Effect of colonoscopy on colorectal cancer incidence and mortality: an instrumental variable analysis

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1 ORIGINAL ARTICLE: Clinical Endoscopy Effect of colonoscopy on colorectal cancer incidence and mortality: an instrumental variable analysis Binu J. Jacob, MSc, 1,2 Rahim Moineddin, PhD, 2,3 Rinku Sutradhar, PhD, 2,4 Nancy N. Baxter, MD, PhD, 2,5,6 David R. Urbach, MD, MSc 1,2,6,7,8 Toronto, Ontario, Canada Background: Using population-based health services information to estimate the effectiveness of colonoscopy on colorectal cancer (CRC) outcomes is prone to selection bias. Objective: To determine the effect of colonoscopy on CRC incidence and mortality. Design: Population-based retrospective cohort study. Setting: Ontario provincial health data information. Patients: This study involved average-risk persons aged 50 to 74 years from 1996 to 2000 who were alive and free of CRC on January 1, Intervention: Colonoscopy between 1996 and Main Outcome Measurements: CRC incidence and mortality from 2001 to Results: The study cohort contained 1,089,998 persons, 7.9% of whom had undergone a colonoscopy between 1996 and Using primary care physician rate of discretionary colonoscopy as an instrumental variable, the receipt of colonoscopy was associated with a 0.60% (95% confidence interval [CI], 0.31%-0.78%) absolute reduction in the 7-year colorectal cancer incidence and a 0.17% (95% CI, 0.14%-0.21%) absolute reduction in the 5-year risk of death caused by CRC. This corresponds to a 48% relative decrease in CRC incidence (risk ratio [RR] 0.52; 95% CI, ) and 81% decrease in mortality caused by CRC (RR 0.19, 95% CI, ). In subgroup analyses, the reduction in the risk of death due to CRC was larger in women than men. The reduction in CRC incidence was larger for complete colonoscopies and for left-sided cancers. Limitations: Instrumental variable methods estimate only the marginal effect on the population studied. Conclusion: Increased use of colonoscopy procedures is associated with a reduction in the incidence and mortality of CRC in the population studied. (Gastrointest Endosc 2012;76: ) Abbreviations: CRC, colorectal cancer; PCP, primary care physician. DISCLOSURE: This work was supported by grants from the Canadian Institutes of Health Research and Colon Cancer Canada. The study was supported by the Institute for Clinical Evaluative Sciences (ICES), which is funded by an annual grant from the Ontario Ministry of Health and Long-Term Care (MOHLTC). The opinions, results, and conclusions reported in this article are those of the authors and are independent from the funding sources. No endorsement by ICES or the Ontario MOHLTC is intended or should be inferred. Nancy Baxter holds the Cancer Care Ontario Health Services Research Chair and an Early Researchers Award from the Ontario Ministry of Research and Innovation. No other financial relationships relevant to this publication were disclosed. Use your mobile device to scan this QR code and watch the author interview. Download a free QR code scanner by searching QR Scanner in your mobile device s app store. Copyright 2012 by the American Society for Gastrointestinal Endoscopy /$ Received January 10, Accepted March 15, Current affiliations: Institute of Medical Science (1), University of Toronto, Institute for Clinical Evaluative Sciences (2), Toronto, Department of Family and Community Medicine (3), University of Toronto, Dalla Lana School of Public Health (4), University of Toronto, Department of Surgery and Keenan Research Centre (5), Li Ka Shing Knowledge Institute, St. Michael s Hospital, Toronto, Department of Health Policy, Management and Evaluation (6), University of Toronto, Cancer Care Ontario (7), Department of Surgery (8), University of Toronto, Toronto, Canada. Reprint requests: Binu Jacob, MSc, Clinical Decision Making & Health Care, 13 EN Toronto General Hospital, 200 Elizabeth Street, Toronto, ON M5G 2C4 Canada. Volume 76, No. 2 : 2012 GASTROINTESTINAL ENDOSCOPY 355

2 Jacob et al Colorectal cancer (CRC) is the third most common cancer and second leading cause of cancer death among Canadian men and women, with an estimated 22,500 people newly diagnosed with colorectal cancer and 9100 CRC deaths in ,2 Screening for CRC is effective, 3,4 and colonoscopy is an effective tool to prevent the disease. 5 Detection and removal of colon polyps through colonoscopy reduces the risk of CRC. 6,7 The use of screening colonoscopy has increased as a result of patient demand, 8 advocacy by professional organizations, 9-11 and economic arguments. 12,13 In the absence of randomized controlled trials of colonoscopy, observational studies have shown that colonoscopy use is associated with a reduction in CRC mortality In Canada, the rate of colonoscopy has increased significantly over the past 15 years. 16,17 Ontario s cancer agency has introduced policies intended to expand access to colonoscopy, through direct referral as well as by increased use of fecal occult blood testing. However, we do not know the effect of the increased use of colonoscopy in reducing both CRC incidence and mortality at the population level. It is difficult to study the effect of screening colonoscopy by using population-based observational data because colonoscopy is performed not just for cancer screening but also for diagnosis, evaluation, and follow-up of patients with CRC or colon polyps. Patients with CRC symptoms or risk factors are more likely to undergo a colonoscopy than those without them. Primary care physicians (PCPs) strongly influence their patients screening behavior, 18,19 and there is substantial variation in PCPs use of colonoscopy. 16 Comparing CRC outcomes between patients who do or do not undergo colonoscopy to estimate the effect of colonoscopy in a population-based study is prone to selection biases. However, it is possible to examine the effect of colonoscopy by using instrumental variable analysis methods, which explicitly incorporate treatment selection bias. Instrumental variable analysis methods are particularly useful for the question of screening colonoscopy, especially when framed as a question of health policy rather than treatment of a specific person. The objective of this study was to estimate the effect of colonoscopy on the incidence and mortality of CRC by using the PCP rate of discretionary colonoscopy colonoscopy procedures in average-risk patients, unassociated with a CRC diagnosis as an instrumental variable. METHODS Take-home Message Increasing the rate of colonoscopy in the population even among people who may not have a clinical indication for colonoscopy has the potential to make a substantial impact on colorectal cancer incidence and mortality. The effectiveness of colonoscopy was stronger for prevention of colorectal cancer in the left side of the colon and the rectum. Overview We first identified persons aged 50 to 74 years in Ontario who received health care from the same PCP from 1996 to We then determined whether each patient underwent a colonoscopy for any reason during this 5-year period. Because we were interested in characterizing PCPs use of colonoscopy, we linked each participant to a PCP, and the intensity of colonoscopy use for each PCP was measured. To obtain an estimate of each PCP s inclination to use colonoscopy in apparent screening situations where the risk of CRC did not appear to be elevated we identified colonoscopy procedures that appeared likely to be discretionary in nature. For the purpose of profiling PCP colonoscopy behavior, discretionary colonoscopy procedures were defined as those performed on apparently low-risk, screen-eligible persons, which did not result in a subsequent diagnosis of CRC within 3 years of colonoscopy. We then identified a cohort of these participants who remained alive and free of CRC on January 1, 2001, and observed them until December 31, 2007, for the occurrence of CRC outcomes. We used a quasi-randomized approach, by using instrumental variable analysis to account for selection bias and case-mix variation, by using the PCP rate of discretionary colonoscopy as an instrumental variable. Data sources We used linked information from several administrative data sources and a cancer registry. The Registered Persons Data Base contains the demographic information on all residents eligible for health care in Ontario. The Ontario Health Insurance Plan database contains information on claims for physicians services provided to Ontario residents and includes virtually all medical services provided in Ontario. The Canadian Institute for Health Information Discharge Abstract Database contains information on all discharges from acute care facilities for residents of Ontario, including patient demographics, diagnoses, procedures, and discharge status. The Ontario Cancer Registry has records of all Ontario residents newly diagnosed with cancer or who died from cancer. The Institute for Clinical Evaluative Sciences Physician Database contains information about the demographics, specialty training, certification, and location of practice for Ontario physicians. The study was approved by the Research Ethics Board of Sunnybrook Health Sciences Centre, Toronto, Canada. Study cohort We identified a cohort of 1,089,998 persons in Ontario who were alive, eligible for Ontario Health Insurance Plan 356 GASTROINTESTINAL ENDOSCOPY Volume 76, No. 2 :

3 Jacob et al benefits, and free of CRC on January 1, 2001, and whose PCP and exposure to colonoscopy could be ascertained between 1996 and All study participants appeared to be appropriate for CRC screening during the period from 1996 to 2000, as defined by age 50 to 74 years; no prior diagnosis of CRC, inflammatory bowel disease, or colon polyps; no colon or rectal surgery; and no colonoscopy in the previous 4 years (a window selected to represent a stale period between screening colonoscopy examinations). The diagnostic and procedure codes used in the study are shown in the Appendix, available online at We linked each person to the PCP who provided the most continuous care each calendar year by using the continuity of care measure 23 to adjudicate ties. Persons who could not be assigned to an individual PCP were excluded from this analysis, as were persons who did not have the same PCP over the 5 years before 2001, with at least 2 years of follow-up after January We also excluded persons residing in areas where specialist physicians did not submit fee-for-service claims for colonoscopy ( 5% of the cohort). Identification of exposure We identified all colonoscopies performed on study participants from 1996 to 2000 by using Ontario Health Insurance Plan fee codes. Participants were classified as exposed to a colonoscopy if there was a receipt of any colonoscopy service at any time during the 5-year period. Colonoscopies were further categorized as complete (to the cecum or terminal ileum) or incomplete by using appropriate physician billing codes. Instrumental variable: primary care physician use of discretionary colonoscopy Primary care physicians vary in their use of colonoscopy. Some PCPs send many of their patients for colonoscopy presumably with the intent of colorectal cancer screening whereas others send fewer of their patients for colonoscopy. Patients with certain characteristics will undergo a colonoscopy regardless of their PCP s propensity to use colonoscopy; for example, patients with symptoms of large intestine obstruction, anemia, or a colon mass detected on a CT scan. Conversely, minimally symptomatic persons might be likely to undergo colonoscopies only if their PCPs are colonoscopy enthusiasts. Ontario Health Insurance Plan fee codes for colonoscopy do not distinguish screening colonoscopies from diagnostic, surveillance, or therapeutic colonoscopies. We developed a retrospective method that uses longitudinal follow-up information on the incidence of colorectal cancer to identify a subset of colonoscopies that were unlikely to have been done for an indication other than screening (we call these discretionary colonoscopies). For this study, a discretionary colonoscopy was defined according to these criteria: (1) the first colonoscopy procedure on a person aged from 50 to 74 years, (2) person with no known risk factors for colorectal cancer, (3) procedure not performed during an inpatient stay, (4) and procedure not associated with a diagnosis of colorectal cancer at the time of colonoscopy or within a 3-year period after the colonoscopy. Whether or not a discretionary colonoscopy was actually performed with the intent of colorectal cancer screening, the colonoscopy was done in an apparently low-risk person of a CRC screen-eligible age and did not result in a diagnosis of colorectal cancer. Our objective in measuring discretionary colonoscopy use was to obtain an estimate of each PCP s tendency to use colonoscopy in a patient without an obvious indication other than screening. As long as the rate of discretionary colonoscopy is proportional to a PCP s tendency to use colonoscopy in these discretionary circumstances, this estimate is a useful instrumental variable for our analysis, even if many of these colonoscopies were not actually performed for screening purposes. We assigned each PCP a rate of discretionary colonoscopy, defined as the rate of discretionary colonoscopy per 100 screen-eligible persons from 1996 to 2000, and used this as the instrumental variable for our analysis. To avoid including general practitioners who were not primarily responsible for medical referrals for their patients such as providers of psychotherapy or methadone maintenance therapy we included only patients whose PCPs referred for colonoscopy more than 3% of the patients linked to them. We also excluded patients of PCPs with fewer than 10 screen-eligible patients. Incident CRC and death due to CRC were identified in the Ontario Cancer Registry, including anatomic site (right side of colon, left side of colon, unknown). Because PCPs might suddenly increase their use of colonoscopy in response to the occurrence of CRC diagnoses among their patients, we studied the effect of colonoscopies performed among study participants before the follow-up period. Cohort participants were observed from January 1, 2001, up to December 31, 2007, for CRC incidence and up to December 31, 2005, for CRC death, to account for delays in ascertaining cause of death. Characteristics of screen-eligible participants and their PCPs Participant characteristics included age, sex, comorbidity as measured by the Adjusted Diagnostic Groups casemix system, 24 neighborhood income quintile, and rural residence. PCP characteristics included age, sex, and country of medical education. Statistical analysis CRC incidence and mortality are influenced not only by use of colonoscopy but also by many other measured and unmeasured determinants of prognosis, such as diet, eth- Volume 76, No. 2 : 2012 GASTROINTESTINAL ENDOSCOPY 357

4 Jacob et al nicity, and family history of CRC. Comparing CRC outcome events between persons who had a colonoscopy and those who did not will yield biased estimates of the effect of colonoscopy if conventional analysis used. We used instrumental variable analysis methods for this study. Instrumental variable analysis methods allow for the estimation of treatment effects in the presence of unmeasured confounding. 25 Instrumental variable analysis is best suited to health policy questions (What is the ideal rate of colonoscopy in a population?) rather than questions about the treatment of a particular patient (Should this patient have a colonoscopy?). An instrumental variable should be strongly associated with the exposure but not an independent determinant of the outcome of interest. 26 In our study, the PCP rate of discretionary colonoscopy is an ideal instrument because it is highly correlated with the probability of a patient s exposure to colonoscopy and by definition is entirely unrelated to the outcomes of CRC incidence and mortality. Initially, we compared the characteristics of patients who underwent colonoscopy with those who did not. Crude probabilities of CRC incidence and death were estimated by using Kaplan-Meier methods. We then used instrumental variable analysis to account for selection bias. First, we categorized participants into quintiles of the instrumental variable (their PCPs rates of discretionary colonoscopy). We estimated a simple unadjusted instrumental variable as the difference in outcome between the highest and lowest quintile divided by the difference in the PCP rate of discretionary colonoscopy use. Cox proportional hazards regression models were used to compare the incidence and mortality rates between groups, adjusting for patient-level covariates. To account for the clustering of patients within PCPs, we used a marginal approach with a robust sandwich estimator for estimating the covariance matrix 27 and tested the proportional hazards assumption by using numerical and graphic methods. 28 We then performed instrumental variable analysis by using 2-stage probit models. 29,30 In the first stage, we used the PCP rate of discretionary colonoscopy to predict a patients probability of undergoing a colonoscopy. In the second stage, we modeled the probability of CRC incidence and mortality by using the predicted probability of colonoscopy as an independent variable and adjusting for PCP (age, sex, country of medical training) and participant characteristics (age, sex, Adjusted Diagnostic Groups score, and income quintile). The 2-stage approach has the advantage of incorporating the predicted treatment into the outcome model and therefore accounts for selection bias attributable to PCPs, as long as there are no major imbalances of patient characteristics between PCPs. To account for the clustering of patient-level observations, parameters and standard errors were estimated robustly by using a generalized estimating equation approach. We reported the marginal probabilities with 95% confidence Figure 1. Study cohort. CRC, colorectal cancer; PCP, primary care physician. intervals (CIs) of the outcomes for patients according to use of colonoscopy. We then estimated the absolute risk reduction and the relative rates. Sensitivity analyses limited to discretionary colonoscopy as the exposure yielded similar results. We performed analyses stratified for age, sex, anatomic site of CRC (right side of colon, left side of colon, or unknown), and completeness of the colonoscopy. Analyses were performed by using STATA 11.1 and SAS version 9.2. RESULTS Of the 2,900,321 screen-eligible Ontario residents aged 50 to 74 years during the period from 1996 to 2000, 85.7% could be linked to a PCP. Of these, 73.8% had the same PCP over 5 years, and 73.1% had at least 2 years of continuous care from the same PCP. The study cohort was made up of 1,089,998 persons who were alive and free of CRC on January 1, 2001, and whose PCPs sent at least 3% of his or her linked patients for colonoscopy (Fig. 1). The mean age of patients was 62 years, and 54.9% were 358 GASTROINTESTINAL ENDOSCOPY Volume 76, No. 2 :

5 Jacob et al TABLE 1. Baseline characteristics of study Patients according to undergoing colonoscopy Characteristic All data presented as % Predicted 1-year risk of CRC per 100 persons,* mean (SD) Sex Underwent colonoscopy No (n 1,003,161) Yes (n 86,837) Incidence 0.19 (0.11) 0.15 (0.08) Mortality 0.02 (0.01) 0.01 (0.01) Female TABLE 1. (continued) Characteristic All data presented as % Mortality (per 100 persons) Underwent colonoscopy No (n 1,003,161) Yes (n 86,837) Within 1 y Within 4 y CRC, Colorectal cancer; SD, standard deviation; ADG, Adjusted Diagnostic Groups. *Predicted 1-year risks were estimated by using the Cox proportional hazards regression, including all baseline patient characteristics. Derived by the Kaplan-Meier method. Male Age group, y Income, quintile 1 (lowest) (highest) Missing Rural area of living No Yes Missing ADG comorbidity score CRC outcomes Incidence (per 100 persons) Within 1 y Within 4 y women. A total of 86,837 patients (7.9%) had a colonoscopy, of which 82,548 (95.2%) were discretionary procedures. Table 1 shows the characteristics of the study cohort according to receipt of colonoscopy. Patients who had a higher neighborhood income and had more comorbidity were more likely to undergo a colonoscopy. During the 7 years from 2001 to 2007, a total of 14,455 persons (1.3%) were newly diagnosed with colorectal cancer, a total of 2394 patients (0.2%) died of colorectal cancer, and 140,584 patients (12.9%) died from other causes. Among patients who developed new CRC, 4651 (32.2%) had cancer in the right side of the colon, 7800 (53.9%) had cancer in the left side of the colon, and 2004 (13.9%) had cancer of an unknown primary site. Of those who died of CRC, 782 (32.7%) had cancer of the right side of the colon, 1221 (51.0%) had cancer in the left side of the colon, and 391 (16.3%) had cancer of an unknown primary site. Eighty three percent of all colonoscopies were classified as complete. Table 2 shows characteristics of study patients according to quintiles of their PCP s use of discretionary colonoscopy. The PCP rates of discretionary colonoscopy ranged from 3% to 62.5%. The mean 1-year predicted CRC incidence and mortality were similar across quintiles, suggesting that unmeasured risk factors for CRC incidence and death were relatively balanced. There was a 0.09% absolute reduction in cumulative probability of CRC diagnosed within 4 years between the highest (0.72%) and lowest (0.81%) quintiles of discretionary colonoscopy use. This reduction in incidence was associated with an 8.42% increase (12.12%-3.70%) in the median rate of discretionary colonoscopy, yielding a simple unadjusted instrumental variable estimate of an absolute decrease in the incidence of CRC of 0.011% for every 1% increase in the PCP rate of discretionary colonoscopy. Table 3 shows the instrumental variable estimated marginal probabilities of CRC incidence and death. After Volume 76, No. 2 : 2012 GASTROINTESTINAL ENDOSCOPY 359

6 Jacob et al TABLE 2. Characteristics of study patients according to quintiles of their primary care physicians rates of discretionary colonoscopy Characteristic Quintiles of PCP rate of discretionary colonoscopy, % No. of patients 218, , , , ,169 Rate of discretionary colonoscopy, median Predicted 1-year risk of CRC per 100 persons,* mean (SD) Incidence 0.19 (0.12) 0.20 (0.12) 0.19 (0.12) 0.19 (0.12) 0.17 (0.11) Mortality 0.02 (0.01) 0.02 (0.01) 0.02 (0.01) 0.01 (0.01) 0.02 (0.01) Sex (%) Female Male Age group (%), y Income (%), quintile 1 (lowest) (highest) Missing Rural area of residence (%) No Yes Missing ADG comorbidity score (%) CRC outcomes (per 100 persons) Incidence Within 1 y Within 4 y (Continued on text page) 360 GASTROINTESTINAL ENDOSCOPY Volume 76, No. 2 :

7 Jacob et al TABLE 2. (Continued) Quintiles of PCP rate of discretionary colonoscopy, % Characteristic Mortality Within 1 y Within 4 y Adjusted hazards ratio, (95% CI) Incidence (0.89, 0.99) 0.95 (0.91, 1.00) 0.96 (0.91, 1.01) 0.92 (0.88, 0.97) Mortality (0.78, 1.00) 0.89 (0.78, 1.01) 0.94 (0.83, 1.06) 0.83 (0.73, 0.94) PCP, Primary care physician; CRC, colorectal cancer; SD, standard deviation; ADG, Adjusted Diagnostic Groups; CI, confidence interval. *Predicted 1-year rates were estimated by using Cox proportional hazards regression, including all baseline patient characteristics. Kaplan-Meier estimates. Hazard ratios and 95% CIs were estimated by using Cox proportional hazards regression, using a marginal model approach to account for clustering and adjusted for patient and PCP characteristics. adjusting for patient and PCP characteristics, we found that the cumulative predicted probability of CRC incidence was 1.24% for patients who did not have a colonoscopy and 0.65% for patients who did. The corresponding probabilities for CRC death were 0.21% and 0.04%. Performance of colonoscopy was associated with a 0.60% (95% CI, 0.31%- 0.78%) absolute reduction in CRC incidence and a 0.17% (95% CI, 0.14%-0.21%) absolute reduction in CRC death during the study period. This corresponds to a 48% relative decrease in CRC incidence (risk ratio [RR] 0.52; 95% CI, ) and an 81% relative decrease in CRC mortality (RR 0.19; 95% CI, ). In stratified analyses, colonoscopy was statistically associated with a reduced rate of CRC among persons aged from 60 to 69 years (RR 0.61; 95% CI, ) and from 70 to 79 years (RR 0.40; 95% CI, ) but not for those aged 50 to 59 years. Similarly, CRC mortality was statistically reduced only in the 60 to 69 year age group (RR 0.15; 95% CI, ). The relative reduction in the risk of CRC death was larger in women than in men. The reduction in CRC incidence was larger for complete colonoscopies and for cancers in the left side of the colon (Table 4). There was a higher risk for CRC of unknown site associated with colonoscopy (RR 2.71; 95% CI, ). DISCUSSION By using instrumental variable methods to estimate the effectiveness of colonoscopy in the prevention of CRC among persons aged 50 to 74 years, we found that use of colonoscopy was associated with a relative 7-year decrease in CRC incidence of 48% and a relative 5-year decrease in CRC death of 81%. Increasing the rate of colonoscopy in the population even among people who may not have a clinical indication for colonoscopy has the potential to make a substantial impact on CRC incidence and mortality. Our crude analysis showed that the risk of developing CRC at 4 years decreases by 0.011% for each additional 1% of patients sent for colonoscopy by their PCPs. If the 4-year risk of CRC is approximately 0.80%, this can be reduced by 0.22% (to 0.58%) if a PCP increases the proportion of his or her patients having colonoscopy by 20% and by 0.44% (to 0.36%) if a PCP increases the proportion of his or her patients having colonoscopy by 40%. We also found that the effectiveness of colonoscopy was stronger for prevention of CRC events in the left side of the colon and rectum than in the right side of the colon. Reduction in CRC incidence and mortality associated with a previous colonoscopy varies among published studies Lack of an incidence effect among patients aged 50 to 59 years in our study might be related to the low prevalence of colonoscopy in this group. Age-sex differences in the prevalence estimates of colonoscopy in the population have been reported, 34,35 with a low prevalence of colonoscopy in the 50 to 54 year age group compared with the 70 to 79 year age group. 35 The protection of colonoscopy limited to left-side colon CRC is analogous to other studies 14,32,36,37 and is of concern. There also was a paradoxical higher risk of CRC of unknown site among participants who had a colonoscopy. This actually is not surprising because persons with a tumor of unknown site likely never had a satisfactory colonoscopy (which would presumably have identified a primary site) or may have presented with metastatic CRC. There is controversy regarding the optimal method of CRC screening, with current screening options including fecal occult blood testing, fecal immunohistochemical testing, CT colonography, flexible sigmoidoscopy, and colonoscopy. 38,39 Randomized trials of flexible sigmoid- Volume 76, No. 2 : 2012 GASTROINTESTINAL ENDOSCOPY 361

8 Jacob et al TABLE 3. Instrumental variable-adjusted* estimates of colorectal cancer incidence and death according to exposure to colonoscopy Predicted probability No colonoscopy Colonoscopy Absolute difference RR Incidence Percentage (95% CI) RR (95% CI) Overall 1.24 ( ) 0.65 ( ) 0.60 (-0.78, -0.31) 0.52 ( ) Sex Men 1.55 ( ) 0.80 ( ) 0.75 (-1.03, -0.19) 0.52 ( ) Women 1.03 ( ) 0.54 ( ) 0.49 (-0.68, -0.08) 0.52 ( ) Age group (y) ( ) 0.37 ( ) 0.36 (-0.51, 0.08) 0.51 ( ) ( ) 0.94 ( ) 0.60 (-0.91, -0.06) 0.61 ( ) ( ) 0.90 ( ) 1.36 (-1.78, -0.26) 0.40 ( ) Mortality Overall 0.21 ( ) 0.04 ( ) 0.17 (-0.21, -0.14) 0.19 ( ) Sex Men 0.24 ( ) 0.10 ( ) 0.14 (-0.18, -0.11) 0.41 ( ) Women 0.21 ( ) 0.02 ( ) 0.19 (-0.23, -0.14) 0.08 ( ) Age group (y) ( ) 0.02 ( ) 0.09 (-0.17, 0.01) 0.17 ( ) ( ) 0.04 ( ) 0.24 (-0.27, -0.22) 0.15 ( ) ( ) 0.11 ( ) 0.35 (-0.47, -0.25) 0.24 ( ) PCP, Primary care provider; CRC, colorectal cancer; RR, risk ratio; CI, confidence interval. *Absolute and relative risk reductions were estimated by using 2-stage probit models. In the first stage, the probability of undergoing colonoscopy was modeled as a function of the PCP rate of colonoscopy. In the second stage, the probability of CRC incidence and mortality was modeled by using the predicted probability of colonoscopy as an independent variable, adjusted for PCP and patient characteristics. Negative values indicate a reduction in the absolute risk of CRC incidence or mortality. Cumulative incidence up to 7 years. Cumulative mortality up to 5 years. oscopy screening have demonstrated reductions in CRC incidence and mortality. 40,41 Because randomized trials of screening colonoscopy are not expected to yield results in the near future, we must rely on non-experimental evidence to assess the effectiveness of colonoscopy screening for the time being. Our findings are broadly consistent with case control studies on colonoscopy and CRC mortality. 14,15 Use of colonoscopy is influenced by PCPs, who have significant influence on the screening behavior of their patients. There is wide variation in the use of colonoscopy between PCPs. In this study, we sought to quantify the effect of a PCP s rate of colonoscopy on CRC outcomes in his or her patients. This is a difficult question to study by using non-experimental methods. Person-level variables that influence the risk and prognosis of CRC are likely to influence a PCP s decision to use colonoscopy in a particular patient. These variables often are unmeasured in observational studies, resulting in biased estimates of effect. Instrumental variable analysis methods allow for the estimation of treatment effects in the presence of unobserved confounding provided that a suitable instrumental variable is available, 25 permitting the natural randomization of patients to different exposure categories. We used the PCP rate of discretionary colonoscopy as the instrumental variable in our study. Physician level instruments have been used in other studies An instrumental variable is a factor that is strongly related to the probability of assignment to a treatment but is not independently related to the outcome under study. 45 There is substantial variation in the use of colonoscopy by PCPs. 16 Because of the way we defined discretionary colonoscopy by definition, a discretionary colonoscopy cannot occur in a patient who subsequently develops CRC a PCP s rate of 362 GASTROINTESTINAL ENDOSCOPY Volume 76, No. 2 :

9 Jacob et al TABLE 4. Instrumental variable adjusted* estimates according to completeness of colonoscopy and anatomic site of CRC Colonoscopy CRC incidence CRC mortality Absolute difference (95% CI) RR (95% CI) Absolute difference (95% CI) RR (95% CI) Complete 0.69 (-0.87, -0.37) 0.45 ( ) 0.22 (-0.14, 0.32) 0.02 ( ) Incomplete 0.27 (-1.05, 3.58) 0.78 ( ) 0.16 (-0.15, -0.12) 0.18 ( ) Anatomic site of CRC Right 0.08 (-0.13, 0.49) 1.23 ( ) 0.04 (-0.5, 0.06) 0.44 ( ) Left 1.27 (-1.29, -1.20) 0.15 ( ) 0.25 (-0.16, -0.32) 0.05 ( ) Unknown 0.77 (0.03, 2.44) 2.71 ( ) 0.05 (-0.05, 0.89) 1.65 ( ) CRC, Colorectal cancer; PCP, Primary care provider; CI, confidence interval; RR, risk ratio. *Absolute and relative risk reductions were estimated by using 2-stage probit models. In the first stage, the probability of receiving colonoscopy was modeled as a function of the PCP rate of colonoscopy. In the second stage, the probability of CRC incidence and mortality was modeled by using the predicted probability of colonoscopy as an independent variable, adjusted for PCP and patient characteristics. Cumulative incidence up to 7 years. Cumulative mortality up to 5 years. Negative values indicate a reduction in the absolute risk of CRC incidence or mortality. discretionary colonoscopy is not independently associated with the risk of CRC among his or her patients. The estimates from our study are substantially less biased than those of other non-experimental study designs and provide a reasonable estimate of the effect of colonoscopy among marginal patients 46 those who would have a colonoscopy if their PCPs were colonoscopy enthusiasts rather than colonoscopy skeptics. An objective of our study was to estimate the potential benefit of increasing the population or environmental rate of colonoscopy. Instrumental variable analysis is wellsuited to policy questions about rates of health services, rather than addressing questions about treatment of a particular patient. Marginal participants are most susceptible to changes in screening policy and are those whose outcomes are actually estimated in an instrumental variable analysis. Because treatment effect is estimated among marginal participants only, instrumental variable estimates tend to have smaller overall effect sizes than other study designs. Our study has several limitations. First, even though instrumental variable analysis is a useful practical alternative to randomized, controlled trials, its external validity depends on the population studied. Instrumental variable analysis estimates only the marginal effect on the population under study, which differs from the average effect. The marginal population excludes persons who would always or never receive colonoscopy, focusing on patients whose indications for colonoscopy are more discretionary. Second, because of the cross-classified structure of the data, patients may not be nested completely within physicians. To address this limitation, we included only participants who had the same PCP over the 5-year period. Third, our definition of continuity of care required patients to have at least 2 visits with a PCP per year to be included in the study. We did not include the small number of apparently healthy patients who had only 1 or no visits per year. Fourth, although we sought to distinguish discretionary colonoscopy from diagnostic colonoscopy, it is impossible to completely establish the indication for a colonoscopy by using our data. However, because we used the discretionary colonoscopy rate as an instrumental variable not as the actual exposure variable our study is less susceptible to bias because of misclassification of diagnostic colonoscopies as screening colonoscopies. Fifth, some potential confounders were not directly measured in our study, such as a family history of CRC. However, our analytic approach largely accounts for this type of unmeasured confounding. 24,25 Sixth, because age of study participants was limited to 50 to 74 years, we could not estimate the effect of colonoscopy among persons aged 75 years and older. Finally, we did not consider other types of screening in our study, such as fecal occult blood testing or flexible sigmoidoscopy. Because we focused only on the potential benefits of colonoscopy and not the potential harms, any estimates of the overall benefit of colonoscopy should explicitly incorporate both benefits and risks. Overall, the limitations of our study design do not substantially affect the ability to accomplish our principal research objective of estimating the population level effect of colonoscopy use by PCPs. In conclusion, increased use of colonoscopy was associated with a reduction in incidence and mortality from CRC in persons aged from 50 to 74 years. REFERENCES 1. Canadian Cancer Society/National cancer Institute of Canada. Canadian Cancer Statistics 2010, CCS/NCIC, Toronto, Canada. cancer ca. cancer ca.accessed October 5, Volume 76, No. 2 : 2012 GASTROINTESTINAL ENDOSCOPY 363

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11 Jacob et al APPENDIX: Diagnostic codes Diagnosis and procedure codes used in the analyses Colorectal cancer ICD-9 codes , ICD-10 codes C18.0-C20 Right-sided cancer (Cecum to transverse colon) ICD-9 codes 153.4, 153.6, 153.0, Left-sided cancer (Splenic flexture to rectum) ICD-9 codes 154.1, 154.0, 153.3, 153.2, Inflammatory bowel disease ICD-9 codes 556, Ulcerative colitis ICD-9codes 555, Crohn s disease ICD-10 codes K , K Procedure codes Any colonoscopy (colonoscopy to descending colon) Complete colonoscopy Polypectomy OHIP billing code Z555 OHIP billing code Z555 with accompanying codes E747 colonoscopy to cecum or E705 colonoscopy to terminal ileum OHIP billing codes, Z571, E720 Previous colorectal resections OHIP billing codes S162, S166, S167, S168, S169, S170, S171, S172, S173, S174, S177, S188, S213, S214, S215, S216, S217 ICD-9 codes 57.5x, 57.6x, 60.4x, 60.5x ICD-10 codes 1.NM.87x, 1.NM.89x, 1.NM.91x, 1.NQ.87x, 1.NQ.89x, 1.NQ.90x Other CRC screening codes OHIP billing codes G004, L181, X112, X113, Z535, Z580, E740 CRC, Colorectal cancer; OHIP, Ontario Health Insurance Plan. Volume 76, No. 2 : 2012 GASTROINTESTINAL ENDOSCOPY 364.e1