Dietary Fiber Intake and Risk of Advanced and Aggressive Forms of Prostate Cancer: A Pooled Analysis of 15 Prospective Cohort Studies.

BACKGROUND: Evidence of an association between dietary fiber intake and risk of advanced and aggressive forms of prostate cancer (PC) and PC mortality is limited. OBJECTIVE: To examine associations between intakes of dietary fiber overall and by food source and risk of advanced and aggressive forms of PC. DESIGN: Pooled analysis of the primary data in 15 cohorts in three continents. Baseline dietary fiber intake was assessed using a validated food frequency questionnaire or diet history in each study. PARTICIPANTS/SETTING: 842,149 men were followed for up to 9-22 years between 1985-2009 across studies. MAIN OUTCOME MEASURES: The primary outcome measures were advanced (stage T4, N1, or M1 or PC mortality), advanced restricted (excluded men with missing stage and those with localized PC who died of PC), high grade (Gleason score ≥8 or poorly differentiated/undifferentiated) PC, and PC mortality. STATISTICAL ANALYSIS: Study-specific multivariable hazard ratios (MVHR) were calculated using Cox proportional hazards regression and pooled using random effects models. RESULTS: Intake of dietary fiber overall, from fruits, and from vegetables was not associated with risk of advanced (n=4,863), advanced restricted (n=2,978), or high-grade PC (n=9,673) or PC mortality (n=3,097). Dietary fiber intake from grains was inversely associated with advanced PC (MVHR comparing the highest vs. lowest quintile=0.84, 95% confidence interval [CI] 0.76-0.93), advanced restricted PC (MVHR=0.85, 95%CI 0.74-0.97), and PC mortality (MVHR=0.78, 95%CI 0.68-0.89); statistically significant trends were noted for each of these associations (p≤0.03), while a null association was observed for high grade PC for the same comparison (MVHR=1.00, 95%CI 0.93-1.07). The comparable results were 1.06 (95%CI 1.01-1.10, p-value, test for trend=0.002) for localized (n=35,199) and 1.05 (95%CI 0.99-1.11, , p-value, test for trend=0.04) for low/intermediate grade (n=34,366) PC. CONCLUSIONS: Weak nonsignificant associations were observed between total dietary fiber intake and risk of advanced forms of PC, high grade PC, and PC mortality. High dietary fiber intake from grains was associated with a modestly lower risk of advanced forms of PC and PC mortality.

Partial substitution of red meat or processed meat with plant-based foods and the risk of colorectal cancer.

OBJECTIVES: Shifting from animal-based to plant-based diets could reduce colorectal cancer (CRC) incidence. Currently, the impacts of these dietary shifts on CRC risk are ill-defined. Therefore, we examined partial substitutions of red or processed meat with whole grains, vegetables, fruits or a combination of these in relation to CRC risk in Finnish adults. METHODS: We pooled five Finnish cohorts, resulting in 43 788 participants aged ≥ 25 years (79% men). Diet was assessed by validated food frequency questionnaires at study enrolment. We modelled partial substitutions of red (100 g/week) or processed meat (50 g/week) with corresponding amounts of plant-based foods. Cohort-specific hazard ratios (HR) for CRC were calculated using Cox proportional hazards models and pooled together using random-effects models. Adjustments included age, sex, energy intake and other relevant confounders. RESULTS: During the median follow-up of 28.8 years, 1124 CRCs were diagnosed. We observed small risk reductions when red meat was substituted with vegetables (HR 0.97, 95% CI 0.95 - 0.99), fruits (0.97, 0.94 - 0.99), or whole grains, vegetables and fruits combined (0.97, 0.95 - 0.99). For processed meat, these substitutions yielded 1% risk reductions. Substituting red or processed meat with whole grains was associated with a decreased CRC risk only in participants with < median whole grain intake (0.92, 0.86 - 0.98; 0.96, 0.93 - 0.99, respectively; pinteraction=0.001). CONCLUSIONS: Even small, easily implemented substitutions of red or processed meat with whole grains, vegetables or fruits could lower CRC risk in a population with high meat consumption. These findings broaden our insight into dietary modifications that could foster CRC primary prevention.

Adherence to 2018 WCRF/AICR Cancer Prevention Recommendations and Risk of Cancer: The Melbourne Collaborative Cohort Study.

BACKGROUND: We examined associations between adherence to adaptations of the 2018 World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) cancer prevention recommendations and total, exposure-related and site-specific cancer risk. METHODS: A total of 20,001 participants ages 40 to 69 years at enrollment into the Melbourne Collaborative Cohort Study in 1990 to 1994, who had diet, body size, and lifestyle reassessed in 2003 to 2007 ("baseline"), were followed-up through June 2021. We constructed diet and standardized lifestyle scores based on core WCRF/AICR recommendations on diet, alcohol intake, body size and physical activity, and additional scores incorporating weight change, sedentary behavior, and smoking. Associations with cancer risk were estimated using Cox regression, adjusting for confounders. RESULTS: During follow-up (mean = 16 years), 4,710 incident cancers were diagnosed. For highest quintile ("most adherent") of the standardized lifestyle score, compared with lowest ("least adherent"), a HR of 0.82 [95% confidence interval (CI): 0.74-0.92] was observed for total cancer. This association was stronger with smoking included in the score (HR = 0.74; 95% CI: 0.67-0.81). A higher score was associated with lower breast and prostate cancer risk for the standardized score, and with lung, stomach, rectal, and pancreatic cancer risk when the score included smoking. Our analyses identified alcohol use, waist circumference and smoking as key drivers of associations with total cancer risk. CONCLUSIONS: Adherence to WCRF/AICR cancer prevention recommendations is associated with lower cancer risk. IMPACT: With <0.2% of our sample fully adherent to the recommendations, the study emphasizes the vast potential for preventing cancer through modulation of lifestyle habits.

Lifetime dairy product consumption and breast cancer risk: a prospective cohort study by tumor subtypes.

BACKGROUND: Previous literature on dairy products and risk of breast cancer is inconsistent, and the relationship may depend on the life-period of dietary assessment. OBJECTIVE: We examined dairy consumption from adolescence through later adulthood and incidence of breast cancer by menopausal status and tumor molecular subtypes in the Nurses' Health Study (NHS), a prospective cohort study. METHODS: We analyzed data from 63,847 females in the NHS collected from 1980 to 2018. Average intake of dairy products during adulthood was assessed by validated semiquantitative food frequency questionnaires throughout follow-up. Participants recalled adolescent dietary intake in 1986. Multivariable Cox proportional hazards models were used to estimate hazard ratios (HRs) relating dairy product consumption to breast cancer risk overall, by menopausal status, and by subtypes. RESULTS: We documented 5733 incident cases of invasive breast cancer during 32 y of follow-up (n = 5298 postmenopausal). Lifetime, adolescent, adulthood, and postmenopausal total dairy and milk intakes were not associated with overall breast cancer risk (nonsignificant HRs comparing highest with lowest quintile range = 0.97-1.08), although there was a suggestive positive association between adolescent milk intake and breast cancer risk (HR: 1.09; 95% CI: 1.00, 1.18). Higher lifetime and premenopausal cheese intakes were associated with modestly lower risks of breast cancer (comparing highest with lowest quintile, HR for lifetime cheese intake: 0.90; 95% CI: 0.82, 0.98; HR for premenopausal cheese intake: 0.89; 95% CI: 0.79, 1.00). Results varied by tumor subtype and some evidence for heterogeneity was observed for an association between premenopausal milk intake and breast cancer (HR for estrogen receptor [ER]-positive: 0.84; 95% CI: 0.72, 0.99; ER-negative: 1.36; 95% CI: 1.00, 1.84; P heterogeneity = 0.04). CONCLUSIONS: These findings suggest that overall dairy consumption was not associated with risk of breast cancer. However, heterogeneity was observed for type of dairy food, period of life, and tumor subtypes.

The effects of glycemic index on prostate cancer progression in a xenograft mouse model.

BACKGROUND: Previously, we found low-carbohydrate diets slowed prostate cancer (PC) growth and increased survival vs. a Western diet in mice, by inhibiting the insulin/IGF-1 axis. Thus, we tested whether modifying carbohydrate quality to lower glycemic index (GI) without changing quantity results in similar benefits as with reduced quantity. METHODS: Male SCID mice injected with LAPC-4 cells were single-housed and randomized when their tumors reached 200 mm3 on average to a LoGI (48% carbohydrate kcal, from Hylon-VII) or HiGI Western diet (48% carbohydrate kcal, from sucrose). Body weight and tumor volume were measured weekly. Body composition was assessed 35 days after randomization. Blood glucose and serum insulin, IGF-1 and IGFBP3 were measured at study end when tumor volumes reached 800 mm3. We analyzed gene expression of mice tumors by RNA-sequencing and human tumors using the Prostate Cancer Transcriptome Atlas. RESULTS: There were no significant differences in tumor volume (P > 0.05), tumor proliferation (P = 0.29), and overall survival (P = 0.15) between groups. At 35 days after randomization, the LoGI group had 30% lower body fat (P = 0.007) despite similar body weight (P = 0.58). At sacrifice, LoGI mice had smaller livers (P < 0.001) and lower glucose (P = 0.15), insulin (P = 0.11), IGF-1 (P = 0.07) and IGF-1:IGFBP3 ratio (P = 0.05), and higher IGFBP3 (P = 0.09) vs. HiGI, although none of these metabolic differences reached statistical significance. We observed differential gene expression and pathway enrichment in mice tumors by diet. The most upregulated and downregulated gene in the LoGI group showed expression patterns more closely resembling expression in human benign prostate tissue vs. PC. CONCLUSIONS: In this single mouse xenograft model, consuming a low GI diet did not delay PC growth or survival vs. a high GI diet despite suggestions of decreased activation of the insulin/IGF-1 pathway. These data suggest that improving carbohydrate quality alone while consuming a high carbohydrate diet may not effectively slow PC growth.

Moderate alcohol consumption, types of beverages and drinking pattern with cardiometabolic biomarkers in three cohorts of US men and women.

Underlying mechanisms of the inverse relationship between moderate alcohol consumption and cardiometabolic disorders are unclear. Modification by types of alcoholic beverages consumed and drinking pattern remains understudied. We aimed to provide insight into the mechanisms by examining 14 insulinemic/glycemic, inflammatory and lipid markers. We used cross-sectional data from 15,436 women in the Nurses' Health Study, 19,318 women in the Nurses' Health Study II, and 6872 men in the Health Professionals Follow-up Study. Multivariable linear regression was used to estimate the percentage differences in biomarker concentrations according to alcohol intakes. The average alcohol intake in the combined cohort was 3.3 servings/week. We found a 1 serving/d increment in alcohol intake (14 g ethanol, 44 ml liquor or 355 ml beer or 118 ml wine per day) was associated with a 0.6% lower level of HbA1c, 1.7-3.6% lower proinflammatory markers and 4.2% higher adiponectin, as well as 7.1% higher HDL-cholesterol and 2.1% lower triglyceride with a significant linear trend. Wine, especially red wine, was associated with lower inflammation in particular. Beer had weaker favorable to null associations with blood lipids and adiponectin. Liquor was associated with higher C-peptide and interleukin-6, yet equally associated with lower HbA1c and higher HDL-cholesterol as other beverages. Drinking 3 days or more per week was related to a better biomarker profile than nonregular drinking independent of intake levels. Drinking appeared to have similar associations irrespective whether done with meals or not. Our data indicated moderate alcohol intake, especially if consumed from wine and done regularly, was associated with favorable profiles of insulinemic/glycemic and inflammatory markers and blood lipids.

Associations of Dietary Inflammatory Potential with Esophageal Precancerous Lesions and Esophageal Squamous-Cell Cancer: A Cross-Sectional Study.

Chronic inflammation plays a central role in the progression from esophageal precancerous lesions (EPLs) to esophageal squamous-cell cancer (ESCC). However, few studies have investigated the relationship between the overall inflammatory potential of diets and EPLs and ESCC. We aimed to study the association between the Dietary Inflammatory Index (DII) and EPLs and ESCC. As part of the National Cohort of Esophageal Cancer (NCEC) in China, 3967 residents (1993 men and 1974 women) aged from 40 to 69 years living in Yanting County received free gastroscopy screenings from 2017 to 2019. Dietary intake during the past year was assessed at enrollment of the cohort before screening and DII scores were calculated based on 28 food parameters. EPLs (classified into mild, moderate, and severe dysplasia) and ESCC were histologically confirmed by biopsy. Multivariable logistic regression was used to examine the associations of DII scores with EPLs and ESCC. A total of 312 participants were diagnosed with EPLs (226 with mild dysplasia, 40 with moderate dysplasia, and 46 with severe dysplasia) and 72 were diagnosed with ESCC. A statistically significant positive association was observed between DII scores and overall EPLs (ORT3 vs. T1 = 1.45, 95%CI = 1.01-2.09); the association was similar but not statistically significant for mild dysplasia (ORone-unit-increment = 1.11, 95%CI = 0.95-1.34) and for moderate and severe dysplasia combined (ORone-unit-increment = 1.15, 95%CI = 0.87-1.51). The association with ESCC was similar in magnitude but not significant, likely due to the small number of cases. In this cross-sectional study of a population in China at high risk of ESCC, DII scores were positively associated with odds of EPLs and ESCC. Consumption of anti-inflammatory foods may be beneficial to prevent EPLs and ESCC.

Association between use of vitamin and mineral supplement and non-alcoholic fatty liver disease in hypertensive adults.

Non-alcoholic fatty liver disease (NAFLD) is the most common hepatic metabolic disorder in hypertensive adults. Impaired metabolism of micronutrients may increase NAFLD risk by exacerbating oxidative stress, insulin resistance, and inflammation among hypertensive adults. In this first cross-sectional analysis of 7,376 hypertensive adults with 2,015 NAFLD cases in the Korea National Health and Nutrition Examination Survey, vitamin and mineral supplements (VMS) use was identified via questionnaire. NAFLD was defined by a hepatic steatosis index > 36. Multivariable-adjusted odds ratios (MVOR) and 95% confidence intervals (CIs) were calculated using logistic regression models. In our study, 18.6% were current users of VMS; of these, 76.7% used multi-vitamin/mineral supplements. Current VMS users had significantly lower odds of NAFLD, compared with non-users (MVOR [95% CI]: 0.73 [0.58-0.92]). The inverse association became attenuated and non-significant among those consuming VMS at higher frequency (≥ 2 times/day), for longer duration (> 16 months), and taking ≥ 2 VMS products. The inverse association with current use of VMS was only evident in those aged < 56 years (MVOR [95% CI]: 0.54 [0.40-0.72]) and men (MVOR [95% CI]: 0.56 [0.40-0.80])(Pinteraction ≤ 0.04). Our results suggest that VMS use may lower NAFLD risk, particularly among younger or male hypertensive adults, if taken in moderation.

Different operationalizations of the 2018 WCRF/AICR cancer prevention recommendations and risk of cancer.

BACKGROUND: The standardized scoring system assessing adherence to the 2018 World Cancer Research Fund (WCRF)/American Institute for Cancer Research (AICR) cancer prevention recommendations assigns equal weight for each recommendation, thereby giving higher weight to dietary factors collectively (5 points) than adiposity (1 point) and physical activity (1 point). An alternative score assigning equal weights to the adiposity, physical activity, alcohol, and other dietary (composite) recommendations may better predict cancer associations. METHODS: We examined associations between standardized and alternative scores with cancer risk in two US prospective cohorts. Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox regression. RESULTS: During 28 years of follow-up, 16,342 incident cancer cases in women and 8729 cases in men occurred. Individuals in the highest versus lowest quintile of the standardized score had a reduced overall cancer risk (women: HR = 0.89, 95% CI: 0.85, 0.94; men: HR = 0.87, 95% CI: 0.81, 0.94). Results were slightly stronger for the alternative score (women: HR = 0.83, 95% CI: 0.79, 0.87; men: HR = 0.81, 95% CI: 0.75, 0.86). Similar patterns were observed for obesity-related, alcohol-related, smoking-related, and digestive system cancers. CONCLUSIONS: Greater adherence to the WCRF/AICR cancer prevention recommendations was associated with lower cancer risk. A score assigning equal weights to the adiposity, physical activity, alcohol, and all remaining diet components yielded stronger associations than the standardized score.

Influence of analytic methods, data sources, and repeated measurements on the population attributable fraction of lifestyle risk factors.

Population attributable risk (PAR%) reflects the preventable fraction of disease. However, PAR% estimates of cancer have shown large variation across populations, methods, data sources, and timing of measurements. Three statistical methods to estimate PAR% were identified from a systematic literature review: the Levin's formula, the comparative incidence rate method, and the comparative risk assessment method. We compared the variations in PAR% of postmenopausal breast cancer in the Nurses' Health Study to evaluate the influence by method choice, source of prevalence data, use of single vs repeated exposure measurements, and potential joint effects of obesity, alcohol, physical activity, fruit and vegetable intake. Across models of the three methods, the estimated PAR% using repeated measurements were higher than that using baseline measurement; overall PAR% for the baseline, simple update, and cumulative average models were 13.8%, 21.1%, 18.6% by Levin's formula; 13.7%, 28.0%, 31.2% by comparative risk assessment; and 17.4%, 25.2%, 29.3% by comparative incidence rate method. The estimated PAR% of the combination of multiple risk factors was higher than the product of the individual PAR%: 18.9% when assuming independence and 31.2% when considering the risk factors jointly. The three methods provided similar PAR% based on the same data source, timing of measurements, and target populations. However, sizable increases in the PAR% were observed for repeated measures over a single measure and for calculations based on achieving all recommendations jointly rather than individually.

Pre-diagnostic cigarette smoking and risk of second primary cancer: The Melbourne Collaborative Cohort Study.

Enhanced survival following a diagnosis of cancer has led to a steep rise in the number of individuals diagnosed with a second primary cancer. We examined the association between pre-cancer cigarette smoking and risk of second cancer in 9785 participants diagnosed with first invasive cancer after enrolment in the Melbourne Collaborative Cohort Study. Follow-up was from date of first invasive cancer until diagnosis of second primary invasive cancer, death, or 31 July 2019, whichever came first. Data on cigarette smoking was collected at enrolment (1990-94) along with information on other lifestyle factors including body size, alcohol intake and diet. We estimated hazard ratios (HR) and 95 % confidence intervals (CI) for incident second cancer with several smoking measures, adjusted for potential confounders. After a mean follow-up of 7.3 years, 1658 second cancers were identified. All measures of smoking were associated with increased risk of second cancer. We observed a 44 % higher risk of second cancer for smokers of ≥ 20 cigarettes/day (HR=1.44, 95 % CI: 1.18-1.76), compared with never smokers. We also observed dose-dependent associations with number of cigarettes smoked (HR=1.05 per 10 cigarettes/day, 95 % CI: 1.01-1.09) and duration of smoking (HR=1.07 per 10 years, 95 % CI: 1.03-1.10). The risk of second cancer increased by 4 % per 10 pack-years of smoking (HR=1.04, 95 % CI: 1.02-1.06; p < 0.001). There was suggestive evidence of stronger associations with number of cigarettes smoked and pack-years of smoking for women (pinteraction<0.05), particularly for the highest risk categories of both variables. These associations with pre-diagnostic smoking were markedly stronger for second cancers known to be smoking-related than for others (phomogeneity<0.001). Our findings for pre-diagnostic cigarette smoking indicated increased risk of second primary cancer for cancer sites considered smoking-related, highlighting the importance of assessing smoking habits in cancer survivors.

Calcium Intake and Lung Cancer Risk: A Pooled Analysis of 12 Prospective Cohort Studies.

BACKGROUND: Previous studies on calcium intake and lung cancer risk reported inconsistent associations, possibly due to the differences in intake amounts and contributing sources of calcium and smoking prevalence. OBJECTIVES: We investigated the associations of lung cancer risk with intake of calcium from foods and/or supplements and major calcium-rich foods in 12 studies. METHODS: Data from 12 prospective cohort studies conducted in the United States, Europe, and Asia were pooled and harmonized. We applied the DRI to categorize calcium intake based on the recommendations and quintile distribution to categorize calcium-rich food intake. We ran multivariable Cox regression by each cohort and pooled risk estimates to compute overall HR (95% CI). RESULTS: Among 1,624,244 adult men and women, 21,513 incident lung cancer cases were ascertained during a mean follow-up of 9.9 y. Overall, the dietary calcium intake was not significantly associated with lung cancer risk; the HRs (95% CI) were 1.08 (0.98-1.18) for higher (>1.5 RDA) and 1.01 (0.95-1.07) for lower intake (<0.5 RDA) comparing with recommended intake (EAR to RDA). Milk and soy food intake were positively or inversely associated with lung cancer risk [HR (95% CI) = 1.07 (1.02-1.12) and 0.92 (0.84-1.00)], respectively. The positive association with milk intake was significant only in European and North American studies (P-interaction for region = 0.04). No significant association was observed for calcium supplements. CONCLUSIONS: In this largest prospective investigation, overall, calcium intake was not associated with risk of lung cancer, but milk intake was associated with a higher risk. Our findings underscore the importance of considering food sources of calcium in studies of calcium intake.

Specific botanical groups of fruit and vegetable consumption and liver cancer and chronic liver disease mortality: a prospective cohort study.

BACKGROUND: Beyond alcohol and coffee, the relationship between other dietary factors, including specific vegetables and fruits, and liver outcomes remains poorly understood. OBJECTIVE: To evaluate the associations between fruit and vegetable intake with the risk of liver cancer and chronic liver disease (CLD) mortality. METHODS: This study was based on the National Institutes of Health-American Association of Retired Persons Diet and Health Study, including 485,403 participants aged 50-71 y from 1995 to 1996. Fruit and vegetable intake was estimated using a validated food frequency questionnaire. Cox proportional hazards regression was used to estimate the multivariable hazard ratios (HR) and 95% confidence intervals (CI) for liver cancer incidence and CLD mortality. RESULTS: During a median follow-up of 15.5 y, 947 incident liver cancers and 986 CLD deaths (other than liver cancer) were confirmed. A higher intake of total vegetables was associated with a lower risk of liver cancer (HRQuintile 5 vs. Quintile 1 = 0.72, 95% CI: 0.59, 0.89; Ptrend < 0.001). When further subclassified into botanical groups, the observed inverse association was mainly driven by lettuce and the cruciferous family (broccoli, cauliflower, cabbage, etc.) (Ptrend < 0.005). Additionally, higher total vegetable intake was associated with a lower risk of CLD mortality (HRQuintile5 vs. Quintile1 = 0.61, 95% CI: 0.50, 0.76; Ptrend < 0.001). Inverse associations were observed for lettuce, sweet potatoes, cruciferous vegetables, legumes, and carrots with CLD mortality (all Ptrend < 0.005). In contrast, total fruit intake was not associated with liver cancer or CLD mortality. CONCLUSIONS: Higher intakes of total vegetables, especially lettuce and cruciferous vegetables, were associated with lower liver cancer risk. Higher intakes of lettuce, sweet potatoes, cruciferous vegetables, legumes, and carrots were associated with a lower risk of CLD mortality.

Total calcium, dairy foods and risk of colorectal cancer: a prospective cohort study of younger US women.

BACKGROUND: Although colorectal cancer (CRC) incidence is declining among adults aged ≥65 years, CRC incidence in younger adults has been rising. The protective role of calcium in colorectal carcinogenesis has been well established, but evidence is lacking on whether the association varies by age at diagnosis. We investigated the association between total calcium intake and risk of overall CRC and CRC before age 55 years. METHODS: In the Nurses' Health Study II (1991-2015), 94 205 women aged 25-42 years at baseline were included in the analysis. Diet was assessed every 4 years through validated food frequency questionnaires. Multivariable-adjusted hazard ratios (HRs) and 95% CIs for CRC were estimated using the Cox proportional hazards model. RESULTS: We documented 349 incident CRC cases during 2 202 604 person-years of follow-up. Higher total calcium intake was associated with a reduced risk of CRC. Compared with those with <750 mg/day of total calcium intake, the HR of CRC was 0.61 (95% CI, 0.38-0.97) for those who consumed ≥1500 mg/day (P for trend = 0.01). The HR per 300 mg/day increase was 0.85 (95% CI, 0.76-0.95). There was a suggestive inverse association between total calcium intake and CRC before age 55 years (HR per 300 mg/day increase, 0.87; 95% CI, 0.75-1.00), suggesting the importance of calcium intake in the younger population. CONCLUSIONS: In a cohort of younger women, which reflects the birth cohorts, time periods and age ranges paralleling the recent rise in CRC, higher calcium intake was associated with a decreased risk of CRC.

A repeated measures approach to pooled and calibrated biomarker data.

Participant-level meta-analysis across multiple studies increases the sample size for pooled analyses, thereby improving precision in effect estimates and enabling subgroup analyses. For analyses involving biomarker measurements as an exposure of interest, investigators must first calibrate the data to address measurement variability arising from usage of different laboratories and/or assays. In practice, the calibration process involves reassaying a random subset of biospecimens from each study at a central laboratory and fitting models that relate the study-specific "local" and central laboratory measurements. Previous work in this area treats the calibration process from the perspective of measurement error techniques and imputes the estimated central laboratory value among individuals with only a local laboratory measurement. In this work, we propose a repeated measures method to calibrate biomarker measurements pooled from multiple studies with study-specific calibration subsets. We account for correlation between measurements made on the same person and between measurements made at the same laboratory. We demonstrate that the repeated measures approach provides valid inference, and compare it to existing calibration approaches grounded in measurement error techniques in an example describing the association between circulating vitamin D and stroke.

Association of Chlorhexidine Use and Scaling and Root Planing With Birth Outcomes in Pregnant Individuals With Periodontitis: A Systematic Review and Meta-analysis.

Importance: Chlorhexidine mouthwash enhances treatment effects of conventional periodontal treatment, but data on chlorhexidine as a source of heterogeneity in meta-analyses assessing the treatment of maternal periodontitis in association with birth outcomes are lacking. Objective: To assess possible heterogeneity by chlorhexidine use in randomized clinical trials (RCTs) evaluating the effect of periodontal treatment (ie, scaling and root planing [SRP]) vs no treatment on birth outcomes. Data Sources: Cochrane Oral Health's Trials Register, Cochrane Pregnancy and Childbirth's Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE Ovid, Embase Ovid, LILACS BIREME Virtual Health Library (Latin American and Caribbean Health Science Information database), US National Institutes of Health Ongoing Trials Register (ClinicalTrials.gov), and the WHO International Clinical Trials Registry Platform were searched through March 2022. Study Selection: RCTs were included if they were conducted among pregnant individuals with periodontitis, used interventions consisting of SRP vs no periodontal treatment, and assessed birth outcomes. Data Extraction and Synthesis: Data were abstracted with consensus of 2 reviewers using Rayyan and assessed for bias with the Cochrane Risk of Bias 2 tool before random effects subgroup meta-analyses. Analyses were conducted following the Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guideline. Main Outcomes and Measures: Outcomes of interest were preterm birth (ie, <37 weeks' gestation) and low birth weight (ie, <2500 g). Results: There were 12 studies with a total of 5735 participants evaluating preterm birth. Control group participants did not receive any treatment or use chlorhexidine during pregnancy. All intervention group participants received SRP; in 5 of these studies (with 2570 participants), pregnant participants in the treatment group either received chlorhexidine mouthwash or advice to use it, but participants in the remaining 7 studies (with 3183 participants) did not. There were 8 studies with a total of 3510 participants evaluating low birth weight, including 3 studies with SRP plus chlorhexidine (with 594 participants) and 6 studies with SRP only (with 2916 participants). The SRP plus chlorhexidine groups had lower risk of preterm birth (relative risk [RR], 0.56; 95% CI, 0.34-0.93) and low birth weight (RR, 0.47; 95% CI, 0.32-0.68) but not the SRP-only groups (preterm birth: RR, 1.03; 95% CI, 0.82-1.29; low birth weight: RR, 0.82; 95% CI, 0.62-1.08). Conclusions and Relevance: These findings suggest that treating maternal periodontitis with chlorhexidine mouthwash plus SRP was associated with reduced risk of preterm and low birth weight. Well-conducted RCTs are needed to test this hypothesis.

Long-term diet and risk of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection and Coronavirus Disease 2019 (COVID-19) severity.

BACKGROUND: The role of diet on Coronavirus Disease 2019 (COVID-19) is emerging. We investigated the association between usual diet before the onset of the pandemic and risk and severity of subsequent SARS-CoV-2 infection. METHODS: We included 42,935 participants aged 55-99 y in 2 ongoing cohort studies, the Nurses' Health Study II and Health Professionals Follow-up Study, who completed a series of COVID-19 surveys in 2020 and 2021. Using data from FFQs before COVID-19, we assessed diet quality using the Alternative Healthy Eating Index (AHEI)-2010, the alternative Mediterranean Diet (AMED) score, an Empirical Dietary Index for Hyperinsulinemia (EDIH), and an Empirical Dietary Inflammatory Pattern (EDIP). We calculated multivariable-adjusted ORs and 95% CIs for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection and severity of COVID-19 after controlling for demographic, medical, and lifestyle factors. RESULTS: Among 19,754 participants tested for SARS-CoV-2, 1941 participants reported a positive result. Of these, 1327 reported symptoms needing assistance and another 109 were hospitalized. Healthier diets, represented by higher AHEI-2010 and AMED scores and lower EDIH and EDIP scores, were associated with lower likelihood of SARS-CoV-2 infection (quartile 4 compared with quartile 1: OR: 0.80; 95% CI: 0.69, 0.92 for AHEI-2010; OR: 0.78; 95% CI: 0.67, 0.92 for AMED; OR: 1.36; 95% CI: 1.16, 1.57 for EDIH; and OR: 1.13; 95% CI: 0.99, 1.30 for EDIP; all P-trend ≤ 0.01). In the analysis of COVID-19 severity, participants with healthier diet had lower likelihood of severe infection and were less likely to be hospitalized owing to COVID-19. However, associations were no longer significant after controlling for BMI and pre-existing medical conditions. CONCLUSIONS: Diet may be an important modifiable risk factor for SARS-CoV-2 infection, as well as for severity of COVID-19. This association is partially mediated by BMI and pre-existing medical conditions.

Healthy and unhealthy plant-based diets in relation to the incidence of colorectal cancer overall and by molecular subtypes.

BACKGROUND: Plant-based foods have been recommended for health. However, not all plant foods are healthy, and little is known about the association between plant-based diets and specific molecular subtypes of colorectal cancer (CRC). We examined the associations of healthy and unhealthy plant-based diets with the incidence of CRC and its molecular subtypes. METHODS: While 123 773 participants of the Nurses' Health Study and the Health Professionals Follow-up Study had been followed up (3 143 158 person-years), 3077 of them had developed CRC. Healthy and unhealthy plant-based diet indices (hPDI and uPDI, respectively) were calculated using repeated food frequency questionnaire data. We determined the tumoural status of microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and BRAF and KRAS mutations. RESULTS: Higher hPDI was associated with lower CRC incidence (multivariable hazard ratio [HR] comparing extreme quartiles, 0.86, 95% confidence interval [CI]: 0.77, 0.96; P-trend = .04), whereas higher uPDI was associated with higher CRC incidence (multivariable HR comparing extreme quartiles, 1.16, 95% CI: 1.04, 1.29; P-trend = .005). The association of hPDI significantly differed by KRAS status (P-heterogeneity = .003) but not by other tumour markers. The hPDI was associated with lower incidence of KRAS-wildtype CRC (multivariable HR comparing extreme quartiles, 0.74, 95% CI: 0.57, 0.96; P-trend = .004) but not KRAS-mutant CRC (P-trend = .22). CONCLUSIONS: While unhealthy plant-based diet enriched with refined grains and sugar is associated with higher CRC incidence, healthy plant-based diet rich in whole grains, fruits and vegetables is associated with lower incidence of CRC, especially KRAS-wildtype CRC.

Spline Analysis of Biomarker Data Pooled from Multiple Matched/Nested Case-Control Studies.

Pooling biomarker data across multiple studies enables researchers to obtain precise estimates of the association between biomarker measurements and disease risks due to increased sample sizes. However, biomarker measurements often vary significantly across different assays and laboratories; therefore, calibration of the local laboratory measurements to a reference laboratory is necessary before pooling data. We propose two methods for estimating the dose-response curves that allow for a nonlinear association between the continuous biomarker measurements and log relative risk in pooling projects of matched/nested case-control studies. Our methods are based on full calibration and internalized calibration methods. The full calibration method uses calibrated biomarker measurements for all subjects, even for people with reference laboratory measurements, while the internalized calibration method uses the reference laboratory measurements when available and otherwise uses the calibrated biomarker measurements. We conducted simulation studies to compare these methods, as well as a naive method, where data are pooled without calibration. Our simulation and theoretical results suggest that, in estimating the dose-response curves for biomarker-disease relationships, the internalized and full calibration methods perform substantially better than the naive method, and the full calibration approach is the preferred method for calibrating biomarker measurements. We apply our methods in a pooling project of nested case-control studies to estimate the association of circulating Vitamin D levels with risk of colorectal cancer.

Prediagnosis Leisure-Time Physical Activity and Lung Cancer Survival: A Pooled Analysis of 11 Cohorts.

BACKGROUND: Little is known about the association between physical activity before cancer diagnosis and survival among lung cancer patients. In this pooled analysis of 11 prospective cohorts, we investigated associations of prediagnosis leisure-time physical activity (LTPA) with all-cause and lung cancer-specific mortality among incident lung cancer patients. METHODS: Using self-reported data on regular engagement in exercise and sports activities collected at study enrollment, we assessed metabolic equivalent hours (MET-h) of prediagnosis LTPA per week. According to the Physical Activity Guidelines for Americans, prediagnosis LTPA was classified into inactivity, less than 8.3 and at least 8.3 MET-h per week (the minimum recommended range). Cox regression was used to estimate hazard ratios (HRs) and 95% confidence interval (CIs) for all-cause and lung cancer-specific mortality after adjustment for major prognostic factors and lifetime smoking history. RESULTS: Of 20 494 incident lung cancer patients, 16 864 died, including 13 596 deaths from lung cancer (overall 5-year relative survival rate = 20.9%, 95% CI = 20.3% to 21.5%). Compared with inactivity, prediagnosis LTPA of more than 8.3 MET-h per week was associated with a lower hazard of all-cause mortality (multivariable-adjusted HR = 0.93, 95% CI = 0.88 to 0.99), but not with lung cancer-specific mortality (multivariable-adjusted HR = 0.99, 95% CI = 0.95 to 1.04), among the overall population. Additive interaction was found by tumor stage (Pinteraction = .008 for all-cause mortality and .003 for lung cancer-specific mortality). When restricted to localized cancer, prediagnosis LTPA of at least 8.3 MET-h per week linked to 20% lower mortality: multivariable-adjusted HRs were 0.80 (95% CI = 0.67 to 0.97) for all-cause mortality and 0.80 (95% CI = 0.65 to 0.99) for lung cancer-specific mortality. CONCLUSIONS: Regular participation in LTPA that met or exceeded the minimum Physical Activity Guidelines was associated with reduced hazards of mortality among lung cancer patients, especially those with early stage cancer.