Publications by authors named "Andrew T Chan"

653 Publications

Gallstones and risk of cancers of the liver, biliary tract and pancreas: a prospective study within two U.S. cohorts.

Br J Cancer 2022 Jun 17. Epub 2022 Jun 17.

Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

Background: Gallstones may result in inflammation, altered bile flow, and changes in metabolic hormone levels, thereby increasing cancer risk. However, previous studies for gallstones and cancers of the liver, biliary tract and pancreas in the U.S. were relatively limited.

Methods: We followed 115,036 women from the Nurses' Health Study (1982-2012) and 49,729 men from the Health Professionals Follow-up Study (1986-2012). History of gallstones, including with or without performed cholecystectomy, was reported at baseline and updated through biennial questionnaires. The Cox proportional hazard regression model was used to calculate multivariable hazard ratios (HRs) and 95% confidence intervals (95% CIs).

Results: During up to 30-year follow-up, we identified 204 incidents of liver cancer, 225 biliary tract cancer and 1147 pancreatic cancer cases. Compared to those without gallstones diagnosis, the multivariable HRs for individuals with gallstones (untreated or with cholecystectomy) were 1.60 for liver cancer (95% CI: 1.14-2.26), 4.79 for biliary tract cancer (95% CI: 3.02-7.58), and 1.13 for pancreatic cancer (95% CI: 0.96-1.32). The multivariable HRs for individuals with cholecystectomy were 1.33 for liver cancer (95% CI: 0.90-1.95) and 1.15 for pancreatic cancer (95% CI: 0.98-1.36).

Conclusions: Gallstones were associated with a higher risk of cancers of the liver, biliary tract and possibly pancreas.
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http://dx.doi.org/10.1038/s41416-022-01877-5DOI Listing
June 2022

Adherence to a healthy lifestyle in relation to colorectal cancer incidence and all-cause mortality after endoscopic polypectomy: a prospective study in three U.S. cohorts.

Int J Cancer 2022 Jun 18. Epub 2022 Jun 18.

Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

It remains unknown whether maintenance of a healthy lifestyle after endoscopic polypectomy could still confer benefit for colorectal cancer (CRC) incidence and mortality. In this study, we defined a healthy lifestyle score based on body mass index, smoking, physical activity, alcohol consumption, and diet (range, 0-5). We used Cox proportional hazards regression to estimate the hazard ratios (HRs) for the associations of healthy lifestyle score and individual lifestyle factors with CRC incidence and all-cause mortality. During a median of 10 years of follow-up of 24668 participants who underwent endoscopic polypectomy, we documented 161 CRC cases and 4857 all-cause deaths. A higher healthy lifestyle score after endoscopic polypectomy was associated with lower risk of CRC and all-cause mortality. Compared to individuals with 0-1 healthy lifestyle factors, those with 2, 3, and 4-5 healthy lifestyle factors had a HR for CRC risk of 0.86 [95% confidence interval (CI), 0.60-1.24], 0.73 (95% CI, 0.47-1.14), and 0.52 (95% CI, 0.27-1.01), respectively (P =0.03). The corresponding HR (95% CI) for all-cause mortality was 0.83 (95% CI, 0.76-0.90), 0.63 (95% CI, 0.56-0.70), and 0.56 (95% CI, 0.48-0.65), respectively (P <0.0001). In the joint analysis of pre- and post-polypectomy periods, patients with a healthy post-polypectomy lifestyle had a lower incidence of CRC regardless of their pre-polypectomy exposure, whereas those with a healthy lifestyle in both periods had a lower mortality than those with an unhealthy lifestyle in either period. In conclusion, adherence to a healthy lifestyle after polypectomy may confer significant benefit for CRC prevention and reduction in all-cause mortality. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/ijc.34176DOI Listing
June 2022

Identifying colorectal cancer caused by biallelic MUTYH pathogenic variants using tumor mutational signatures.

Nat Commun 2022 Jun 6;13(1):3254. Epub 2022 Jun 6.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

Carriers of germline biallelic pathogenic variants in the MUTYH gene have a high risk of colorectal cancer. We test 5649 colorectal cancers to evaluate the discriminatory potential of a tumor mutational signature specific to MUTYH for identifying biallelic carriers and classifying variants of uncertain clinical significance (VUS). Using a tumor and matched germline targeted multi-gene panel approach, our classifier identifies all biallelic MUTYH carriers and all known non-carriers in an independent test set of 3019 colorectal cancers (accuracy = 100% (95% confidence interval 99.87-100%)). All monoallelic MUTYH carriers are classified with the non-MUTYH carriers. The classifier provides evidence for a pathogenic classification for two VUS and a benign classification for five VUS. Somatic hotspot mutations KRAS p.G12C and PIK3CA p.Q546K are associated with colorectal cancers from biallelic MUTYH carriers compared with non-carriers (p = 2 × 10 and p = 6 × 10, respectively). Here, we demonstrate the potential application of mutational signatures to tumor sequencing workflows to improve the identification of biallelic MUTYH carriers.
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http://dx.doi.org/10.1038/s41467-022-30916-1DOI Listing
June 2022

Incident Cancer Risk and Signatures Among Older MUTYH Carriers: Analysis of Population-Based and Genomic Cohorts.

Cancer Prev Res (Phila) 2022 May 24. Epub 2022 May 24.

Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States.

MUTYH carriers have an increased colorectal cancer (CRC) risk in case-control studies, with loss of heterozygosity (LOH) as the presumed mechanism. We evaluated cancer risk among carriers in a prospective, population-based cohort of older adults. Additionally, we assessed if cancers from carriers demonstrated mutational signatures (G:C>T:A transversions) associated with early LOH. We calculated incident risk of cancer and CRC among 13,131 sequenced study participants of the ASPirin in Reducing Events in the Elderly (ASPREE) cohort, stratified by sex and adjusting for age, smoking, alcohol use, BMI, polyp history, history of cancer, and aspirin use. MUTYH carriers were identified among 13,033 participants in The Cancer Genome Atlas and International Cancer Genome Consortium, and somatic signatures of cancers were analyzed. Male MUTYH carriers demonstrated an increased risk for overall cancer incidence (multivariable HR 1.66, 95% CI [1.03, 2.68]; P = 0.038) driven by increased CRC incidence (multivariable HR 3.55, 95% CI [1.42, 8.78]; P = 0.007), as opposed to extracolonic cancer incidence (multivariable HR 1.40, 95% CI [0.81, 2.44]; P = 0.229). Female carriers did not demonstrate increased risk of cancer, CRC, or extracolonic cancers. Analysis of mutation signatures from cancers of MUTYH carriers revealed no significant contribution toward early mutagenesis from widespread G:C>T:A transversions among gastrointestinal epithelial cancers. Among cancers from carriers, somatic transversions associated with base-excision repair deficiency are uncommon, suggestive of diverse mechanisms of carcinogenesis in carriers compared to those who inherit biallelic MUTYH mutations.
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http://dx.doi.org/10.1158/1940-6207.CAPR-22-0080DOI Listing
May 2022

Stability and reproducibility of proteomic profiles in epidemiological studies: comparing the Olink and SOMAscan platforms.

Proteomics 2022 May 21:e2100170. Epub 2022 May 21.

Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

Limited data exist on the performance of high-throughput proteomics profiling in epidemiological settings, including the impact of specimen collection and within-person variability over time. Thus, the Olink (972 proteins) and SOMAscan7Kv4.1 (7322 proteoforms of 6596 proteins) assays were utilized to measure protein concentrations in archived plasma samples from the Nurses' Health Studies and Health Professionals Follow-Up Study. Spearman's correlation coefficients (r) and intraclass correlation coefficients (ICCs) were used to assess agreement between (1) 42 triplicate samples processed immediately, 24-h or 48-h after blood collection from 14 participants; and (2) 80 plasma samples from 40 participants collected 1-year apart. When comparing samples processed immediately, 24-h, and 48-h later, 55% of assays had an ICC/r ≥ 0.75 and 87% had an ICC/r ≥ 0.40 in Olink compared to 44% with an ICC/r ≥ 0.75 and 72% with an ICC/r ≥ 0.40 in SOMAscan7K. For both platforms, >90% of the assays were stable (ICC/r ≥ 0.40) in samples collected 1-year apart. Among 817 proteins measured with both platforms, Spearman's correlations were high (r > 0.75) for 14.7% and poor (r < 0.40) for 44.8% of proteins. High-throughput proteomics profiling demonstrated reproducibility in archived plasma samples and stability after delayed processing in epidemiological studies, yet correlations between proteins measured with the Olink and SOMAscan7K platforms were highly variable.
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http://dx.doi.org/10.1002/pmic.202100170DOI Listing
May 2022

Association between hypertension and cutaneous melanoma, and the effect of aspirin: extended follow-up of a large randomised controlled trial.

Cancer Epidemiol 2022 May 11;79:102173. Epub 2022 May 11.

School of Public Health and Preventive Medicine, Monash University, 553 St Kilda Road, Melbourne, VIC 3004, Australia; Victorian Melanoma Service, Alfred Health, 55 Commercial Road, Melbourne, VIC 3004, Australia.

Background: The association between hypertension and melanoma is unclear, and previous analyses of data from the ASPirin in Reducing Events in the Elderly (ASPREE) study demonstrated a reduced number of invasive melanoma events amongst aspirin-exposed hypertensive individuals.

Methods: Data from the ASPREE study which included (1) the intervention period with a median follow-up of 4.7 years, and (2) the observational period with an additional 2 years follow-up, were combined for this analysis. Logistic regression analyses examined the association between baseline hypertension and treatment status and past melanoma history. Survival analyses examined the association between hypertension and melanoma risk, and the effect of aspirin across hypertension groups. Cox proportional hazards models were used to compare incidence across groups.

Results: 19,114 participants (median age of 74 years) were randomised to daily 100 mg aspirin or placebo. At baseline, hypertension and past melanoma history were recorded in 14,195 and 685 individuals, respectively. After adjustment for confounders, hypertension was significantly associated with past melanoma history (OR=1.34, 95%CI: 1.11-1.62). In a prospective analysis, baseline hypertension was not associated with melanoma risk. However, aspirin was associated with a reduced risk of incident melanoma amongst individuals with uncontrolled hypertension (blood pressure ≥140/90 mmHg; HR=0.63, 95%CI 0.44-0.89), but not in those with controlled hypertension (HR=1.04, 95%CI 0.74-1.46).

Conclusion: Our results support a reduced melanoma incidence amongst individuals with uncontrolled hypertension exposed to aspirin. Additional studies are required to confirm these findings.
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http://dx.doi.org/10.1016/j.canep.2022.102173DOI Listing
May 2022

Genome-Wide Interaction Analysis of Genetic Variants with Menopausal Hormone Therapy for Colorectal Cancer Risk.

J Natl Cancer Inst 2022 May 5. Epub 2022 May 5.

Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, 3010, Victoria, Australia.

Background: The use of menopausal hormone therapy (MHT) may interact with genetic variants to influence colorectal cancer (CRC) risk.

Methods: We conducted a genome-wide gene-environment interaction between single nucleotide polymorphisms and the use of any MHT, estrogen-only, and combined estrogen-progestogen therapy with CRC risk, among 28,486 postmenopausal women (11,519 cases and 16,967 controls) from 38 studies, using logistic regression, two-step method, and 2- or 3-degree-of-freedom (d.f.) joint test. A set-based score test was applied for rare genetic variants.

Results: The use of any MHT, estrogen-only and estrogen-progestogen were associated with a reduced CRC risk [odds ratio (OR) with 95% confidence interval (95% CI) of 0.71 (0.64-0.78), 0.65 (0.53-0.79), and 0.73 (0.59-0.90), respectively]. The two-step method identified a statistically significant interaction between a GRIN2B variant rs117868593 and MHT use, whereby MHT-associated CRC risk was significantly reduced in women with the GG genotype [0.68 (0.64-0.72)] but not within strata of GC or CC genotypes. A statistically significant interaction between a DCBLD1 intronic variant at 6q22.1 (rs10782186) and MHT use was identified by the 2-d.f. joint test. The MHT-associated CRC risk was reduced with increasing number of rs10782186-C alleles, showing ORs of 0.78 (0.70-0.87) for TT, 0.68 (0.63-0.73) for TC, and 0.66 (0.60-0.74) for CC genotypes. In addition, five genes in rare variant analysis showed suggestive interactions with MHT (two-sided P < 1.2x10-4).

Conclusion: Genetic variants that modify the association between MHT and CRC risk were identified, offering new insights into pathways of CRC carcinogenesis and potential mechanisms involved.
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http://dx.doi.org/10.1093/jnci/djac094DOI Listing
May 2022

Age at Initiation of Lower Gastrointestinal Endoscopy and Colorectal Cancer Risk Among US Women.

JAMA Oncol 2022 May 5. Epub 2022 May 5.

Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston.

Importance: In the past 4 years, the American Cancer Society and the US Preventive Services Task Force updated recommendations to initiate colorectal cancer (CRC) screening at 45 years of age to address the increasing incidence of CRC among adults younger than 50 years. However, empirical evidence evaluating the potential benefits of screening in younger populations is scant.

Objective: To examine the association between endoscopy initiation at different ages and risk of CRC among US women.

Design, Setting, And Participants: This prospective cohort study used data from the Nurses' Health Study II, which included US female health professionals followed up from 1991 through 2017. Data analysis was performed from August 2020 to June 2021.

Exposure: Age at initiation of sigmoidoscopy or colonoscopy for screening (routine screening or because of family history) or symptoms.

Main Outcomes And Measures: Incident CRC, confirmed by medical records, pathology reports, and the National Death Index. Cumulative incidence of CRC in each group was estimated with age as the time scale, and the absolute risk reduction associated with endoscopy initiation at different ages through 60 years was calculated. Cox proportional hazards regression was used to calculate hazard ratios (HRs) and 95% CIs, stratified by age and calendar year of questionnaire cycle and adjusted for CRC risk factors in the multivariable models.

Results: Among 111 801 women aged 26 to 46 years (median, 36 years) at enrollment, 519 incident CRC cases were documented over 26 years, encompassing 2 509 358 person-years of follow-up. In the multivariable analysis, compared with no endoscopy, undergoing endoscopy was associated with a significantly lower risk of incident CRC for age at initiation before 45 years (HR, 0.37; 95% CI, 0.26-0.53), 45 to 49 years (HR, 0.43; 95% CI, 0.29-0.62), 50 to 54 years (HR, 0.47; 95% CI, 0.35-0.62), and 55 years or older (HR, 0.46; 95% CI, 0.30-0.69). The absolute reduction in the estimated cumulative incidence of CRC through 60 years of age was 72 per 100 000 persons for initiation of endoscopy at 45 to 49 years of age vs 50 to 54 years of age. Compared with no endoscopy, initiation of endoscopy before 50 years of age was also associated with a reduced risk of CRC diagnosed before 55 years of age (<45 years: HR, 0.45 [95% CI, 0.29-0.70]; 45-49 years: HR, 0.43 [95% CI, 0.24-0.76]).

Conclusions And Relevance: In this cohort study, compared with no endoscopy, initiation of endoscopy before 50 years of age was associated with a reduced risk of CRC, including CRC diagnosed before 55 years of age. Screening before 50 years of age was associated with greater absolute reduction in CRC risk compared with initiation of CRC screening at 50 years of age or later.
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http://dx.doi.org/10.1001/jamaoncol.2022.0883DOI Listing
May 2022

Proinflammatory Diet Is Associated With Increased Risk of Fecal Incontinence Among Older Women: Prospective Results From the Nurses' Health Study.

Clin Gastroenterol Hepatol 2022 Apr 30. Epub 2022 Apr 30.

Clinical and Translational Epidemiology Unit, Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. Electronic address:

Fecal incontinence (FI) is a debilitating gastrointestinal disorder with a devastating impact on quality of life, particularly on older women, partly because of unique risk factors including parity and menopause. Therefore, identifying modifiable factors, such as diet, are crucial for developing effective prevention strategies for FI among those at risk. We previously found higher dietary fiber intake was associated with lower FI risk, providing the first population-based data to connect diet and FI prevention. However, prospective evidence on other dietary factors and FI risk has been limited. Dietary patterns may be associated with gut microbiome characteristics, which may influence inflammatory responses in the gastrointestinal tract and drive neurosensory disturbances. Moreover, chronic inflammation may drive reduced muscle mass and function, and pelvic floor dysfunction is an established FI risk factor. We hypothesized that a proinflammatory dietary pattern may be associated with increased FI risk and tested this hypothesis in the Nurses' Health Study.
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http://dx.doi.org/10.1016/j.cgh.2022.04.011DOI Listing
April 2022

Sugar-sweetened beverage and sugar consumption and colorectal cancer incidence and mortality according to anatomic subsite.

Am J Clin Nutr 2022 Jun;115(6):1481-1489

Department of Nutrition, Harvard TH Chan School of Public Health, Boston, MA, USA.

Background: Recent preclinical research strongly suggests that dietary sugars can enhance colorectal tumorigenesis by direct action, particularly in the proximal colon that unabsorbed fructose reaches.

Objectives: We aimed to examine long-term consumption of sugar-sweetened beverages (SSBs) and total fructose in relation to incidence and mortality of colorectal cancer (CRC) by anatomic subsite.

Methods: We followed 121,111 participants from 2 prospective US cohort studies, the Nurses' Health Study (1984-2014) and Health Professionals Follow-Up Study (1986-2014), for incident CRC and related death. Cox proportional hazards regression was used to compute HRs and 95% CIs.

Results: During follow-up, we documented 2733 incident cases of CRC with a known anatomic location, of whom 901 died from CRC. Positive associations of SSB and total fructose intakes with cancer incidence and mortality were observed in the proximal colon but not in the distal colon or rectum (Pheterogeneity ≤ 0.03). SSB consumption was associated with a statistically significant increase in the incidence of proximal colon cancer (HR per 1-serving/d increment: 1.18; 95% CI: 1.03, 1.34; Ptrend = 0.02) and a more pronounced elevation in the mortality of proximal colon cancer (HR: 1.39; 95% CI: 1.13, 1.72; Ptrend = 0.002). Similarly, total fructose intake was associated with increased incidence and mortality of proximal colon cancer (HRs per 25-g/d increment: 1.18; 95% CI: 1.03, 1.35; and 1.42; 95% CI: 1.12, 1.79, respectively). Moreover, SSB and total fructose intakes during the most recent 10 y, rather than those from a more distant period, were associated with increased incidence of proximal colon cancer.

Conclusions: SSB and total fructose consumption were associated with increased incidence and mortality of proximal colon cancer, particularly during later stages of tumorigenesis.
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http://dx.doi.org/10.1093/ajcn/nqac040DOI Listing
June 2022

App-based COVID-19 syndromic surveillance and prediction of hospital admissions in COVID Symptom Study Sweden.

Nat Commun 2022 04 21;13(1):2110. Epub 2022 Apr 21.

ZOE Limited, 164 Westminster Bridge Road, London, SE1 7RW, UK.

The app-based COVID Symptom Study was launched in Sweden in April 2020 to contribute to real-time COVID-19 surveillance. We enrolled 143,531 study participants (≥18 years) who contributed 10.6 million daily symptom reports between April 29, 2020 and February 10, 2021. Here, we include data from 19,161 self-reported PCR tests to create a symptom-based model to estimate the individual probability of symptomatic COVID-19, with an AUC of 0.78 (95% CI 0.74-0.83) in an external dataset. These individual probabilities are employed to estimate daily regional COVID-19 prevalence, which are in turn used together with current hospital data to predict next week COVID-19 hospital admissions. We show that this hospital prediction model demonstrates a lower median absolute percentage error (MdAPE: 25.9%) across the five most populated regions in Sweden during the first pandemic wave than a model based on case notifications (MdAPE: 30.3%). During the second wave, the error rates are similar. When we apply the same model to an English dataset, not including local COVID-19 test data, we observe MdAPEs of 22.3% and 19.0% during the first and second pandemic waves, respectively, highlighting the transferability of the prediction model.
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http://dx.doi.org/10.1038/s41467-022-29608-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9023535PMC
April 2022

Beyond GWAS of Colorectal Cancer: Evidence of Interaction with Alcohol Consumption and Putative Causal Variant for the 10q24.2 Region.

Cancer Epidemiol Biomarkers Prev 2022 05;31(5):1077-1089

Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.

Background: Currently known associations between common genetic variants and colorectal cancer explain less than half of its heritability of 25%. As alcohol consumption has a J-shape association with colorectal cancer risk, nondrinking and heavy drinking are both risk factors for colorectal cancer.

Methods: Individual-level data was pooled from the Colon Cancer Family Registry, Colorectal Transdisciplinary Study, and Genetics and Epidemiology of Colorectal Cancer Consortium to compare nondrinkers (≤1 g/day) and heavy drinkers (>28 g/day) with light-to-moderate drinkers (1-28 g/day) in GxE analyses. To improve power, we implemented joint 2df and 3df tests and a novel two-step method that modifies the weighted hypothesis testing framework. We prioritized putative causal variants by predicting allelic effects using support vector machine models.

Results: For nondrinking as compared with light-to-moderate drinking, the hybrid two-step approach identified 13 significant SNPs with pairwise r2 > 0.9 in the 10q24.2/COX15 region. When stratified by alcohol intake, the A allele of lead SNP rs2300985 has a dose-response increase in risk of colorectal cancer as compared with the G allele in light-to-moderate drinkers [OR for GA genotype = 1.11; 95% confidence interval (CI), 1.06-1.17; OR for AA genotype = 1.22; 95% CI, 1.14-1.31], but not in nondrinkers or heavy drinkers. Among the correlated candidate SNPs in the 10q24.2/COX15 region, rs1318920 was predicted to disrupt an HNF4 transcription factor binding motif.

Conclusions: Our study suggests that the association with colorectal cancer in 10q24.2/COX15 observed in genome-wide association study is strongest in nondrinkers. We also identified rs1318920 as the putative causal regulatory variant for the region.

Impact: The study identifies multifaceted evidence of a possible functional effect for rs1318920.
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http://dx.doi.org/10.1158/1055-9965.EPI-21-1003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9081195PMC
May 2022

Symptom prevalence, duration, and risk of hospital admission in individuals infected with SARS-CoV-2 during periods of omicron and delta variant dominance: a prospective observational study from the ZOE COVID Study.

Lancet 2022 04 7;399(10335):1618-1624. Epub 2022 Apr 7.

Department of Twin Research and Genetic Epidemiology, King's College London, London, UK. Electronic address:

Background: The SARS-CoV-2 variant of concern, omicron, appears to be less severe than delta. We aim to quantify the differences in symptom prevalence, risk of hospital admission, and symptom duration among the vaccinated population.

Methods: In this prospective longitudinal observational study, we collected data from participants who were self-reporting test results and symptoms in the ZOE COVID app (previously known as the COVID Symptoms Study App). Eligible participants were aged 16-99 years, based in the UK, with a body-mass index between 15 and 55 kg/m, had received at least two doses of any SARS-CoV-2 vaccine, were symptomatic, and logged a positive symptomatic PCR or lateral flow result for SARS-CoV-2 during the study period. The primary outcome was the likelihood of developing a given symptom (of the 32 monitored in the app) or hospital admission within 7 days before or after the positive test in participants infected during omicron prevalence compared with those infected during delta prevalence.

Findings: Between June 1, 2021, and Jan 17, 2022, we identified 63 002 participants who tested positive for SARS-CoV-2 and reported symptoms in the ZOE app. These patients were matched 1:1 for age, sex, and vaccination dose, across two periods (June 1 to Nov 27, 2021, delta prevalent at >70%; n=4990, and Dec 20, 2021, to Jan 17, 2022, omicron prevalent at >70%; n=4990). Loss of smell was less common in participants infected during omicron prevalence than during delta prevalence (16·7% vs 52·7%, odds ratio [OR] 0·17; 95% CI 0·16-0·19, p<0·001). Sore throat was more common during omicron prevalence than during delta prevalence (70·5% vs 60·8%, 1·55; 1·43-1·69, p<0·001). There was a lower rate of hospital admission during omicron prevalence than during delta prevalence (1·9% vs 2·6%, OR 0·75; 95% CI 0·57-0·98, p=0·03).

Interpretation: The prevalence of symptoms that characterise an omicron infection differs from those of the delta SARS-CoV-2 variant, apparently with less involvement of the lower respiratory tract and reduced probability of hospital admission. Our data indicate a shorter period of illness and potentially of infectiousness which should impact work-health policies and public health advice.

Funding: Wellcome Trust, ZOE, National Institute for Health Research, Chronic Disease Research Foundation, National Institutes of Health, and Medical Research Council.
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http://dx.doi.org/10.1016/S0140-6736(22)00327-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8989396PMC
April 2022

Effect of Aspirin on Melanoma Incidence in Older Persons: Extended Follow-up of a Large Randomized Double-blind Placebo-controlled Trial.

Cancer Prev Res (Phila) 2022 Jun;15(6):365-375

School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.

The effects of aspirin on melanoma are unclear, with studies reporting conflicting results. Data from two periods of the ASPirin in Reducing Events in the Elderly (ASPREE) study; the randomized placebo-controlled trial period examining daily 100 mg aspirin in older adults with a median follow-up of 4.7 years, and the second period, an additional 2 years of observational follow-up, were utilized in this secondary analysis to examine whether aspirin exposure is associated with a reduced cutaneous melanoma incidence. All melanoma cases were adjudicated and Cox proportional hazards models were used to compare incidence between randomized treatment groups. ASPREE recruited 19,114 participants with a median age of 74 years. During the trial period, 170 individuals (76 aspirin, 94 placebo) developed an invasive melanoma, and no significant effect of aspirin was observed on incident melanoma [HR = 0.81; 95% confidence interval (CI), 0.60-1.10]. Including the additional 2 years of observational follow-up (median follow-up of 6.3 years), 268 individuals (119 aspirin, 149 placebo) developed an invasive melanoma, and similar results were observed (HR = 0.81; 95% CI, 0.63-1.03). A reduced number of events was observed with aspirin among females in a subgroup analysis (HR = 0.65; 95% CI, 0.44-0.92); however, the interaction effect with males (HR = 0.92; 95% CI, 0.68-1.25) was nonsignificant (P = 0.17). Our findings from this randomized trial do not provide strong support that aspirin is associated with a reduced risk of invasive melanoma in older individuals. Additional studies are required to further explore this relationship.

Prevention Relevance: Melanoma prevention is an important strategy to improve outcomes and while preventive efforts have largely focused on sun protection, the role of potential chemopreventive agents such as aspirin warrants investigation.
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http://dx.doi.org/10.1158/1940-6207.CAPR-21-0244DOI Listing
June 2022

Desmoplastic Reaction, Immune Cell Response, and Prognosis in Colorectal Cancer.

Front Immunol 2022 22;13:840198. Epub 2022 Mar 22.

Program in Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States.

Background: The relationships between tumor stromal features (such as desmoplastic reaction, myxoid stroma, and keloid-like collagen bundles) and immune cells in the colorectal carcinoma microenvironment have not yet been fully characterized.

Methods: In 908 tumors with available tissue among 4,465 incident colorectal adenocarcinoma cases in two prospective cohort studies, we examined desmoplastic reaction, myxoid stroma, and keloid-like collagen bundles. We conducted multiplex immunofluorescence for T cells [CD3, CD4, CD8, CD45RO (PTPRC), and FOXP3] and for macrophages [CD68, CD86, IRF5, MAF, and MRC1 (CD206)]. We used the inverse probability weighting method and the 4,465 incident cancer cases to adjust for selection bias.

Results: Immature desmoplastic reaction was associated with lower densities of intraepithelial CD3CD8CD45RO cells [multivariable odds ratio (OR) for the highest (vs. lowest) density category, 0.43; 95% confidence interval (CI), 0.29-0.62; P <0.0001] and stromal M1-like macrophages [the corresponding OR, 0.44; 95% CI, 0.28-0.70; P = 0.0011]. Similar relations were observed for myxoid stroma [intraepithelial CD3CD8CD45RO cells (P <0.0001) and stromal M1-like macrophages (P = 0.0007)] and for keloid-like collagen bundles (P <0.0001 for intraepithelial CD3CD8CD45RO cells). In colorectal cancer-specific survival analyses, multivariable-adjusted hazard ratios (with 95% confidence intervals) were 0.32 (0.23-0.44; P <0.0001) for mature (vs. immature) desmoplastic reaction, 0.25 (0.16-0.39; P <0.0001) for absent (vs. marked) myxoid stroma, and 0.12 (0.05-0.28; P <0.0001) for absent (vs. marked) keloid-like collagen bundles.

Conclusions: Immature desmoplastic reaction and myxoid stroma were associated with lower densities of tumor intraepithelial memory cytotoxic T cells and stromal M1-like macrophages, likely reflecting interactions between tumor, immune, and stromal cells in the colorectal tumor microenvironment.
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http://dx.doi.org/10.3389/fimmu.2022.840198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8980356PMC
March 2022

Tooth count, untreated caries and mortality in US adults: a population-based cohort study.

Int J Epidemiol 2022 Apr 7. Epub 2022 Apr 7.

Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St Louis, MO, USA.

Background: The link between oral diseases and mortality remains under-explored. We aimed to evaluate the associations between tooth count, untreated caries and risk of all-cause and cause-specific mortality.

Methods: Data on 24 029 adults from the National Health and Nutrition Examination Survey 1988-94/1999-2010, with mortality linkage to the National Death Index to 31 December 2015, were analysed. Baseline total number of permanent teeth and any untreated caries were assessed by trained dental professionals.

Results: During up to 27 years of follow-up, 5270 deaths occurred. Fewer permanent teeth were associated with higher all-cause mortality, including heart disease and cancer mortality (all P <0.05 for trend) but not cerebrovascular disease mortality. For every 10 teeth missing, the multivariable-adjusted hazard ratios (HRs) were 1.13 (95% CI: 1.08 to 1.18) for all-cause, 1.16 (95% CI: 1.05, 1.29) for heart disease and 1.19 (95% CI: 1.09, 1.29) for cancer mortality. Untreated caries was associated with increased all-cause (HR: 1.26, 95% CI: 1.15, 1.39) and heart disease mortality (HR: 1.48, 95% CI: 1.17, 1.88) but not cerebrovascular disease/cancer mortality, after adjusting for tooth count, periodontitis and sociodemographic/lifestyle factors. Compared with those without untreated caries and with 25-28 teeth, individuals with untreated caries and 1-16 teeth had a 53% increased risk of all-cause mortality (HR: 1.53, 95% CI: 1.27, 1.85) and 96 % increased risk of heart disease mortality (HR: 1.96, 95% CI: 1.28, 3.01).

Conclusions: In nationally representative cohorts, fewer permanent teeth and untreated caries were associated with all-cause and heart disease mortality. Fewer teeth were also associated with higher cancer mortality.
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http://dx.doi.org/10.1093/ije/dyac072DOI Listing
April 2022

Diabetes mellitus in relation to colorectal tumor molecular subtypes: A pooled analysis of more than 9000 cases.

Int J Cancer 2022 Aug 22;151(3):348-360. Epub 2022 Apr 22.

Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

Diabetes is an established risk factor for colorectal cancer. However, colorectal cancer is a heterogeneous disease and it is not well understood whether diabetes is more strongly associated with some tumor molecular subtypes than others. A better understanding of the association between diabetes and colorectal cancer according to molecular subtypes could provide important insights into the biology of this association. We used data on lifestyle and clinical characteristics from the Colorectal Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), including 9756 colorectal cancer cases (with tumor marker data) and 9985 controls, to evaluate associations between reported diabetes and risk of colorectal cancer according to molecular subtypes. Tumor markers included BRAF and KRAS mutations, microsatellite instability and CpG island methylator phenotype. In the multinomial logistic regression model, comparing colorectal cancer cases to cancer-free controls, diabetes was positively associated with colorectal cancer regardless of subtype. The highest OR estimate was found for BRAF-mutated colorectal cancer, n = 1086 (OR : 1.67, 95% confidence intervals [CI]: 1.36-2.05), with an attenuated association observed between diabetes and colorectal cancer without BRAF-mutations, n = 7959 (OR : 1.33, 95% CI: 1.19-1.48). In the case only analysis, BRAF-mutation was differentially associated with diabetes (P  = .03). For the other markers, associations with diabetes were similar across tumor subtypes. In conclusion, our study confirms the established association between diabetes and colorectal cancer risk, and suggests that it particularly increases the risk of BRAF-mutated tumors.
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http://dx.doi.org/10.1002/ijc.34015DOI Listing
August 2022

Dietary lignans, plasma enterolactone levels, and metabolic risk in men: exploring the role of the gut microbiome.

BMC Microbiol 2022 03 29;22(1):82. Epub 2022 Mar 29.

Department of Nutrition, Harvard T.H. Chan School of Public Health, 665 Huntington Avenue, Boston, MA, 02115, USA.

Background: The conversion of plant lignans to bioactive enterolignans in the gastrointestinal tract is mediated through microbial processing. The goal of this study was to examine the relationships between lignan intake, plasma enterolactone concentrations, gut microbiome composition, and metabolic risk in free-living male adults.

Results: In 303 men participating in the Men's Lifestyle Validation Study (MLVS), lignan intake was assessed using two sets of 7-day diet records, and gut microbiome was profiled through shotgun sequencing of up to 2 pairs of fecal samples (n = 911). A score was calculated to summarize the abundance of bacteria species that were significantly associated with plasma enterolactone levels. Of the 138 filtered species, plasma enterolactone levels were significantly associated with the relative abundances of 18 species at FDR < 0.05 level. Per SD increment of lignan intake was associated with 20.7 nM (SEM: 2.3 nM) higher enterolactone concentrations among participants with a higher species score, whereas the corresponding estimate was 4.0 nM (SEM: 1.7 nM) among participants with a lower species score (P for interaction < 0.001). A total of 12 plasma metabolites were also significantly associated with these enterolactone-predicting species. Of the association between lignan intake and metabolic risk, 19.8% (95%CI: 7.3%-43.6%) was explained by the species score alone, 54.5% (95%CI: 21.8%-83.7%) by both species score and enterolactone levels, and 79.8% (95%CI: 17.7%-98.6%) by further considering the 12 plasma metabolites.

Conclusion: We identified multiple gut bacteria species that were enriched or depleted at higher plasma levels of enterolactone in men. These species jointly modified the associations of lignan intake with plasma enterolactone levels and explained the majority of association between lignan intake and metabolic risk along with enterolactone levels and certain plasma metabolites.
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http://dx.doi.org/10.1186/s12866-022-02495-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8966171PMC
March 2022

Aspirin and the risk of colorectal cancer according to genetic susceptibility among older individuals.

Cancer Prev Res (Phila) 2022 Mar 29. Epub 2022 Mar 29.

Massachusetts General Hospital, Boston, MA, United States.

Although aspirin has been considered a promising agent for prevention of colorectal cancer (CRC), recent data suggest a lack of benefit among older individuals. Whether some individuals with higher risk of CRC may benefit from aspirin remains unknown. We used a 95-variant CRC polygenic risk score (PRS) to explore the association between genetic susceptibility to CRC and aspirin use in a prospective study of 12,609 individuals of European descent aged {greater than or equal to} 70 years, enrolled in the ASPREE (ASPirin in Reducing Events in the Elderly) double-blinded, placebo-controlled randomized trial (RCT). Cox proportional hazards models were used to assess the association of aspirin use on CRC, as well as the interaction between the PRS and aspirin treatment on CRC. Over a median of 4.7 years follow-up, 143 participants were diagnosed with incident CRC. Aspirin assignment was not associated with incidence of CRC overall (hazard ratio [HR]=0.94, 95% confidence interval (CI) 0.68-1.30) or within strata of PRS (p for interaction=0.97). However, the PRS was associated with an increased risk of CRC (HR=1.28 per standard deviation [SD], 95% CI 1.09-1.51). Individuals in the top quintile of the PRS distribution had an 85% higher risk compared with individuals in the bottom quintile (HR=1.85, 95% CI 1.08-3.15). In a prospective RCT of older individuals, a PRS is associated with incident CRC risk, but aspirin use was not associated with a reduction of incident CRC, regardless of baseline genetic risk.
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http://dx.doi.org/10.1158/1940-6207.CAPR-22-0011DOI Listing
March 2022

Association of midlife antibiotic use with subsequent cognitive function in women.

PLoS One 2022 23;17(3):e0264649. Epub 2022 Mar 23.

Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.

The gut microbiome is increasingly recognized to play a role in cognition and dementia. Antibiotic use impacts the gut microbiome and has been linked with chronic disease. Despite these data, there is no evidence supporting an association between long-term antibiotic use in adults and cognitive function. We conducted a prospective population-based cohort study among 14,542 participants in the Nurses' Health Study II who completed a self-administered computerized neuropsychological test battery between 2014-2018. Multivariate linear regression models were used to assess if chronic antibiotic use in midlife was associated with cognitive impairment assessed later in life. Women who reported at least 2 months of antibiotic exposure in midlife (mean age 54.7, SD 4.6) had lower mean cognitive scores seven years later, after adjustment for age and educational attainment of the spouse and parent, with a mean difference of -0.11 standard units for the global composite score (Ptrend <0.0001), -0.13 for a composite score of psychomotor speed and attention (Ptrend <0.0001), and -0.10 for a composite score of learning and working memory (Ptrend <0.0001) compared with non-antibiotic users. These differences were not materially changed after multivariate adjustment for additional risk factors, including comorbid conditions. As a benchmark, the mean difference in score associated with each additional year of age was (-0.03) for global cognition, (-0.04) for psychomotor speed and attention, and (-0.03) for learning and working memory; thus the relation of antibiotic use to cognition was roughly equivalent to that found for three to four years of aging. Long-term antibiotic use in midlife is associated with small decreases in cognition assessed seven years later. These data underscore the importance of antibiotic stewardship, especially among aging populations.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0264649PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8942267PMC
April 2022

Association of Primary Care Physicians Per Capita With COVID-19 Vaccination Rates Among US Counties.

JAMA Netw Open 2022 02 1;5(2):e2147920. Epub 2022 Feb 1.

Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston.

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http://dx.doi.org/10.1001/jamanetworkopen.2021.47920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8832176PMC
February 2022

Validity of continuous glucose monitoring for categorizing glycemic responses to diet: implications for use in personalized nutrition.

Am J Clin Nutr 2022 Jun;115(6):1569-1576

School of Medicine, University of Nottingham, Nottingham, United Kingdom.

Background: Continuous glucose monitor (CGM) devices enable characterization of individuals' glycemic variation. However, there are concerns about their reliability for categorizing glycemic responses to foods that would limit their potential application in personalized nutrition recommendations.

Objectives: We aimed to evaluate the concordance of 2 simultaneously worn CGM devices in measuring postprandial glycemic responses.

Methods: Within ZOE PREDICT (Personalised Responses to Dietary Composition Trial) 1, 394 participants wore 2 CGM devices simultaneously [n = 360 participants with 2 Abbott Freestyle Libre Pro (FSL) devices; n = 34 participants with both FSL and Dexcom G6] for ≤14 d while consuming standardized (n = 4457) and ad libitum (n = 5738) meals. We examined the CV and correlation of the incremental area under the glucose curve at 2 h (glucoseiAUC0-2 h). Within-subject meal ranking was assessed using Kendall τ rank correlation. Concordance between paired devices in time in range according to the American Diabetes Association cutoffs (TIRADA) and glucose variability (glucose CV) was also investigated.

Results: The CV of glucoseiAUC0-2 h for standardized meals was 3.7% (IQR: 1.7%-7.1%) for intrabrand device and 12.5% (IQR: 5.1%-24.8%) for interbrand device comparisons. Similar estimates were observed for ad libitum meals, with intrabrand and interbrand device CVs of glucoseiAUC0-2 h of 4.1% (IQR: 1.8%-7.1%) and 16.6% (IQR: 5.5%-30.7%), respectively. Kendall τ rank correlation showed glucoseiAUC0-2h-derived meal rankings were agreeable between paired CGM devices (intrabrand: 0.9; IQR: 0.8-0.9; interbrand: 0.7; IQR: 0.5-0.8). Paired CGMs also showed strong concordance for TIRADA with a intrabrand device CV of 4.8% (IQR: 1.9%-9.8%) and an interbrand device CV of 3.2% (IQR: 1.1%-6.2%).

Conclusions: Our data demonstrate strong concordance of CGM devices in monitoring glycemic responses and suggest their potential use in personalized nutrition.This trial was registered at clinicaltrials.gov as NCT03479866.
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http://dx.doi.org/10.1093/ajcn/nqac026DOI Listing
June 2022

Self-reported COVID-19 vaccine hesitancy and uptake among participants from different racial and ethnic groups in the United States and United Kingdom.

Nat Commun 2022 02 1;13(1):636. Epub 2022 Feb 1.

Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Worldwide, racial and ethnic minorities have been disproportionately impacted by COVID-19 with increased risk of infection, its related complications, and death. In the initial phase of population-based vaccination in the United States (U.S.) and United Kingdom (U.K.), vaccine hesitancy may result in differences in uptake. We performed a cohort study among U.S. and U.K. participants who volunteered to take part in the smartphone-based COVID Symptom Study (March 2020-February 2021) and used logistic regression to estimate odds ratios of vaccine hesitancy and uptake. In the U.S. (n = 87,388), compared to white participants, vaccine hesitancy was greater for Black and Hispanic participants and those reporting more than one or other race. In the U.K. (n = 1,254,294), racial and ethnic minority participants showed similar levels of vaccine hesitancy to the U.S. However, associations between participant race and ethnicity and levels of vaccine uptake were observed to be different in the U.S. and the U.K. studies. Among U.S. participants, vaccine uptake was significantly lower among Black participants, which persisted among participants that self-reported being vaccine-willing. In contrast, statistically significant racial and ethnic disparities in vaccine uptake were not observed in the U.K sample. In this study of self-reported vaccine hesitancy and uptake, lower levels of vaccine uptake in Black participants in the U.S. during the initial vaccine rollout may be attributable to both hesitancy and disparities in access.
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http://dx.doi.org/10.1038/s41467-022-28200-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8807721PMC
February 2022

Smoking behavior changes after diagnosis of inflammatory bowel disease and risk of all-cause mortality.

J Crohns Colitis 2022 Feb 1. Epub 2022 Feb 1.

Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Background And Aims: We examined smoking behavior changes after diagnoses of Crohn's disease (CD) and ulcerative colitis (UC) and evaluated their impact on mortality.

Methods: Study population included incident CD or UC cases from three cohorts of Nurses' Health Study (NHS), NHSII, and Health Professionals Follow-up Study. Smoking and other risk factors were prospectively assessed. Smoking behavior changes were categorized as never, former (i.e. quit smoking before diagnosis), quitters (i.e. quit smoking after diagnosis), and current (i.e. continue smoking after diagnosis). Follow-up for date and cause of death was completed through linkage to the National Death Index. Cox proportional hazard regression was used to estimate HRs and 95% CIs.

Results: Among 909 eligible CD and UC cases, 45% were never smokers, 38% were past smokers, and 16% were active smokers at the time of diagnosis. Among active smokers, 70% of patients with CD and 44% of patients with UC continued to smoke after diagnosis. In patients with CD, compared to current smokers, the multivariable-adjusted HRs (95%CI) of death were 0.19(0.10-0.38) for never smokers, 0.31(0.16-0.57) for former smokers, and 0.41(0.18-0.93) for quitters. Similarly, for UC, compared to current smokers, we observed a reduced risk of mortality for never smokers (HR=0.23, 95%CI 0.10-0.51), former smokers (HR=0.23, 95%CI 0.11-0.48), and quitters (HR=0.28, 95%CI 0.11-0.72).

Conclusions: In three cohorts of health professionals, a substantial proportion of patients with new diagnosis of CD and UC and history of smoking continued to smoke post-diagnosis. Smoking cessation around the time of diagnosis was associated with a significant reduction in mortality.
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http://dx.doi.org/10.1093/ecco-jcc/jjac015DOI Listing
February 2022

Associations Between Glycemic Traits and Colorectal Cancer: A Mendelian Randomization Analysis.

J Natl Cancer Inst 2022 05;114(5):740-752

Nutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France.

Background: Glycemic traits-such as hyperinsulinemia, hyperglycemia, and type 2 diabetes-have been associated with higher colorectal cancer risk in observational studies; however, causality of these associations is uncertain. We used Mendelian randomization (MR) to estimate the causal effects of fasting insulin, 2-hour glucose, fasting glucose, glycated hemoglobin (HbA1c), and type 2 diabetes with colorectal cancer.

Methods: Genome-wide association study summary data were used to identify genetic variants associated with circulating levels of fasting insulin (n = 34), 2-hour glucose (n = 13), fasting glucose (n = 70), HbA1c (n = 221), and type 2 diabetes (n = 268). Using 2-sample MR, we examined these variants in relation to colorectal cancer risk (48 214 case patient and 64 159 control patients).

Results: In inverse-variance models, higher fasting insulin levels increased colorectal cancer risk (odds ratio [OR] per 1-SD = 1.65, 95% confidence interval [CI] = 1.15 to 2.36). We found no evidence of any effect of 2-hour glucose (OR per 1-SD = 1.02, 95% CI = 0.86 to 1.21) or fasting glucose (OR per 1-SD = 1.04, 95% CI = 0.88 to 1.23) concentrations on colorectal cancer risk. Genetic liability to type 2 diabetes (OR per 1-unit increase in log odds = 1.04, 95% CI = 1.01 to 1.07) and higher HbA1c levels (OR per 1-SD = 1.09, 95% CI = 1.00 to 1.19) increased colorectal cancer risk, although these findings may have been biased by pleiotropy. Higher HbA1c concentrations increased rectal cancer risk in men (OR per 1-SD = 1.21, 95% CI = 1.05 to 1.40), but not in women.

Conclusions: Our results support a causal effect of higher fasting insulin, but not glucose traits or type 2 diabetes, on increased colorectal cancer risk. This suggests that pharmacological or lifestyle interventions that lower circulating insulin levels may be beneficial in preventing colorectal tumorigenesis.
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http://dx.doi.org/10.1093/jnci/djac011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9086764PMC
May 2022

Pre-diagnostic telomere length and colorectal cancer risk.

Cancer Epidemiol 2022 04 13;77:102100. Epub 2022 Jan 13.

Department of Global Health, Richard M. Fairbanks School of Public Health, Indiana University, Indianapolis, IN, USA; Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indiana University, Indianapolis, IN, USA. Electronic address:

Background: Progressive telomere shortening may be related to genomic instability and carcinogenesis. Prospective evidence relating telomere length (TL) with colorectal cancer (CRC) risk has been limited and inconsistent.

Methods: We examined the association between pre-diagnostic peripheral blood leukocyte TL and CRC risk in two matched case-control studies nested within the Nurses' Health Study (NHS) and the Health Professionals Follow-Up Study (HPFS). Relative leukocyte TL was measured using qPCR among 356 incident CRC cases and 801 controls (NHS: 186/465, HPFS: 170/336).

Results: We did not find a significant association between pre-diagnostic TL and CRC risk [in all participants, multivariable-adjusted odds ratio (OR) (95% CI) for TL Quartile 1 (shortest) vs. Quartile 4 (longest) = 1.36 (0.85, 2.17), P-trend = 0.27; OR (95% CI) per 1 SD decrease in TL = 1.12 (0.92, 1.36)].

Conclusions: Our prospective analysis did not support a significant association between pre-diagnostic leukocyte TL and CRC risk.
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http://dx.doi.org/10.1016/j.canep.2022.102100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8923959PMC
April 2022

Plasma metabolomic profiles for colorectal cancer precursors in women.

Eur J Epidemiol 2022 Apr 15;37(4):413-422. Epub 2022 Jan 15.

Department of Nutrition, Harvard T.H. Chan School of Public Health, 667 Huntington Avenue, Kresge 906A, Boston, MA, 02115, USA.

How metabolome changes influence the early process of colorectal cancer (CRC) development remains unknown. We conducted a 1:2 matched nested case-control study to examine the associations of pre-diagnostic plasma metabolome (profiled using LC-MS) with risk of CRC precursors, including conventional adenomas (n = 586 vs. 1141) and serrated polyps (n = 509 vs. 993), in the Nurses' Health Study (NHS) and NHSII. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). We used the permutation-based Westfall and Young approach to account for multiple testing. Subgroup analyses were performed for advanced conventional adenomas (defined as at least one adenoma of ≥ 10 mm or with high-grade dysplasia, or tubulovillous or villous histology) and high-risk serrated polyps that were located in the proximal colon or with size of ≥ 10 mm. After multiple testing correction, among 207 metabolites, higher levels of C36:3 phosphatidylcholine (PC) plasmalogen were associated with lower risk of conventional adenomas, with the OR (95% CI) comparing the 90th to the 10th percentile of 0.62 (0.48-0.81); C54:8 triglyceride (TAG) was associated with higher risk of serrated polyps (OR = 1.79, 95% CI: 1.31-2.43), and phenylacetylglutamine (PAG) was associated with lower risk (OR = 0.57, 95% CI:0.43-0.77). PAG was also inversely associated with advanced adenomas (OR = 0.57, 95% CI: 0.36-0.89) and high-risk serrated polyps (OR = 0.54, 95% CI: 0.32-0.89), although the multiple testing-corrected p value was > 0.05. Our findings suggest potential roles of lipid metabolism and phenylacetylglutamine, a microbial metabolite, in the early stage of colorectal carcinogenesis, particularly for the serrated pathway.
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http://dx.doi.org/10.1007/s10654-021-00834-5DOI Listing
April 2022

Risk Factors for Incident Inflammatory Bowel Disease According to Disease Phenotype.

Clin Gastroenterol Hepatol 2022 Jan 12. Epub 2022 Jan 12.

Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts; Clinical and Translation Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Broad Institute of MIT and Harvard, Cambridge, Massachusetts. Electronic address:

Background & Aims: We examined whether relationships between known risk factors for Crohn's disease (CD) and ulcerative colitis (UC) differ according to disease phenotype, defined by Montreal classification, at the time of diagnosis.

Methods: We performed a prospective cohort study of 208,070 adults from the Nurses' Health Study (NHS), NHSII, and Health Professionals Follow-Up Study (HPFS). Dietary, lifestyle, and medical data were obtained at baseline and every 2-4 years. We confirmed cases of inflammatory bowel disease (IBD) and their phenotypes via medical record review. We tested for heterogeneity across CD subtypes using the likelihood ratio test and for linear heterogeneity across UC subtypes using the meta-regression method.

Results: We ascertained 346 cases of CD and 456 cases of UC over 5,117,021 person-years of follow-up (1986-2016 for NHS and HPFS; 1991-2017 for NHSII). Fiber intake was associated with decreased risk for ileocolonic but not ileal or colonic CD (P = .04). Physical activity was associated with decreased risk of nonstricturing and nonpenetrating CD but not of penetrating CD (P = .02). Higher body mass index and current smoking were associated with decreased risk of proctitis and left-sided UC but not of pan-UC (P= .004 and .02, respectively). The associations between other risk factors examined and risk of CD and UC did not differ by disease phenotype (all P > .06).

Conclusions: In 3 large prospective cohorts, we observed that dietary and lifestyle risk factors for IBD may differ according to disease phenotype. These findings highlight the need for disease stratification in future epidemiologic studies.
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http://dx.doi.org/10.1016/j.cgh.2022.01.003DOI Listing
January 2022
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