Clinical Gastroenterology and Hepatology 2014;-:-–-
Association Between Colonic Diverticular Disease and Colorectal Cancer: A Nationwide Population-Based Study Wen–Yen Huang,*,‡ Che–Chen Lin,§ Yee–Min Jen,* Yen–Jung Chang,§ Cheng–Wen Hsiao,jj Muh–Hwa Yang,‡,¶ Chun–Shun Lin,* Fung–Chang Sung,§,# Ji–An Liang,**,‡‡ and Chia–Hung Kao**,§§ *Department of Radiation Oncology, jjDivision of Colon and Rectal Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei; ‡Institute of Clinical Medicine, National Yang-Ming University, Taipei; § Management Office for Health Data, #Department of Public Health, **Graduate Institute of Clinical Medicine Science and School of Medicine, College of Medicine, ‡‡Department of Radiation Oncology, §§Department of Nuclear Medicine and Positron Emission Tomography Center, China Medical University Hospital, Taichung; and ¶Division of Hematology-Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan BACKGROUND & AIMS:
We investigated whether a diagnosis of colonic diverticular disease is associated with an increased risk for subsequent development of colorectal cancer (CRC) in a nationwide population-based retrospective study.
METHODS:
We identified 41,359 individuals diagnosed with colonic diverticular disease as inpatients from 2000 through 2009 from the Taiwan National Health Insurance Research Database (study cohort) and collected data for 165,436 randomly selected additional subjects, matched by sex, age, and baseline year (comparison cohort). Data were collected until individuals developed CRC or withdrew from the National Health Insurance system, or until December 31, 2010. Cumulative incidences and hazard ratios (HRs) of CRC development were determined. To assess for ascertainment bias, we conducted an analysis excluding the first 12 months of follow-up evaluation.
RESULTS:
The risk of CRC was significantly higher in the study cohort than in the comparison cohort (HR adjusted for age, sex, and comorbidities, 4.54; 95% confidence interval, 4.19–4.91; P < .0001). In a sensitivity analysis, we excluded the first 12 months of follow-up evaluation after a diagnosis of colonic diverticular disease; subsequent incidence rates for CRC in the study and comparison cohorts were 15.13 and 15.74 per 10,000 person-years, respectively (adjusted HR, 0.96; 95% confidence interval, 0.83–1.11).
CONCLUSIONS:
Colonic diverticular disease is not associated with an increased risk of subsequent CRC after the first year of diagnosis of colonic diverticular disease. An increased risk was observed in the first year, possibly owing to misclassification and screening effects.
Keywords: Diverticulitis; Colon Cancer; NHIRD; Epidemiology.
olonic diverticular disease and colorectal cancer (CRC) are important global health care problems. Both are extremely common, and the overall economic burden is considerable.1,2 Autopsy studies have found colonic diverticular disease to have a prevalence rate of 5% to 52% in the West, and of 1% to 19% in Asia.3 The sequelae arising from colonic diverticular disease are important causes of morbidity, including inflammation, obstruction, infection, bleeding, fistula formation, perforation, and death.4 CRC is the third most common cancer in men and the second most common cancer in women worldwide, with more than 1.2 million new cancer cases and 608,700 deaths estimated to have occurred in 2008.2
C
Colonic diverticular disease and CRC share certain characteristics. In epidemiology, the incidence rates of them are much higher in the West than in other areas of the world and they are diseases that primarily affect the elderly.1–4 In etiology, lack of physical activity and obesity also are associated with both diseases in
Abbreviations used in this paper: CI, confidence interval; CRC, colorectal cancer; HR, hazard ratio; ICD-9-CM, International Classification of Diseases, 9th revision, Clinical Modification; NHIRD, National Health Insurance Research Database. © 2014 by the AGA Institute 1542-3565/$36.00 http://dx.doi.org/10.1016/j.cgh.2013.11.039
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Huang et al
prospective cohort studies and meta-analysis.5–8 Therefore, their epidemiologic correlation is an interesting issue. There have been some reports published to date to investigate their association. Certain reports have shown a positive correlation between colonic diverticular disease and CRC.9–13 However, other publications have failed to show an association14–16 or a negative correlation.17,18 The results are discrepant and insufficiently strong to draw firm conclusions. Most studies have focused on the population in the West. To the best of our knowledge, no study has been conducted in Asia to investigate the epidemiologic association between colonic diverticular disease and CRC using a nationwide population-based data set. In Taiwan, CRC is the second most common cancer for both men and women, with an incidence of 53.99 per 100,000 for men and 41.43 per 100,000 for women, according to the 2008 cancer report released by the Taiwan Department of Health.19 The Taiwan National Health Insurance Research Database (NHIRD) is composed of deidentified medical claims from 99% of Taiwan’s 23 million people. The database is available to researchers in Taiwan and has been used extensively in epidemiologic studies.20,21 Furthermore, the accuracy and high validity of the data in the NHIRD also have been shown.22,23 This study provides an opportunity to examine our hypothesis that a diagnosis of colonic diverticular disease is associated with an increased risk of subsequent CRC development in a nationwide population-based cohort study in Taiwan.
Methods Data Source The Taiwan NHI program became a universal insurance system in 1996, covering nearly 99% of 23 million citizens in Taiwan in 1998. The National Health Research Institute established and managed the NHIRD, which involved annual reimbursement claim data from the Taiwan NHI program. All personal identification information was encoded to protect patient privacy before being released for research. The National Health Research Institute created a secret, anonymous identification number to link each patient’s information, including sex, birth date, and medical service registry such as diagnosis codes, prescription drugs, surgery code, and so forth. In this study, disease diagnosis was defined by the International Classification of Diseases, 9th revision, Clinical Modification (ICD-9-CM) from NHIRD inpatient data. This study was approved by the Ethics Review Board at China Medical University (CMU-REC-101-012).
Study Population This was a population-based, retrospective cohort study. The participants in both the study and
Clinical Gastroenterology and Hepatology Vol.
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comparison cohort were extracted from the NHIRD. In the study cohort, the inclusion criteria were patients who were admitted in 2000 to 2009 with a newly diagnosed colonic diverticular disease (ICD-9-CM 562.1), and patients who were age 18 years or older. The exclusion criterion was those who had a history of any cancer. In the comparison cohort, the participants were extracted by random selection from all of NHIinsured individuals without a diagnosis of ICD-9-CM 562.1 during the same period. We matched each diverticular disease patient to 4 nondiverticular disease patients by age, sex, and baseline year. The diagnosis of CRC (ICD-9-CM 153 and 154) was collected from the registry of the Catastrophic Illness Patient Database, a subset of the NHIRD, which only included patients with histologic confirmation and supporting evidence. The accuracy and high validity of diagnoses identified in the NHIRD have been shown in previous studies.22,23 We performed a subanalysis and defined the diverticulosis group as inpatients with a diagnosis of diverticulosis (ICD-9 CM-562.10 and/or 562.12). The diverticulitis group was defined as inpatients with a diagnosis of diverticulitis (ICD-9-CM 562.11 and/or 562.13) or with both diverticulosis (ICD-9 CM-562.10 and/or 562.12) and diverticulitis (ICD-9-CM 562.11 and/or 562.13). This research excluded patients with cancer or patients younger than age 18. Subsequent CRC, the main event of this study, was defined by ICD-9-CM 153 and 154 from the registry of the Catastrophic Illness Patient Database. A cancer that was discovered very soon after the diverticular disease was diagnosed actually may represent an incorrect initial diagnosis (because the symptoms are similar) or the subsequent diagnosis of cancer because a colonoscopy then was performed. To detect this problem, a sensitivity analysis was performed to assess for ascertainment bias and we excluded the first 12 months of follow-up evaluation after a diagnosis of colonic diverticular disease. The follow-up evaluation was terminated when CRC occurred, when the patient lost insurance, or on December 31, 2010. The database only provided the date of insurance withdrawal, but did not record the reason why the insurance was removed. Common reasons for insurance withdrawal include fulfilling mandatory military service requirements, being expatriated to another country, imprisonment, and death. We considered demographic factors and CRCassociated comorbidity confounding factors. The CRC-associated comorbidities included hypertension (ICD-9-CM 401-405), diabetes (ICD-9-CM 250), and hyperlipidemia (ICD-9-CM 272). They were all risk factors for CRC and their prevalence rates were extremely high in Taiwan. We chose them as the factors that should be adjusted, with concern for their potential confounding effect. Furthermore, we also used the Charlson Comorbidity Index to adjust comorbidities.
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2014
Statistical Analysis We showed the mean and standard deviation for continuous variables, the number and percentage for category variables to describe colonic diverticular disease distribution and the comparison cohort, and we used the t test for continuous variables and the chisquare test for category variables to test the difference between the 2 cohorts. The total incidence, demographicspecific incidence, and comorbidity-specific incidence of developing CRC was calculated per 10,000 person-years. The Kaplan–Meier method was used to estimate the cumulative CRC incidence curves for study cohorts and the log-rank test was used to test the difference of these 2 curves. Demographic-specific incidence and the hazard ratio (HR) of CRC stratified by age, sex, and comorbidities also were analyzed. The Cox proportional hazards regression model with adjusted potential confounding factors was used to estimate the HR and the confidence interval (CI) for the study cohort, compared with the comparison cohort. Data management and analysis were performed using SAS 9.1 software (SAS Institute, Cary, NC). The competing risk analysis and the plot of the cumulative incidence curve was performed using STATA SE 11 (Stata Corp, College Station, TX). The data initially were analyzed including the entire population. Because potential confounding factors might have exaggerated or lessened differences, the 5 comorbidities previously noted for which information was available in the database were considered separately: age, sex, hypertension, diabetes, and hyperlipidemia. Because multiple analyses were being performed, a P value of .01 was used as the measure of significance.
Results The cohort included 41,359 patients with diverticular disease. Of these patients, 28,909 had diverticulitis and 12,450 had diverticulosis. There was a total of 165,436 individuals in the comparison cohort. Table 1 shows the demographic characteristic distribution of the cohorts. The mean age of these 2 cohorts was 56 years, and men comprised 56% of the study population. The proportion of all comorbidities in the study cohort was greater than that in the comparison cohort (all P values < .0001). The analysis with the start of follow-up since the index date (no lag period) showed that the participants with colonic diverticular disease had a significantly increased risk of subsequent CRC (adjusted HR, 4.54; 95% CI, 4.19–4.91; P < .0001) (Table 2). The cumulative subsequent CRC incidence curve for the participants with colonic diverticular disease was significantly higher than the curve for the comparison group (Figure 1A, P value for log-rank < .0001). The high incidence of CRC in the first year, especially in the first 4 months, contributed
Diverticular Disease and Colon Cancer
3
Table 1. Baseline Demographic Status and Comorbidities of the Comparison and Study Cohorts
Variable Age, y (SD)a .99
>.99 72,716 (44.0) 92,720 (56.0)
18,179 (44.0) 23,180 (56.0)
129,018 (78.0)
24,938 (60.3)
5
837 655 500 361 246
653,094 618,172 563,941 495,988 418,702
12.82 10.60 8.87 7.28 5.88
171 130 102 83 56
159,265 150,376 136,350 119,291 100,474
10.74 8.64 7.48 6.96 5.57
NOTE. Model adjusted for age, sex, hypertension, diabetes, and hyperlipidemia. All P > .05. PY, person-year; rate, incidence rate per 10,000 person-years.
Crude HR (95% CI) 0.84 0.83 0.85 0.97 0.96
(0.72–1.00) (0.68–1.00) (0.69–1.06) (0.76–1.23) (0.72–1.29)
Adjusted HR (95% CI) 0.85 0.84 0.87 0.98 0.98
(0.72–1.01) (0.69–1.02) (0.70–1.08) (0.77–1.25) (0.73–1.33)
6
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Table 5. Demographic- and Comorbidity-Specific Incidence of Subsequent CRC and Multivariate Cox Proportional Hazards Regression Analysis Measured HR for the Study Cohort Comparison cohort Variable Age group, y
Association Between Colonic Diverticular Disease and Colorectal Cancer: A Nationwide Population-Based Study Wen–Yen Huang,*,‡ Che–Chen Lin,§ Yee–Min Jen,* Yen–Jung Chang,§ Cheng–Wen Hsiao,jj Muh–Hwa Yang,‡,¶ Chun–Shun Lin,* Fung–Chang Sung,§,# Ji–An Liang,**,‡‡ and Chia–Hung Kao**,§§ *Department of Radiation Oncology, jjDivision of Colon and Rectal Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei; ‡Institute of Clinical Medicine, National Yang-Ming University, Taipei; § Management Office for Health Data, #Department of Public Health, **Graduate Institute of Clinical Medicine Science and School of Medicine, College of Medicine, ‡‡Department of Radiation Oncology, §§Department of Nuclear Medicine and Positron Emission Tomography Center, China Medical University Hospital, Taichung; and ¶Division of Hematology-Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan BACKGROUND & AIMS:
We investigated whether a diagnosis of colonic diverticular disease is associated with an increased risk for subsequent development of colorectal cancer (CRC) in a nationwide population-based retrospective study.
METHODS:
We identified 41,359 individuals diagnosed with colonic diverticular disease as inpatients from 2000 through 2009 from the Taiwan National Health Insurance Research Database (study cohort) and collected data for 165,436 randomly selected additional subjects, matched by sex, age, and baseline year (comparison cohort). Data were collected until individuals developed CRC or withdrew from the National Health Insurance system, or until December 31, 2010. Cumulative incidences and hazard ratios (HRs) of CRC development were determined. To assess for ascertainment bias, we conducted an analysis excluding the first 12 months of follow-up evaluation.
RESULTS:
The risk of CRC was significantly higher in the study cohort than in the comparison cohort (HR adjusted for age, sex, and comorbidities, 4.54; 95% confidence interval, 4.19–4.91; P < .0001). In a sensitivity analysis, we excluded the first 12 months of follow-up evaluation after a diagnosis of colonic diverticular disease; subsequent incidence rates for CRC in the study and comparison cohorts were 15.13 and 15.74 per 10,000 person-years, respectively (adjusted HR, 0.96; 95% confidence interval, 0.83–1.11).
CONCLUSIONS:
Colonic diverticular disease is not associated with an increased risk of subsequent CRC after the first year of diagnosis of colonic diverticular disease. An increased risk was observed in the first year, possibly owing to misclassification and screening effects.
Keywords: Diverticulitis; Colon Cancer; NHIRD; Epidemiology.
olonic diverticular disease and colorectal cancer (CRC) are important global health care problems. Both are extremely common, and the overall economic burden is considerable.1,2 Autopsy studies have found colonic diverticular disease to have a prevalence rate of 5% to 52% in the West, and of 1% to 19% in Asia.3 The sequelae arising from colonic diverticular disease are important causes of morbidity, including inflammation, obstruction, infection, bleeding, fistula formation, perforation, and death.4 CRC is the third most common cancer in men and the second most common cancer in women worldwide, with more than 1.2 million new cancer cases and 608,700 deaths estimated to have occurred in 2008.2
C
Colonic diverticular disease and CRC share certain characteristics. In epidemiology, the incidence rates of them are much higher in the West than in other areas of the world and they are diseases that primarily affect the elderly.1–4 In etiology, lack of physical activity and obesity also are associated with both diseases in
Abbreviations used in this paper: CI, confidence interval; CRC, colorectal cancer; HR, hazard ratio; ICD-9-CM, International Classification of Diseases, 9th revision, Clinical Modification; NHIRD, National Health Insurance Research Database. © 2014 by the AGA Institute 1542-3565/$36.00 http://dx.doi.org/10.1016/j.cgh.2013.11.039
2
Huang et al
prospective cohort studies and meta-analysis.5–8 Therefore, their epidemiologic correlation is an interesting issue. There have been some reports published to date to investigate their association. Certain reports have shown a positive correlation between colonic diverticular disease and CRC.9–13 However, other publications have failed to show an association14–16 or a negative correlation.17,18 The results are discrepant and insufficiently strong to draw firm conclusions. Most studies have focused on the population in the West. To the best of our knowledge, no study has been conducted in Asia to investigate the epidemiologic association between colonic diverticular disease and CRC using a nationwide population-based data set. In Taiwan, CRC is the second most common cancer for both men and women, with an incidence of 53.99 per 100,000 for men and 41.43 per 100,000 for women, according to the 2008 cancer report released by the Taiwan Department of Health.19 The Taiwan National Health Insurance Research Database (NHIRD) is composed of deidentified medical claims from 99% of Taiwan’s 23 million people. The database is available to researchers in Taiwan and has been used extensively in epidemiologic studies.20,21 Furthermore, the accuracy and high validity of the data in the NHIRD also have been shown.22,23 This study provides an opportunity to examine our hypothesis that a diagnosis of colonic diverticular disease is associated with an increased risk of subsequent CRC development in a nationwide population-based cohort study in Taiwan.
Methods Data Source The Taiwan NHI program became a universal insurance system in 1996, covering nearly 99% of 23 million citizens in Taiwan in 1998. The National Health Research Institute established and managed the NHIRD, which involved annual reimbursement claim data from the Taiwan NHI program. All personal identification information was encoded to protect patient privacy before being released for research. The National Health Research Institute created a secret, anonymous identification number to link each patient’s information, including sex, birth date, and medical service registry such as diagnosis codes, prescription drugs, surgery code, and so forth. In this study, disease diagnosis was defined by the International Classification of Diseases, 9th revision, Clinical Modification (ICD-9-CM) from NHIRD inpatient data. This study was approved by the Ethics Review Board at China Medical University (CMU-REC-101-012).
Study Population This was a population-based, retrospective cohort study. The participants in both the study and
Clinical Gastroenterology and Hepatology Vol.
-,
No.
-
comparison cohort were extracted from the NHIRD. In the study cohort, the inclusion criteria were patients who were admitted in 2000 to 2009 with a newly diagnosed colonic diverticular disease (ICD-9-CM 562.1), and patients who were age 18 years or older. The exclusion criterion was those who had a history of any cancer. In the comparison cohort, the participants were extracted by random selection from all of NHIinsured individuals without a diagnosis of ICD-9-CM 562.1 during the same period. We matched each diverticular disease patient to 4 nondiverticular disease patients by age, sex, and baseline year. The diagnosis of CRC (ICD-9-CM 153 and 154) was collected from the registry of the Catastrophic Illness Patient Database, a subset of the NHIRD, which only included patients with histologic confirmation and supporting evidence. The accuracy and high validity of diagnoses identified in the NHIRD have been shown in previous studies.22,23 We performed a subanalysis and defined the diverticulosis group as inpatients with a diagnosis of diverticulosis (ICD-9 CM-562.10 and/or 562.12). The diverticulitis group was defined as inpatients with a diagnosis of diverticulitis (ICD-9-CM 562.11 and/or 562.13) or with both diverticulosis (ICD-9 CM-562.10 and/or 562.12) and diverticulitis (ICD-9-CM 562.11 and/or 562.13). This research excluded patients with cancer or patients younger than age 18. Subsequent CRC, the main event of this study, was defined by ICD-9-CM 153 and 154 from the registry of the Catastrophic Illness Patient Database. A cancer that was discovered very soon after the diverticular disease was diagnosed actually may represent an incorrect initial diagnosis (because the symptoms are similar) or the subsequent diagnosis of cancer because a colonoscopy then was performed. To detect this problem, a sensitivity analysis was performed to assess for ascertainment bias and we excluded the first 12 months of follow-up evaluation after a diagnosis of colonic diverticular disease. The follow-up evaluation was terminated when CRC occurred, when the patient lost insurance, or on December 31, 2010. The database only provided the date of insurance withdrawal, but did not record the reason why the insurance was removed. Common reasons for insurance withdrawal include fulfilling mandatory military service requirements, being expatriated to another country, imprisonment, and death. We considered demographic factors and CRCassociated comorbidity confounding factors. The CRC-associated comorbidities included hypertension (ICD-9-CM 401-405), diabetes (ICD-9-CM 250), and hyperlipidemia (ICD-9-CM 272). They were all risk factors for CRC and their prevalence rates were extremely high in Taiwan. We chose them as the factors that should be adjusted, with concern for their potential confounding effect. Furthermore, we also used the Charlson Comorbidity Index to adjust comorbidities.
-
2014
Statistical Analysis We showed the mean and standard deviation for continuous variables, the number and percentage for category variables to describe colonic diverticular disease distribution and the comparison cohort, and we used the t test for continuous variables and the chisquare test for category variables to test the difference between the 2 cohorts. The total incidence, demographicspecific incidence, and comorbidity-specific incidence of developing CRC was calculated per 10,000 person-years. The Kaplan–Meier method was used to estimate the cumulative CRC incidence curves for study cohorts and the log-rank test was used to test the difference of these 2 curves. Demographic-specific incidence and the hazard ratio (HR) of CRC stratified by age, sex, and comorbidities also were analyzed. The Cox proportional hazards regression model with adjusted potential confounding factors was used to estimate the HR and the confidence interval (CI) for the study cohort, compared with the comparison cohort. Data management and analysis were performed using SAS 9.1 software (SAS Institute, Cary, NC). The competing risk analysis and the plot of the cumulative incidence curve was performed using STATA SE 11 (Stata Corp, College Station, TX). The data initially were analyzed including the entire population. Because potential confounding factors might have exaggerated or lessened differences, the 5 comorbidities previously noted for which information was available in the database were considered separately: age, sex, hypertension, diabetes, and hyperlipidemia. Because multiple analyses were being performed, a P value of .01 was used as the measure of significance.
Results The cohort included 41,359 patients with diverticular disease. Of these patients, 28,909 had diverticulitis and 12,450 had diverticulosis. There was a total of 165,436 individuals in the comparison cohort. Table 1 shows the demographic characteristic distribution of the cohorts. The mean age of these 2 cohorts was 56 years, and men comprised 56% of the study population. The proportion of all comorbidities in the study cohort was greater than that in the comparison cohort (all P values < .0001). The analysis with the start of follow-up since the index date (no lag period) showed that the participants with colonic diverticular disease had a significantly increased risk of subsequent CRC (adjusted HR, 4.54; 95% CI, 4.19–4.91; P < .0001) (Table 2). The cumulative subsequent CRC incidence curve for the participants with colonic diverticular disease was significantly higher than the curve for the comparison group (Figure 1A, P value for log-rank < .0001). The high incidence of CRC in the first year, especially in the first 4 months, contributed
Diverticular Disease and Colon Cancer
3
Table 1. Baseline Demographic Status and Comorbidities of the Comparison and Study Cohorts
Variable Age, y (SD)a .99
>.99 72,716 (44.0) 92,720 (56.0)
18,179 (44.0) 23,180 (56.0)
129,018 (78.0)
24,938 (60.3)
5
837 655 500 361 246
653,094 618,172 563,941 495,988 418,702
12.82 10.60 8.87 7.28 5.88
171 130 102 83 56
159,265 150,376 136,350 119,291 100,474
10.74 8.64 7.48 6.96 5.57
NOTE. Model adjusted for age, sex, hypertension, diabetes, and hyperlipidemia. All P > .05. PY, person-year; rate, incidence rate per 10,000 person-years.
Crude HR (95% CI) 0.84 0.83 0.85 0.97 0.96
(0.72–1.00) (0.68–1.00) (0.69–1.06) (0.76–1.23) (0.72–1.29)
Adjusted HR (95% CI) 0.85 0.84 0.87 0.98 0.98
(0.72–1.01) (0.69–1.02) (0.70–1.08) (0.77–1.25) (0.73–1.33)
6
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Table 5. Demographic- and Comorbidity-Specific Incidence of Subsequent CRC and Multivariate Cox Proportional Hazards Regression Analysis Measured HR for the Study Cohort Comparison cohort Variable Age group, y
