Risk of colorectal cancer in patients with alcoholism: A nationwide, population-based nested case-control study.

BACKGROUND: Colorectal cancer (CRC) is regarded as a multifactorial disease and shares many risk factors with alcoholism. However, the association between alcoholism and CRC remains controversial.
OBJECTIVES: In this study, we aimed to evaluate the association between alcoholism and risk of CRC.
METHODS: We performed a large-scale, population-based nested case-control study using the Longitudinal Health Insurance Database 2013, derived from Taiwan's National Health Insurance Research Database, and collected data from 2000 to 2013. There were 49,095 diagnosed cases of CRC defined according to the International Classification of Diseases, Ninth Revision, Clinical Modification. Each case was matched with three controls by sex, age, index date of CRC, and annual medical visits; a total of 147,285 controls were identified. Multiple risk factors of CRC in alcoholism cases were investigated using unconditional multiple logistic regression analysis.
RESULTS: Among 49,095 cases of CRC, alcoholism was associated with a significantly higher risk of CRC (adjusted odds ratio (OR), 1.631; 95% CI, 1.565-1.699) in multivariate logistic regression, after adjusting other CRC risk factors, and in stratified analysis with multivariate logistic regression. In addition, there was a time-dependent relationship between alcoholism duration and CRC risk in >1 year, > 2 years, >5 years, and > 11 years groups (adjusted ORs, 1.875, 2.050, 2.662 and 2.670; 95% CI, 1.788-1.967, 1.948-2.158, 2.498-2.835, and 2.511-2.989 respectively).
CONCLUSION: An association between alcoholism and risk of CRC was found in this study. Furthermore, patients with longer alcoholism history showed higher likelihood of developing CRC, which indicates a time-dependent relationship between alcoholism exposure and CRC. Further research on colorectal tumorigenesis is needed.

Introduction

Alcohol use disorder (AUD) is characterized by habitual alcohol consumption, loss of control over alcohol intake, having a negative emotional state when not using alcohol, and is considered a composite of alcohol dependence syndrome and alcoholism[1, 2]. The 2016 World Health Organization Global Burden of Diseases, Injuries, and Risk Factors Study warned that alcohol use was the seventh leading cause of death and the highest factor for disability-adjusted life-years worldwide[3, 4]. Alcohol consumption seems to have a strong relationship with developing cancers of the oral cavity, pharynx, esophagus, stomach, colorectum, central nervous system, pancreas, breast, and prostate[5, 6]. Colorectal cancer (CRC) is a major health challenge and has become the most common cancer in Taiwan, with the third leading age-standardized mortality rate among all fatal cancers[7, 8].

Several studies have reported that CRC is a multifactorial disease process and seems to share many risk factors with alcoholism[9, 10], which might have direct effects on colon carcinogenesis processes via multiple molecular metabolites, including oxidative and non-oxidative byproducts and changes in gut environmental factors that can progressively affect genetic alterations, followed by cancer cell proliferation[11]. However, the association between alcohol and CRC remains controversial. Some studies have revealed alcohol consumption as an independent and important risk factor for CRC that may also influence prognosis and enhance mortality rate[12, 13]. Other studies have showed no or even an inverse relationship between alcohol and CRC, particularly wine[14-16].

To extend the understanding between risk of CRC and alcoholism, we conducted a large, nationwide, population-based nested case-control study using the Taiwan’s National Health Insurance Research Database (NHIRD) to investigate the effect of alcoholism on CRC risk.

Methods

Data source

The National Health Insurance program (NHIP), run by the government of Taiwan, was started in 1995 and covers more than 99% of the Taiwanese population (i.e., more than 23 million beneficiaries per year). The NHIRD was derived in 1997 from the NHIP, which contains all original claims data and medical records including the characteristics of ambulatory care, hospital inpatient care, patients seen in emergency departments, prescription records, and disease diagnoses. Therefore, the database is representative of the population of Taiwan and had been used for health economics and research on health care utilization, preventive healthcare, and other medical research purposes, in addition to national health policy[17]. We analyzed the Longitudinal Health Insurance Database (LHID), which is a dataset of one million people randomly sampled in 2013 from the NHIRD, with identifying information of each patient encrypted to protect privacy. Among all beneficiaries, we collected data on 989,753 individuals with 26,769,418 medical events from January 1, 2000, to December 31, 2013. The conformation and features of individuals registered in the LHID were normally distributed. Owing to the ability to easily link with data of population-based screening for cancers using personal patient identification numbers, the selected sample of patients with CRC was free of selection and participation bias[17, 18].

In Taiwan, strict measures are adopted for cancer diagnoses. Insured patients with CRC are diagnosed by a clinical physician with confirmation through the pathological examination of tissue biopsy, and the inclusion criteria of alcoholism and CRC are well defined on the basis of International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM). To register the details of diagnosed patients in their catastrophic illness certificates, coding of diagnoses are processed rigorously by clinical physicians, with formal reviews conducted by medical professionals of the National Health Insurance Administration (NHIA)[19]. Therefore, these data are monitored and strictly evaluated by the Bureau of National Health Insurance for reimbursement purposes, and the diagnoses of alcoholism and CRC are highly reliable.

Study design, participants, and ethics

We conducted a nested case-control study to examine the association between alcoholism and CRC. We used ICD-9-CM coding system to identify diagnoses. CRC is defined as ICD-9-CM codes 153, 153.0–153.3, 153.6–153.9, 154, 154.0–154.3, 154.8, and 159. Alcoholism is defined as ICD-9-CM codes 291.0–291.5, 291.81, 291.89, 291.9, 303.00–303.03, 303.90–303.93, 350.00–350.03, 571.0–571.3, 571.40, 571.41, 571.49, V11.3, V61.41, and V79.1. Other types of malignancy are defined as ICD-9-CM codes 140–208.

We enrolled patients with at least three outpatient or inpatient visits who were diagnosed between 2000 and 2013, to ensure validity. We excluded beneficiaries with any prior history of cancer diagnosed before CRC, patients younger than 18 years old, and those with unknown or missing information of sex. Patients without CRC in the control group were randomly selected from the LHID using a strategy for matching according to sex, age (with the same birth year), the index date (date of the first diagnosed record of CRC), and annual medical visits. The ratio for selection was 1:3 (case:control). The same exclusion criteria were applied to the control group. Over the 14-year study period, we identified 49,095 cases of CRC and acquired 147,285 patients as a control group (Fig 1).

Fig 1

The flowchart of study design (nested case-control study) from National Health Insurance Research Database in Taiwan.

This study was approved by the Institutional Review Board of Tri-Service General Hospital (TSGHIRB NO. 2-106-05-029).

Variables of interest, comorbidities

Sociodemographic characteristics are recorded in the LHID, including age, sex, insurance premium, location, hospital level, residential urbanization level, and other comorbidities. The 368 cities/towns in Taiwan are divided into four groups ranked by urbanization level according to several indicators and based on population size. Level 1 refers to the most urbanized areas and Level 4 refers to the least urbanized areas based on an NHIA report. Comorbid diseases were identified as follows: chronic obstructive pulmonary disease (COPD) (ICD-9-CM codes 490–496), diabetes mellitus (DM) (ICD-9-CM code 250), coronary artery disease (CAD) (ICD-9-CM codes 410–414), hypertension (HTN) (ICD-9-CM codes 401–405), hypercholesterolemia (ICD-9-CM codes 272.0–272.4), peptic ulcer (ICD-9-CM codes 531–533), inflammatory bowel disease (IBD) (ICD-9-CM codes 555–556), and colorectal polyp (ICD-9-CM codes 211.3–211.4, 569.0). Epidemiologic studies have consistently reported a positive association between obesity, smoking and CRC[20, 21]. Nevertheless, data on obesity and cigarette smoking were not available in the NHIRD. In the present study, obesity-related diseases (ICD-9-CM code 250, DM; ICD-9-CM codes 401–405, HTN; ICD-9-CM codes 272.0–272.2, and 272.4, hypercholesterolemia; and ICD-9-CM codes 410–414, CAD) were used as surrogates of obesity, and smoking-related diseases (ICD-9-CM codes 490–496, COPD) were used as surrogates of cigarette smoking; these were treated as potential confounders in multivariable logistic regression analysis.

Statistical analysis

Distributions of sociodemographic data and comorbidities were compared between CRC cases and controls using the chi-squared test for categorial variables and t-test for continuous variables. Unconditional multiple logistic regression analyses were performed to evaluate the risks of CRC associated with alcoholism, adjusted for the confounding effects of age, sex, insurance premium level, and all abovementioned comorbidities. Adjusted models with significant covariates were constructed using backward selection with the likelihood ratio test. Risk factors of CRC analyses were conducted with stratification by different variables. Further analysis was performed for assessing the dose-response effect of alcoholism on risk of CRC according to the duration in years of alcoholism. SAS 9.4 software (SAS Institute, Cary, NC, USA) was used for data analysis. A significance level of P < .05 was used in two-sided tests.

Results

Data were recruited from the LHID from 2000 to 2013, including data of a total 989,753 individuals database in Taiwan. There were 59,308 patients included in this analysis who had at least three outpatient or inpatient visits with a CRC diagnosis. After applying the exclusion criteria, 49,095 patients were identified for inclusion in the case group. For the control group, we applied the same exclusion criteria and used a threefold propensity score matching strategy by sex, age, index date, and annual medical visits, thus identifying 147,285 patients for inclusion in the control group.

Table 1 lists various demographic characteristics of the case and control groups and highlights significant differences between the two groups. The findings revealed that alcoholism, patients’ insurance premium, comorbidities, location, residential urbanization level, and hospital level of care were significantly different between the case and control groups. In particular, patients in the case group were more likely to have comorbidities, including COPD, DM, CAD, HTN, hypercholesterolemia, peptic ulcer, IBD, and colorectal polyp, than the control group (P < .05). In most patients with CRC, their disease was diagnosed and treated in Northern, Middle and Southern Taiwan, which have a combination of urbanization level 1 and 2 cities, and these patients were predominantly treated in medical centers.

Table 1

Demographic characteristics and comorbidities in the study with and without colorectal cancer.

	CRC
	With	Without
Variables	N = 49095	N = 147285	P value
Alcoholism	N (%)	N (%)	<0.001
Without	44,898(91.45)	137,294(93.22)
With	4,197(8.55)	9,991(6.78)
Gender			0.999
Male	28,325(57.69)	84,975(57.69)
Female	20,770(42.31)	62,310(42.31)
Age group (years)			0.999
18–44	3,593(7.32)	10,779(7.32)
45–64	17,649(35.95)	52,947(35.95)
≧65	27,853(56.73)	83,559(56.73)
Insured premium (NT$)			<0.001
<18,000	46,235(94.17)	136,902(92.95)
18,000–34,999	1,897(3.86)	7,820(5.31)
≧35,000	963(1.96)	2,563(1.74)
Comorbidities
COPD	6,424(13.08)	17,404(11.82)	<0.001
DM	12,764(26.00)	27,644(18.77)	<0.001
CAD	9,177(18.69)	24,623(16.72)	<0.001
HTN	20,709(42.18)	42,874(29.11)	<0.001
Hypercholesterolemia	3,614(7.36)	13,204(8.96)	<0.001
Peptic ulcer	10,192(20.76)	18,140(12.32)	<0.001
IBD	212(0.43)	514(0.35)	0.009
Colorectal polyp	740(1.51)	1006(0.68)	<0.001
Location			<0.001
Northern Taiwan	19,906(40.55)	53,168(36.10)
Middle Taiwan	13,361(27.21)	44,371(30.13)
Southern Taiwan	13,305(27.10)	37,306(25.33)
Eastern Taiwan	2,495(5.08)	11,544(7.84)
Outlets islands	28(0.06)	896(0.61)
Urbanization level			<0.001
1 (The highest)	17,466(35.58)	38,410(26.08)
2	21,993(44.80)	64,267(43.63)
3	2,718(5.54)	12,923(8.77)
4 (The lowest)	6,918(14.09)	31,685(21.51)
Level of care			<0.001
Hospital center	20,700(42.16)	38,393(26.07)
Regional hospital	22,555(45.94)	72,614(49.30)
Local hospital	5,840(11.90)	36,278(24.63)
Annual medical visits	9.82±10.34	9.75±10.71	0.206

CRC = colorectal cancer, COPD = chronic obstructive pulmonary disease, DM = diabetes mellitus, CAD = coronary artery disease, HTN = hypertension, IBD = inflammatory bowel disease, P: Chi-square / Fisher exact test on category variables and t-test on continue variables

In Table 2, the differences between the case and control group were analyzed in multivariate logistic regression. After adjusting other CRC risk factors of age, insurance premium, comorbidities, location, and urbanization level, the alcoholism group had a consistently higher risk of CRC than the control group (adjusted odds ratio (OR), 1.631; 95% CI, 1.565–1.699). In Table 3, we conducted a stratified analysis with multivariable logistic regression for the factors between case and control groups. The results indicated that participants with previous alcoholism had higher CRC risk, regardless of sex (adjusted ORs, 3.103 and 1.291; 95% CIs, 2.870–3.358 and 1.224–1.358, respectively, in male and female participants). For age groups 45–64 years, and 65 years or older, participants with alcoholism also showed higher CRC risk (adjusted ORs, 1.110 and 2.649; 95% CIs, 1.028–1.174 and 2.497–2.811, respectively). When we applied stratified analysis according to insurance premium, alcoholism history was associated with increased risk of CRC in both low (premium < 18,000 NTD) and medium (premium 18,000~34,999 NTD) level categories: adjusted ORs (95% CIs) were 1.510 (1.081–2.120) and 1.633 (1.565–1.702), respectively. For comorbidities such as COPD, DM, CAD, HTN, hypercholesterolemia, peptic ulcer, IBD, and colorectal polyp, similar associations were found in that previous alcoholism presented higher CRC risk. Furthermore, when we stratified participants according to residential urbanization levels (the highest level 1 to the lowest level 4) and healthcare levels (hospital center, regional hospital and local hospital), the data revealed that patients with prior alcoholism had significantly greater CRC risk across all patient visit variables (urbanization levels adjusted ORs, 1.790, 1.690, 1.668, and 1.335; 95% CIs, 1.657–1.934, 1.589–1.798, 1.436–1.940, and 1.211–1.470 respectively; healthcare levels adjusted ORs, 1.987, 1.515, and 1.456; 95% CIs, 1.645–2.412, 1.427–1.599, and 1.401–1.708 respectively).

Table 2

Factors of CRC by using multivariable logistic regression.

Variables	Adjusted OR	95% CI
Alcoholism
Without	1 (Reference)
With	1.631	(1.565–1.699) ***
Gender
Male	1.019	(0.997–1.042)
Female	1 (Reference)
Age group (years)
18–44	1 (Reference)
45–64	1.038	(0.993–1.086)
≧65	1.242	(1.187–1.300) ***
COPD
Without	1 (Reference)
With	1.644	(1.625–1.665) ***
DM
Without	1 (Reference)
With	1.814	(1.793–1.835) ***
CAD
Without	1 (Reference)
With	1.666	(1.647–1.685) ***
HTN
Without	1 (Reference)
With	1.724	(1.706–1.742) ***
Hypercholesterolemia
Without	1 (Reference)
With	0.500	(0.480–0.520) ***
Peptic ulcer
Without	1 (Reference)
With	1.007	(0.961–1.035)
IBD
Without	1 (Reference)
With	1.479	(1.247–1.755) ***
Colorectal polyp
Without	1 (Reference)
With	2.195	(1.987–2.432) ***

OR = odds ratio, CI = confidence interval, Adjusted OR = Adjusted odds ratio: Adjusted for the variables listed in Table 1.

*P < .05, **P < .01,

***P < .001

Table 3

Factors of CRC stratified by variables listed in the table by using multivariable logistic regression.

	With Alcoholism vs. without Alcoholism
Stratified	Ratio	Adjusted OR (95%CI)
Total	1.260	1.631(1.565–1.699)***
Gender
Male	1.284	3.103(2.870–3.358)***
Female	1.214	1.291(1.224–1.358)***
Age group (years)
18–44	1.021	1.078(0.914–1.255)
45–64	1.068	1.110(1.028–1.174)**
≧65	1.501	2.649 (2.497–2.811)***
COPD	1.311	1.808(1.650–1.980)***
DM	1.254	1.688(1.604–1.775) ***
CAD	1.388	1.771(1.632–1.922) ***
HTN	1.350	1.751(1.651–1.858) ***
Hypercholesterolemia	1.140	1.414(1.256–1.592) ***
Peptic ulcer	1.176	2.101(1.993–2.211) ***
IBD	1.818	1.757(1.022–3.100) **
Colorectal polyp	1.286	1.879(1.592–2.304) ***
Urbanization level
1 (The highest)	1.518	1.790(1.657–1.934) ***
2	1.349	1.690(1.589–1.798) ***
3	1.276	1.668(1.436–1.940) ***
4 (The lowest)	1.040	1.335(1.211–1.470) ***
Level of healthcare
Hospital center	1.729	1.987(1.645–2.412) ***
Regional hospital	1.252	1.515(1.427–1.599) ***
Local hospital	1.137	1.456(1.401–1.708) ***

Ratio = With/Without alcoholism; Adjusted OR = Adjusted odds ratio: Adjusted for the variables listed in Table 2.; CI = confidence interval

*P < .05, **P < .01,

***P < .001

In subsequent analysis, we additionally stratified participants according to duration of alcoholism in multivariable logistic regression, to further examine the association between alcoholism and CRC. The duration of alcoholism was divided into four groups (> 1 year, > 2 years, > 5 years, and > 11 years); the final results are presented in Table 4. The results of analysis showed a possible time-dependent relationship between alcoholism duration and CRC risk in the > 1 year, > 2 years, > 5 years, and > 11 years groups (adjusted ORs, 1.875, 2.050, 2.662 and 2.670; 95% CI, 1.788–1.967, 1.948–2.158, 2.498–2.835, and 2.511–2.989 respectively). In other words, patients who had a longer alcoholism history showed higher likelihood of CRC.

Table 4

CRC among different retrospective duration by using multivariable logistic regression.

Retrospective duration	With CRC (N = 49,095)	Without CRC (N = 147,285)	With CRC vs. Without CRC
	Alcoholism exposure N (%)		Adjusted OR (95%CI)
Overall	4,197 (8.55)	9,991 (6.78)	1.631 (1.565–1.699) ***
> 1 year	2,980 (6.07)	7,884 (5.35)	1.875 (1.788–1.967) ***
> 2 years	2,513 (5.12)	6,681 (4.54)	2.050 (1.948–2.158) ***
> 5 years	1,552 (3.16)	4,260 (2.89)	2.662 (2.498–2.835) ***
> 11 years	614 (1.25)	1,596 (1.08)	2.670 (2.511–2.989) ***

Adjusted OR = Adjusted odds ratio: Adjusted for the variables listed in Table 2.; CI = confidence interval

Retrospective duration: The last alcoholism exposure diagnosis before the first CRC diagnosis

>11 years: 1997–2013

*P < .05, '**P < .01,

***P < .001

Discussion

This large-scale, population-based study showed that alcoholism was an independent risk factor for CRC (adjusted OR, 1.631; 95% CI, 1.565–1.699). To the best of our knowledge, this study is the first large population-based analysis that shows a possible direct correlation between CRC and alcoholism. In addition, patients who had longer alcoholism exposure history showed higher likelihood of developing CRC. In other studies, alcohol consumption can be only estimated by means of questionnaires to evaluate the effects of dose-response relationship among heavy drinkers with high risks for developing CRC. However, our study illustrated a time-dependent correlation between alcoholism exposure duration and increased CRC, which is demonstrated by a 17 years follow-up database[14–16, 22].

The topic of alcoholism and CRC sparked much interest among researchers. The development of CRC is recognized as a multifactorial disease process[10], which is typically considered to be affected by hereditary components, genetic factors, diet, lifestyle, environmental factors (including obesity, sedentary behavior, smoking, and alcohol consumption, among others), inflammatory conditions of the digestive tract (encompassing ulcerative colitis and Crohn disease), and acquired somatic mutations with normal colonic mucosa dysplasia that finally lead to pre-neoplastic polyps. An epidemiological study demonstrated that long-term alcohol consumption leads to an increased mortality rate and incidence for cancer[23]. This is proven by a recent meta-analysis that utilize questionnaires to estimate alcohol consumption, which have indicated a J-shaped dose-response relationship between alcohol consumption and CRC mortality, with an overall increased risk for heavy drinkers[24, 25]. In conclusion, our study of NHIRD dataset with 17 years follow-up emphasized the direct correlation between alcoholism exposure history and CRC using the time-dependent relationship method.

Previous studies have reported that alcohol consumption has several direct and indirect effects that contribute to carcinogenesis. For instance, acetaldehyde (the first metabolite of ethanol oxidation) seems to be the most toxic metabolite owing to its mutagenic and carcinogenic properties. Moreover, alcohol and its metabolites may induce cancer-promoting cascades, such as DNA adduct formation, oxidative stress, lipid peroxidation, genetic and epigenetic alterations, intestinal epithelial barrier dysfunction, and immune modulatory effects[5, 26, 27]. Besides, alcohol has been thought to be linked with increased risk of some specific type of colorectal polyps by the accumulation of pathogenic mutations and finally lead to CRC[28, 29]. Another study also postulated that the ADH1C polymorphism and ALDH2*2 allele have strong relationships with CRC[30]. Poor dietary habits, low levels of folate (including decreased folate absorption, and inhibition of folate cycle enzymes) and fiber consumption, as well as circadian rhythm disruption, are thought to directly lead to alcohol-induced colon carcinogenesis[31]. Furthermore, chronic alcohol consumption may also cause intestinal inflammation, which includes changes in intestinal microbiota composition and distribution, increased absorbency of the intestinal epithelium, and alteration of intestinal immune equilibrium[11, 32–34].

Notwithstanding the strengths of our study, the present study had several limitations. First, the diagnoses of alcoholism and CRC were based on diagnostic codes registered by a physician in the claims database of the NHIP; therefore, some registration biases might be involved in the CRC risk, acting as potential confounding factors, which were not excluded from the study. Second, patients with asymptomatic alcoholism may not seek health care until they experience considerable discomfort, leading to underestimation of the CRC risk among patients with alcoholism. Third, information on important confounders for the association between alcoholism and CRC risk, such as family history, obesity, smoking habits, and dietary patterns, were unavailable in the NHIRD. In the present study, we used the diagnostic codes for COPD as a proxy for the confounding covariate of smoking because COPD is well known to be related to smoking habits. In addition, obesity is closely related to DM, HTN, hyperlipidemia, and CAD. The aforementioned factors were adjusted for in partial exclusion of the confounding effect of obesity. However, we were unable to control for the confounding effect of dietary patterns. In the literature, a meta-analysis revealed a significant positive association between a Westernized diet and the risk of CRC[35].

Despite these limitations, the use of a nationwide population database, which provided a large sample size, and adjustment for certain covariates related to alcoholism enabled us to detect a significant relation between alcoholism and the risk of developing CRC. Moreover, we explored the possible time-dependent effect of alcoholism on CRC risk. We further found that the longer the alcoholism history; the higher the likelihood of CRC risk. The onset of alcoholism occurs relatively early in life; therefore, early identification of lifestyle risk factors and symptoms are critical to preventing the development of CRC. Besides, the data in our study showed that alcoholism exposure had no significant impact on the survival of CRC patients (survival rate of 90.04% vs. 90.82% respectively, in alcohol exposure and non-exposure groups, P = 0.095), and the CRC patients with alcoholism exposure had higher medical cost than those without alcoholism exposure (S1 & S2 Tables). Further randomized large-scale prospective studies are needed to confirm these issues, and the effects of management of alcoholism on colorectal tumorigenesis should be elucidated.

Survival among CRC patients with and without alcoholism exposure.

(DOCX)

Click here for additional data file.

Medical cost of the CRC with and without alcoholism exposure.

(DOCX)

Click here for additional data file.

3 Oct 2019

PONE-D-19-23287

Risk of Colorectal Cancer in Patients with Alcoholism: A Nationwide, Population-Based Nested Case-Control Study

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Reviewer #1: 1. This is a large-scale population based study, analyzing by national health insurance database.

2. Colorectal cancer is a multifactorial disease. Many chronic systemic diseases and life habit related factors are related to.

3. Using healthy insurance database as an study cohort may reflect a large scale population result, but also confounded by many bias.

4. How about the relationship between alcoholism and treatment result or impact to survival?

5. How about the cost issue? Treatment for CRC patients with alcoholism cost more?

Reviewer #2: In this study, Tzu-Chiao Lin and colleagues analyzed the risk of colorectal cancer in alcoholism by using Taiwan’s National Health Insurance Research Database which was collected data from 2000 to 2013. The results showed significantly higher risk of colorectal cancer in those patients. Furthermore, there was a time-dependent relationship between alcoholism duration and risk of colorectal cancer which strengthen the evidence. Generally, this article is well prepared and few suggest are listed below:

Abstract:

1. “In this study, we aimed to evaluate the association between alcoholism and CRC.” It might be better to use “risk of CRC.”

2. The abbreviation of “OR” was not defined.

Introduction:

3. As mention in list 1, it would be better to directly use “risk of CRC” rather than “CRC” while the aim was proposed.

Method: no suggestion

Results:

4. The authors analyzed variables including DM, HTN, and peptic ulcer. How about the risk of colon polyps and alcoholism? Strongly recommend to add the information in the main results just as the analyses done for investigating the risk of CRC and alcoholism.

Discussion

5. After the suggestion of list 4 was provided, brief discuss is necessary.

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

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Reviewer #1: No

Reviewer #2: Yes: Wen-Wei, Sung

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org. Please note that Supporting Information files do not need this step.

11 Nov 2019

Dear editor Yu Ru Kou:

We have revised our manuscript and thoughtfully addressed the critiques provided by reviewers. We have highlighted that the results of this study need to be interpreted wthin the context of some limitations. In addition, we have taken into considerations of suggestions by the reviewers. Accordingly, we have presented renewed study results in our revised manuscript. We have highlighted amendments in red fonts. We are enthusiastic on resubmission of our revised manuscript to your esteemed Journal for publication.

Sincerely yours,

Chao-Yang Chen, MD

Division of Colorectal Surgery, Department of Surgery

Tri-Service General Hospital, National Defense Medical Center

Taipei, Taiwan, Republic of China

Submitted filename: Responses to Reviewers.docx

Click here for additional data file.

30 Jan 2020

PONE-D-19-23287R1

Risk of Colorectal Cancer in Patients with Alcoholism: A Nationwide, Population-Based Nested Case-Control Study

PLOS ONE

Dear MD Chen,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Reviwer 3 raised several concerns that need to be adequately addressed or revised.

We would appreciate receiving your revised manuscript by Mar 15 2020 11:59PM. When you are ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter.

To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). This letter should be uploaded as separate file and labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'.

Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.

We look forward to receiving your revised manuscript.

Kind regards,

Yu Ru Kou, PhD

Academic Editor

PLOS ONE

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

Reviewer #3: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: Yes

Reviewer #3: Partly

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: No

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The English writing could be better.

This study is a retrospective cohort study, many limitation of data. However, it did provide some interesting information.

Reviewer #2: The authors answered all questions accordingly. I have no question for this manuscript. It is acceptable for publication.

Reviewer #3: The authors present results from a large-scale populations based study in Taiwan of alcoholism as a risk factor for colorectal cancer (CRC). They find that alcoholism is a risk factor and that there is a time-dependent relationship between the duration of alcoholism and CRC. The manuscript will be strengthened if the authors consider the following points.

1. Controls are matched to cases based on age, gender, index date, and number of medical visits. However, on page 9, authors also mention something about matching cases and controls on residential urbanization level (6th line). I do not think this was actually done based on results presented in Table 1. Authors should clarify their statements.

2. Medical events (including the diagnosis of CRC) were identified from 2000-2013. Since alcoholism and duration of alcoholism are key predictors for the models of interest, were the authors able to go back to 1995 to evaluate this exposure? Authors should clarify the time period for identifying case/control status and the time period reviewable for alcoholism.

3. I am very confused by some of the results presented in Table 2 for the crude OR, in particular, but might carry over to the adjusted OR as well. Specifically, for age group, cases and controls were matched on age and based on Table 1, the percentages in the different age groups between cases and controls are identical. I do not see how the authors find a significant OR for age. I actually used the numbers presented in Table 1 for age group and cases and controls to run a logistic regression and find a non-significant result (p-value of 1). The crude OR for gender (though not significant, as expected, since this was a matching variable) doesn't seem to match what you would get with the numbers presented in Table 1. Similar for other crude ORs presented in Table 2. Authors should carefully check all ORs and confidence intervals and, if needed, clarify what is meant by crude OR (if it is not a simple univariate logistic regression with the listed variable as the single predictor of case status).

Minor points.

1. In the Statistical Analysis section, the authors have a sentence about the dose-response effect of CRC (Further analysis was performed....). This sentence either refers to analyses not presented in the results, or the authors switch CRC and alcoholism. I believe the authors mean to say a dose-response effect of alcoholism on risk of CRC. They further state based on the "average number of medical visits for CRC", but the presented results are based on duration in years of alcoholism, which even if CRC is replaced by alcoholism, doesn't necessarily correspond to number of medical visits. Authors should clarify this statement.

2. on page 11, 2nd paragraph, sentence starting with "In addition, patients in the case group..", "were significantly higher in the case group" should be changed to "than the control group".

3. The note under Table 2 does not list all of the variables included in the adjusted model, since not all variables included in the model are included in the table.

4. Table 4: authors should include information about how many cases/controls had alcoholism by the different durations. Also, in these models was the reference group no alcoholism, so that, for example, in the >5 years results, those with alcoholism for less than 5 years were excluded from the analysis? Also, the note about retrospective duration is confusing, so should be clarified.

5. page 13, 3rd line "is the first large population analysis shows" should be "is the first large population-based analysis that shows"

6. Authors provide supplemental tables but do not refer to them in the text anywhere.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: Yes: Wen-Wei Sung

Reviewer #3: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org. Please note that Supporting Information files do not need this step.

9 Feb 2020

Dear editors and reviewers:

We have revised our manuscript and thoughtfully addressed the critiques provided by reviewers. In addition, we have taken into considerations of suggestions by the reviewers. Accordingly, we have presented renewed study results in our revised manuscript.

Submitted filename: Responses to reviewers.docx

Click here for additional data file.

11 Mar 2020

PONE-D-19-23287R2

Risk of Colorectal Cancer in Patients with Alcoholism: A Nationwide, Population-Based Nested Case-Control Study

PLOS ONE

Dear MD Chen,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

The reviewer still had some minor comments that need to be addressed.

We would appreciate receiving your revised manuscript by Apr 25 2020 11:59PM. When you are ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter.

To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). This letter should be uploaded as separate file and labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'.

Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.

We look forward to receiving your revised manuscript.

Kind regards,

Yu Ru Kou, PhD

Academic Editor

PLOS ONE

Journal Requirements:

Additional Editor Comments (if provided):

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #3: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #3: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #3: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #3: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #3: The authors have addressed the majority of my earlier comments. There remain a few minor points that should be addressed:

1. On page 11, the authors added a sentence "In addition...". The previous statement already states that there are differences between groups in comorbidities, so the authors may want to use "In particular" instead. They also end the sentence after "comorbidities" but that makes the next sentence an incomplete sentence.

2. On page 11, the authors state that most CRC patients were treated in Northern and Southern Taiwan - according to Table 1, Middle Taiwan should also be stated, since a slightly higher percentage of CRC patients came from there than from Southern Taiwan.

3. On page 11, "an combination" should be "a combination"

4. On page 11, last paragraph, the authors mention that Table 2 includes univariate results. The authors opted to remove these results from the table based on my earlier critique (I actually think they are useful, though the authors would then need to check results, because their explanation in their response for the age difference that I questioned is not adequate). I leave it to the editor to decide whether the univariate results need to be presented. If they are not, authors should not refer to them in the text.

5. On page 12, the authors mention findings from stratified analyses based on urbanization levels and healthcare levels without giving relevant statistics or data. Authors are encouraged to either include OR and 95% CI in the text to support the statement, add the results to Table 3 or add a supplemental table that includes the information.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #3: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org. Please note that Supporting Information files do not need this step.

15 Mar 2020

Dear editors and reviewers:

We have revised our manuscript and thoughtfully addressed the critiques provided by reviewers. In addition, we have taken into considerations of suggestions by the reviewers. We have highlighted amendments in red fonts.

Submitted filename: Responses to reviewers.docx

Click here for additional data file.

22 Apr 2020

Risk of Colorectal Cancer in Patients with Alcoholism: A Nationwide, Population-Based Nested Case-Control Study

PONE-D-19-23287R3

Dear Dr. Chen,

We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.

Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication.

Shortly after the formal acceptance letter is sent, an invoice for payment will follow. To ensure an efficient production and billing process, please log into Editorial Manager at https://www.editorialmanager.com/pone/, click the "Update My Information" link at the top of the page, and update your user information. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, you must inform our press team as soon as possible and no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

With kind regards,

Yu Ru Kou, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #3: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #3: (No Response)

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #3: (No Response)

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #3: (No Response)

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #3: (No Response)

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #3: (No Response)

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #3: No

1 May 2020

PONE-D-19-23287R3

Risk of Colorectal Cancer in Patients with Alcoholism: A Nationwide, Population-Based Nested Case-Control Study

Dear Dr. Chen:

I am pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

For any other questions or concerns, please email plosone@plos.org.

Thank you for submitting your work to PLOS ONE.

With kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Yu Ru Kou

Academic Editor

PLOS ONE