrine cells whose nonlinear "subunits" extend across the linear receptive field and beyond. However, the central component of the nonlinear mechanism could in theory be driven by bipolar input if that input were rectified. Recording intracellularly from the Y-cell in guinea pig retina, we blocked the peripheral component of the nonlinear mechanism with tetrodotoxin and found the remaining nonlinear receptive field to be precisely co-spatial with the central component of the linear receptive field. Both linear and nonlinear mechanisms were caused by an excitatory postsynaptic potential that reversed near 0 mV. The nonlinear mechanism depended neither on acetylcholine nor on feedback involving GABA or glycine. Thus the central components of the ganglion cell's linear and nonlinear mechanisms are apparently driven by synapses from the same rectifying bipolar cell.

A retinal ganglion cell commonly expresses two spatially overlapping receptive field mechanisms. One is the familiar "center/surround," which sums excitation and inhibition across a region somewhat broader than the ganglion cell's dendritic field. This mechanism responds to a drifting grating by modulating firing at the drift frequency (linear response). Less familiar is the "nonlinear" mechanism, which sums the rectified output of many small subunits that extend for millimeters beyond the dendritic field. This mechanism responds to a contrast-reversing grating by modulating firing at twice the reversal frequency (nonlinear response). We investigated this nonlinear mechanism by presenting visual stimuli to the intact guinea pig retina in vitro while recording intracellularly from large brisk and sluggish ganglion cells. A contrast-reversing grating modulated the membrane potential (in addition to the firing rate) at twice the reversal frequency. This response was initially hyperpolarizing for some cells (either ON or OFF center) and initially depolarizing for others. Experiments in which responses to bars were summed in-phase or out-of-phase suggested that the single class of bipolar cells (either ON or OFF) that drives the center/surround response also drives the nonlinear response. Consistent with this, nonlinear responses persisted in OFF ganglion cells when ON bipolar cell responses were blocked by L-AP-4. Nonlinear responses evoked from millimeters beyond the ganglion cell were eliminated by tetrodotoxin. Thus, to relay the response from distant regions of the receptive field requires a spiking interneuron. Nonlinear responses from different regions of the receptive field added linearly.