Publications by authors named "Molin Wang"

194 Publications

Non-inferiority of low-dose compared to standard high-dose calcium supplementation in pregnancy: study protocol for two randomized, parallel group, non-inferiority trials in India and Tanzania.

Trials 2021 Nov 24;22(1):838. Epub 2021 Nov 24.

Department of Global Health and Population, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.

Background: Hypertensive disorders of pregnancy are important causes of maternal morbidity and mortality, as well as preterm birth, the leading cause of death for children under 5 years globally. The World Health Organization currently recommends that pregnant women receive high-dose calcium supplementation (1500-2000 mg elemental calcium) for prevention of preeclampsia in populations with low dietary calcium intake. Trials of low-dose calcium supplementation (< 1000 mg elemental calcium/day) during pregnancy have also shown similar reductions in the risk of preeclampsia; however, no trials to date have directly compared low-dose to the standard high-dose calcium supplementation. Our objective is to assess the non-inferiority of low-dose as compared to standard high-dose calcium supplementation in pregnancy.

Methods/design: We will conduct two independent trials in Bangalore, India (n = 11,000 pregnancies), and Dar es Salaam, Tanzania (n = 11,000 pregnancies). The trial designs are individually randomized, parallel group, quadruple-blind, non-inferiority trials of low-dose calcium supplementation (500 mg elemental calcium/day) as compared to standard high-dose calcium supplementation (1500 mg elemental calcium/day) among nulliparous pregnant women. Pregnant women will be enrolled in the trial before 20 weeks of gestation and will receive the randomized calcium regimen from randomization until the time of delivery. The co-primary outcomes are (i) preeclampsia and (ii) preterm birth; we will test non-inferiority of the primary outcomes for low-dose as compared to the standard high-dose supplementation regimen in each trial. The trials' secondary outcomes include gestational hypertension, severe features of preeclampsia, pregnancy-related death, third trimester severe anemia, fetal death, stillbirth, low birthweight, small-for-gestational age birth, and infant death.

Discussion: The trials will provide causal evidence on the non-inferiority of low-dose as compared to the standard high-dose supplementation in India and Tanzania. A single tablet, low-dose calcium supplementation regimen may improve individual-level adherence, reduce programmatic costs, and ultimately expand implementation of routine calcium supplementation in pregnancy in populations with low dietary calcium intake.

Trial Registration: ClinicalTrials.gov identifier: NCT03350516 ; registered on 22 November 2018. Clinical Trials Registry-India identifier: CTRI/2018/02/012119 ; registered on 23 February 2018. Tanzania Medicines and Medical Devices Authority Trials Registry identifier: TFDA0018/CTR/0010/5 ; registered on 20 December 2018.
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http://dx.doi.org/10.1186/s13063-021-05811-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8611882PMC
November 2021

Reproducibility and validity of diet quality scores derived from food frequency questionnaires.

Am J Clin Nutr 2021 Nov 11. Epub 2021 Nov 11.

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

Background: Diet quality scores (DQSs) are frequently used to study diet-disease relationships but the validity of these scores derived from food frequency questionnaires (FFQs) has rarely been evaluated.

Objective: To evaluate the validity and reproducibility of six commonly used DQSs derived from the FFQ, including the Alternate Healthy Eating Index-2010 (AHEI-2010), Dietary Approaches to Stop Hypertension (DASH) score, alternative Mediterranean Diet score (AMED), and three plant-based diet indices (overall, healthful, and unhealthful).

Design: This analysis included 1,394 participants from the Men's (n = 652) and Women's (n = 742) Lifestyle Validation Studies. Participants completed a 152-item FFQ at the beginning of the study and one year later, and completed two weighed 7-day dietary records (7DDRs) and donated two blood samples six-month apart between FFQ assessments. The reproducibility of the FFQs was evaluated by rank intraclass correlation coefficients (ICC). The validity was assessed by comparing FFQ-derived DQSs to those from the average of two 7DDRs using Spearman rank correlation coefficients deattenuated for random measurement error in the 7DDRs (rs). Further, we calculated the correlations between DQSs and plasma biomarkers of diet including fatty acids, folate, carotenoids, retinol, and alpha-and gamma-tocopherol.

Results: Six FFQ derived DQSs demonstrated moderate to high reproducibility (energy-adjusted ICCs = 0.61 to 0.84) and validity (energy-adjusted, deattenuated rs = 0.56 to 0.80) in both men and women. We consistently observed expected correlations between FFQ derived DQSs with plasma fatty acids, including long chain N-3 and trans fatty acids, most carotenoids, and gamma-tocopherol (rs>0.2).

Conclusions: Our study demonstrates the validity of the FFQ to evaluate overall diet quality using six commonly used DQSs. In addition, these DQSs have qualitatively demonstrated biological relevance as indicated by their correlations with circulating biomarkers.
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http://dx.doi.org/10.1093/ajcn/nqab368DOI Listing
November 2021

24-Hour Urinary Sodium and Potassium Excretion and Cardiovascular Risk.

N Engl J Med 2021 Nov 13. Epub 2021 Nov 13.

From the Departments of Epidemiology (Y.M., Q.S., G.C.C., M.W., E.B.R., J.E.M., W.C.W., A.H., N.R.C., F.B.H.) and Nutrition (Q.S., C.Y., E.B.R., W.C.W., F.B.H.), Harvard T.H. Chan School of Public Health, and the Channing Division of Network Medicine, the Department of Medicine (Q.S., G.C.C., E.B.R., J.E.M., W.C.W., F.B.H.), Renal Division, the Department of Medicine (G.C.C.), and the Division of Preventive Medicine (J.E.M., N.R.C.), Brigham and Women's Hospital and Harvard Medical School - all in Boston; the Wolfson Institute of Population Health, St. Bartholomew's Hospital and the London School of Medicine and Dentistry, Queen Mary University of London, London (F.J.H., G.A.M.); the Department of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands (L.M.K., S.J.L.B., R.T.G.); and the Departments of Medicine, Community Health Sciences, and Physiology and Pharmacology, O'Brien Institute of Public Health and Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, AB, Canada (N.R.C.C.).

Background: The relation between sodium intake and cardiovascular disease remains controversial, owing in part to inaccurate assessment of sodium intake. Assessing 24-hour urinary excretion over a period of multiple days is considered to be an accurate method.

Methods: We included individual-participant data from six prospective cohorts of generally healthy adults; sodium and potassium excretion was assessed with the use of at least two 24-hour urine samples per participant. The primary outcome was a cardiovascular event (coronary revascularization or fatal or nonfatal myocardial infarction or stroke). We analyzed each cohort using consistent methods and combined the results using a random-effects meta-analysis.

Results: Among 10,709 participants, who had a mean (±SD) age of 51.5±12.6 years and of whom 54.2% were women, 571 cardiovascular events were ascertained during a median study follow-up of 8.8 years (incidence rate, 5.9 per 1000 person-years). The median 24-hour urinary sodium excretion was 3270 mg (10th to 90th percentile, 2099 to 4899). Higher sodium excretion, lower potassium excretion, and a higher sodium-to-potassium ratio were all associated with a higher cardiovascular risk in analyses that were controlled for confounding factors (P≤0.005 for all comparisons). In analyses that compared quartile 4 of the urinary biomarker (highest) with quartile 1 (lowest), the hazard ratios were 1.60 (95% confidence interval [CI], 1.19 to 2.14) for sodium excretion, 0.69 (95% CI, 0.51 to 0.91) for potassium excretion, and 1.62 (95% CI, 1.25 to 2.10) for the sodium-to-potassium ratio. Each daily increment of 1000 mg in sodium excretion was associated with an 18% increase in cardiovascular risk (hazard ratio, 1.18; 95% CI, 1.08 to 1.29), and each daily increment of 1000 mg in potassium excretion was associated with an 18% decrease in risk (hazard ratio, 0.82; 95% CI, 0.72 to 0.94).

Conclusions: Higher sodium and lower potassium intakes, as measured in multiple 24-hour urine samples, were associated in a dose-response manner with a higher cardiovascular risk. These findings may support reducing sodium intake and increasing potassium intake from current levels. (Funded by the American Heart Association and the National Institutes of Health.).
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http://dx.doi.org/10.1056/NEJMoa2109794DOI Listing
November 2021

Weight Change, Lifestyle and Mortality in Patients with Type 2 Diabetes.

J Clin Endocrinol Metab 2021 Nov 6. Epub 2021 Nov 6.

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

Objective: To examine the association between weight change and mortality among participants with incident type 2 diabetes (T2D) and evaluate the impact of adopting a healthy lifestyle on this association.

Research Design And Methods: This prospective analysis included 11,262 incident T2D patients from the Nurses' Health Study and Health Professionals Follow-up Study. We assessed weight change bracketing T2D diagnosis in relation to mortality. We also examined potential effect modification by a healthy lifestyle consisting of high-quality diet, regular physical activity, non-smoking status and moderate alcohol consumption.

Results: On average, T2D patients lost 2.3 kg during a two-year time-window spanning the T2D diagnosis, and body weight increased afterwards following a trajectory similar to that of non-diabetics. Compared with patients with a stable weight, T2D patients who lost ≥10% body weight had a 21% (95% CI: 9%, 35%) increased all-cause mortality. Lifestyle significantly modified these associations: the hazard ratios (95% CIs) of all-cause mortality comparing ≥10% weight loss with stable weight were 1.63 (1.26, 2.09) among participants with a deteriorated lifestyle, 1.27 (1.11, 1.46) for a stable lifestyle, and 1.02 (0.81, 1.27) for an improved lifestyle (Pinteraction <0.001). Major weight loss was associated with increased cause-specific mortality and similar effect modifications by lifestyle were also observed.

Conclusions: Significant weight loss upon T2D incidence was associated with increased mortality, although improved lifestyle quality abolished these associations. These results highlight the role of adopting a healthy lifestyle for newly diagnosed T2D patients, especially among those who might lose weight unintentionally, and improving long-term survival.
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http://dx.doi.org/10.1210/clinem/dgab800DOI Listing
November 2021

Plasma concentrations of leptin at mid-pregnancy are associated with gestational weight gain among pregnant women in Tanzania: a prospective cohort study.

BMC Pregnancy Childbirth 2021 Oct 6;21(1):675. Epub 2021 Oct 6.

Department of Global Health and Population, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, 02120, USA.

Background: Gestational weight gain (GWG) has critical implications for maternal and child health. Inflammation and angiogenesis are implicated in various aspects of maternal metabolism that may play a role in gestational weight gain. The associations of inflammatory, angiogenic, and metabolic pathways with GWG are yet to be elucidated. This study evaluated associations between a panel of inflammatory, angiogenic, and metabolic proteins measured in mid-pregnancy and gestational weight gain.

Methods: Pregnant women were enrolled from Dar es Salaam, Tanzania, between 2001 and 2004. The participants were enrolled at mid-pregnancy (12 to 27 weeks of gestation) and followed up until delivery. This analysis focused on a cohort of 1002 women who were primigravid, had singleton live births, had longitudinal measures of gestational weight, and whose mid-pregnancy plasma samples underwent analysis for 18 proteins.

Results: Higher plasma concentrations of leptin (mean difference in GWG percent adequacy comparing highest with lowest quartiles: 10.24; 95% CI 3.31, 17.16; p-trend = 0.003) and chitinase-3-like protein-1 (CH3L1) (mean difference in GWG percent adequacy comparing highest with lowest quartiles: 7.02; 95% CI 0.31, 13.72; p-trend = 0.007) were associated with greater GWG in a dose-response pattern. Higher leptin concentrations were associated with a lower risk of inadequate GWG (risk ratio comparing highest with lowest quartiles: 0.77; 95% CI 0.65, 0.91; p-trend = 0.001) and a higher risk of excessive GWG (risk ratio comparing highest with lowest quartiles: 1.57; 95% CI 1.03, 2.39; p-trend = 0.03). Higher CH3L1 concentrations were associated with a higher risk of excessive GWG (p-trend = 0.007). The associations of leptin and CH3L1 with inadequate GWG were stronger during the second than the third trimester. The other 16 proteins examined were not significantly associated with GWG.

Conclusions: Mid-pregnancy plasma leptin concentrations may be associated with GWG and have clinical predictive utility in identifying women at a higher risk of inadequate or excessive gestational weight gain.
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http://dx.doi.org/10.1186/s12884-021-04146-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8495974PMC
October 2021

Testing gene-environment interactions in the presence of confounders and mismeasured environmental exposures.

G3 (Bethesda) 2021 09;11(10)

Department of Epidemiology and Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.

Interest in investigating gene-environment (GxE) interactions has rapidly increased over the last decade. Although GxE interactions have been extremely investigated in large studies, few such effects have been identified and replicated, highlighting the need to develop statistical GxE tests with greater statistical power. The reverse test has been proposed for testing the interaction effect between continuous exposure and genetic variants in relation to a binary disease outcome, which leverages the idea of linear discriminant analysis, significantly increasing statistical power comparing to the standard logistic regression approach. However, this reverse approach did not take into consideration adjustment for confounders. Since GxE interaction studies are inherently nonexperimental, adjusting for potential confounding effects is critical for valid evaluation of GxE interactions. In this study, we extend the reverse test to allow for confounders. The proposed reverse test also allows for exposure measurement errors as typically occurs. Extensive simulation experiments demonstrated that the proposed method not only provides greater statistical power under most simulation scenarios but also provides substantive computational efficiency, which achieves a computation time that is more than sevenfold less than that of the standard logistic regression test. In an illustrative example, we applied the proposed approach to the Veterans Aging Cohort Study (VACS) to search for genetic susceptibility loci modifying the smoking-HIV status association.
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http://dx.doi.org/10.1093/g3journal/jkab236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8473983PMC
September 2021

Immune cell profiles in the tumor microenvironment of early-onset, intermediate-onset, and later-onset colorectal cancer.

Cancer Immunol Immunother 2021 Sep 16. Epub 2021 Sep 16.

Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, 221 Longwood Ave., EBRC Room 404A, Boston, MA, 02115, USA.

Background: Despite heightened interest in early-onset colorectal cancer (CRC) diagnosed before age 50, little is known on immune cell profiles of early-onset CRC. It also remains to be studied whether CRCs diagnosed at or shortly after age 50 are similar to early-onset CRC. We therefore hypothesized that immune cell infiltrates in CRC tissue might show differential heterogeneity patterns between three age groups (< 50 "early onset," 50-54 "intermediate onset,"  ≥ 55 "later onset").

Methods: We examined 1,518 incident CRC cases with available tissue data, including 35 early-onset and 73 intermediate-onset cases. To identify immune cells in tumor intraepithelial and stromal areas, we developed three multiplexed immunofluorescence assays combined with digital image analyses and machine learning algorithms, with the following markers: (1) CD3, CD4, CD8, CD45RO (PTPRC), and FOXP3 for T cells; (2) CD68, CD86, IRF5, MAF, and MRC1 (CD206) for macrophages; and (3) ARG1, CD14, CD15, CD33, and HLA-DR for myeloid cells.

Results: Although no comparisons between age groups showed statistically significant differences at the stringent two-sided α level of 0.005, compared to later-onset CRC, early-onset CRC tended to show lower levels of tumor-infiltrating lymphocytes (P = 0.013), intratumoral periglandular reaction (P = 0.025), and peritumoral lymphocytic reaction (P = 0.044). Compared to later-onset CRC, intermediate-onset CRC tended to show lower densities of overall macrophages (P = 0.050), M1-like macrophages (P = 0.062), CD14HLA-DR cells (P = 0.015), and CD3CD4FOXP3 cells (P = 0.039).

Conclusions: This hypothesis-generating study suggests possible differences in histopathologic lymphocytic reaction patterns, macrophages, and regulatory T cells in the tumor microenvironment by age at diagnosis.
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http://dx.doi.org/10.1007/s00262-021-03056-6DOI Listing
September 2021

Alcohol intake and risk of glioma: results from three prospective cohort studies.

Eur J Epidemiol 2021 Sep 4;36(9):965-974. Epub 2021 Sep 4.

Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.

Purpose: The association between alcohol intake and glioma remains unclear. We evaluated the association between alcohol intake and incidence of glioma in three large, prospective cohort studies with repeated alcohol assessments.

Methods: We harnessed data from three studies with repeat alcohol assessment to compute hazard ratios (HR) and 95% confidence intervals (CI) for glioma by overall alcohol intake and intake from specific beverages using Cox proportional hazards regression, adjusted for age, cohort, body mass index, smoking status, and caloric intake. Analyses were conducted separately for glioma overall and for glioblastoma (GBM).

Results: We confirmed 554 incident glioma cases (362 GBM) among 237,505 participants with 6,216,378 person-years of follow up. Cumulative average alcohol intake was associated with reduced risk of glioma (HR = 0.75, 95%CI:0.56-0.99 comparing > 8-15 to ≤ 0.5 g/d; HR = 0.71, 95%CI:0.53-0.96 comparing > 15 g/d to ≤ 0.5 g/d). When stratified by sex, for the same comparisons, the HRs for men were 0.57 (95%CI:0.36-0.89) and 0.79 (0.53-1.16), and for women 0.90 (95%CI:0.62-1.30) and 0.62, 95%CI:0.39-0.97. Results were consistent when examining cumulative average, baseline, and recent intake, and with a 4 year lag.

Conclusion: These results provide evidence against a positive association between alcohol intake and glioma risk. Alcohol intake was associated with reduced risk of glioma in both men and women.
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http://dx.doi.org/10.1007/s10654-021-00800-1DOI Listing
September 2021

Lignan Intake and Risk of Coronary Heart Disease.

J Am Coll Cardiol 2021 Aug;78(7):666-678

Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA; Joslin Diabetes Center, Boston, Massachusetts, USA.

Background: Evidence regarding lignan consumption in relation to coronary heart disease (CHD) risk remains limited and mixed.

Objectives: The aim of this study was to prospectively examine associations between lignan intake and CHD risk in U.S. men and women.

Methods: We prospectively followed 214,108 men and women in 3 cohorts who did not have cardiovascular disease or cancer at baseline. Diet was repeatedly assessed using a validated food frequency questionnaire every 2-4 years since baseline.

Results: During 5,517,225 person-years of follow-up, we documented 10,244 CHD cases, including 6,283 nonfatal myocardial infarction and 3,961 fatal CHD cases. In multivariable-adjusted analyses, comparing extreme quintiles, the pooled hazard ratios of CHD were 0.85 (95% CI: 0.79-0.92) for total lignans, 0.76 (95% CI: 0.71-0.82) for matairesinol, 0.87 (95% CI: 0.81-0.93) for secoisolariciresinol, 0.89 (95% CI: 0.83-0.95) for pinoresinol, and 0.89 (95% CI: 0.83-0.95) for lariciresinol (all P values for trend ≤0.003). Nonlinear relationships were found for total lignan, matairesinol, and secoisolariciresinol: the risk reduction plateaued at intakes above approximately 300 μg/d, 10 μg/d, and 100 μg/d, respectively (P < 0.01 for all nonlinearity). The inverse associations for total lignan intake appeared to be more apparent among participants with higher total fiber intake (P = 0.04 for interaction). In addition, lignan intake was more strongly associated with plasma concentrations of enterolactone when fiber intake was higher.

Conclusions: Increased long-term intake of lignans was associated with a significantly lower risk of total CHD in both men and women. Possible synergistic effects may exist between lignan and fiber intake in relation to CHD risk reduction, possibly through enhancing the production of enterolignans.
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http://dx.doi.org/10.1016/j.jacc.2021.05.049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8432598PMC
August 2021

Adolescent Plant Product Intake in Relation to Later Prostate Cancer Risk and Mortality in the NIH-AARP Diet and Health Study.

J Nutr 2021 Oct;151(10):3223-3231

Division of Public Health Sciences, Department of Surgery, and the Alvin J Siteman Cancer Center, Washington University School of Medicine, St Louis, MO, USA.

Background: Although fruit and vegetable intake during adolescence, a potentially sensitive time period for prostate cancer (PCa) development, has been proposed to protect against PCa risk, few studies have investigated the role of adolescent plant product intake in PCa development.

Methods: Intake of various vegetables, fruit, and grains by males at ages 12-13 y was examined in relation to later PCa risk and mortality in the NIH-AARP Diet and Health Study. Cox proportional hazards regression was used to calculate HRs and 95% CIs of nonadvanced (n = 14,238) and advanced (n = 2,170) PCa incidence and PCa mortality (n = 760) during 1,729,896 person-years of follow-up.

Results: None of the plant products examined were associated consistently with all PCa outcomes. However, greater adolescent intakes of tomatoes (P-trend = 0.004) and nonstarch vegetables (P-trend = 0.025) were associated with reduced risk of nonadvanced PCa, and greater intakes of broccoli (P-trend = 0.050) and fruit juice (P-trend = 0.019-0.025) were associated with reduced risk of advanced PCa and/or PCa mortality. Positive trends were also observed for greater intakes of fruit juice (P-trend = 0.002), total fruit (P-trend = 0.014), and dark bread (P-trend = 0.035) with nonadvanced PCa risk and for greater intakes of legumes (P-trend < 0.001), fiber (P-trend = 0.001), and vegetable protein (P-trend = 0.013-0.040) with advanced PCa risk or PCa mortality.

Conclusions: Our findings do not provide strong evidence to suggest that adolescent plant product intake is associated with reduced PCa risk.
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http://dx.doi.org/10.1093/jn/nxab241DOI Listing
October 2021

Association of mutation and PTEN loss with expression of CD274 (PD-L1) in colorectal carcinoma.

Oncoimmunology 2021 2;10(1):1956173. Epub 2021 Aug 2.

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

Immunotherapy targeting the CD274 (PD-L1)/PDCD1 (PD-1) immune checkpoint axis has emerged as a promising treatment strategy for various cancers. Experimental evidence suggests that phosphatidylinositol-4,5-bisphosphonate 3-kinase (PI3K) signaling may upregulate CD274 expression. Thus, we hypothesized that mutation, PTEN loss, or their combined status might be associated with CD274 overexpression in colorectal carcinoma. We assessed tumor CD274 and PTEN expression by immunohistochemistry and assessed mutation by pyrosequencing in 753 patients among 4,465 incident rectal and colon cancer cases that had occurred in two U.S.-wide prospective cohort studies. To adjust for potential confounders and selection bias due to tissue availability, inverse probability weighted multivariable ordinal logistic regression analyses used the 4,465 cases and tumoral data including microsatellite instability, CpG island methylator phenotype, and mutations. mutation and loss of PTEN expression were detected in 111 of 753 cases (15%) and 342 of 585 cases (58%), respectively. Tumor CD274 expression was negative in 306 (41%), low in 195 (26%), and high in 252 (33%) of 753 cases. PTEN loss was associated with CD274 overexpression [multivariable odds ratio (OR) 1.83; 95% confidence interval (CI), 1.22-2.75; = .004]. mutation was statistically-insignificantly ( = .036 with the stringent alpha level of 0.005) associated with CD274 overexpression (multivariable OR, 1.54; 95% CI, 1.03-2.31). -mutated PTEN-lost tumors (n = 33) showed higher prevalence of CD274-positivity (82%) than -wild-type PTEN-lost tumors (n = 204; 70% CD274-positivity) and PTEN-expressed tumors (n = 147; 50% CD274-positivity) ( = .003). Our findings support the role of PI3K signaling in the CD274/PDCD1 pathway.
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http://dx.doi.org/10.1080/2162402X.2021.1956173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8331006PMC
October 2021

Knockdown of ER-α36 expression inhibits glioma proliferation, invasion and epithelial-to-mesenchymal transition.

Anat Rec (Hoboken) 2021 Jul 31. Epub 2021 Jul 31.

Department of Genetics and Key Laboratory for Experimental Teratology of the Ministry of Education, School of Basic Medical Science, Shandong University, Jinan, China.

Estrogen receptor-α36 (ER-α36), a subtype of the estrogen receptor, is reported to play roles in tumorigenesis and tamoxifen resistance in several tumors, especially breast cancer. However, the role of ER-α36 in glioma proliferation and invasion remains unknown. Here, we explored the function of ER-α36 in glioma cells, using U87 and U251 cell lines. We found that ER-α36 was upregulated in glioma tissues compared to adjacent nontumor tissues. In U87 and U251 glioma cell lines, inhibition of ER-α36 expression by shRNA suppressed cell proliferation and invasion. In addition, the expression of an epithelial marker, ZO-1, was upregulated while that of one mesenchymal marker, N-cadherin, was downregulated with ER-α36 knockdown. We also found that inhibition of ER-α36 inactivated both PI3K/AKT and MEK/ERK signals. Taken together, these data indicated that overexpression of ER-α36 is associated with glioma proliferation and progression but that inhibition of ER-α36 leads to suppressed invasion and the epithelial-to-mesenchymal transition via PI3K/AKT and MEK/ERK pathway inactivation in glioma cells.
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http://dx.doi.org/10.1002/ar.24723DOI Listing
July 2021

Adherence to the World Cancer Research Fund/American Institute for Cancer Research Cancer Prevention Recommendations and Colorectal Cancer Survival.

Cancer Epidemiol Biomarkers Prev 2021 Oct 16;30(10):1816-1825. Epub 2021 Jul 16.

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

Background: Patients with cancer are recommended to follow cancer prevention guidelines due to inadequate evidence for specific recommendations for cancer survivors.

Methods: We examined whether diet and lifestyle scores measuring adherence to the 2018 World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) cancer prevention guidelines were associated with colorectal cancer-specific and overall mortality among 1,491 patients with colorectal cancer in two prospective cohorts. Cox proportional hazards regression models were used to calculate the multivariable-adjusted HRs and 95% confidence intervals (CI).

Results: During a median follow-up of 7.92 years, there were 641 deaths (179 colorectal cancer-specific deaths). Patients in the highest quartile of the post-diagnostic WCRF/AICR lifestyle score including diet, body mass index (BMI), and physical activity had a 24% lower risk (HR = 0.76, 95% CI: 0.49-1.18) of colorectal cancer-specific mortality and a 37% lower risk (HR = 0.63, 95% CI: 0.50-0.78) of overall mortality compared with the lowest quartile. When BMI was not included in the lifestyle score due to potential disease-related weight loss, stronger inverse associations were observed for both colorectal cancer-specific and overall mortality for the same comparison (colorectal cancer-specific: HR = 0.50, 95% CI: 0.32-0.79; overall: HR = 0.59, 95% CI: 0.47-0.75). The post-diagnostic WCRF/AICR diet score was not statistically significantly associated with either colorectal cancer-specific or overall mortality.

Conclusions: Greater adherence to the WCRF/AICR cancer prevention recommendations was associated with improved survival in patients with colorectal cancer.

Impact: This study provides support for patients with colorectal cancer to follow cancer prevention recommendations after diagnosis. Future studies on cancer survivors will continue to contribute to evidence-based diet and lifestyle recommendations for patients with cancer.
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http://dx.doi.org/10.1158/1055-9965.EPI-21-0120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8492523PMC
October 2021

Sugar-sweetened beverage, artificially sweetened beverage and sugar intake and colorectal cancer survival.

Br J Cancer 2021 Sep 15;125(7):1016-1024. Epub 2021 Jul 15.

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

Background: The influence of a high sugar diet on colorectal cancer (CRC) survival is unclear.

Methods: Among 1463 stage I-III CRC patients from the Nurses' Health Study and Health Professionals Follow-up Study, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for CRC-specific and all-cause mortality in relation to intake of post-diagnosis sugar-sweetened beverages (SSB), artificially sweetened beverages (ASB), fruit juice, fructose and other sugars.

Results: Over a median 8.0 years, 781 cases died (173 CRC-specific deaths). Multivariable-adjusted HRs for post-diagnosis intake and CRC-specific mortality were 1.21 (95% CI: 0.87-1.68) per 1 serving SSBs per day (serving/day) and 1.24 (95% CI: 0.95-1.63) per 20 grams fructose per day. Significant positive associations for CRC-specific mortality were primarily observed ≤5 years from diagnosis (HR per 1 serving/day of SSBs = 1.59, 95% CI: 1.06-2.38). Significant inverse associations were observed between ASBs and CRC-specific and all-cause mortality (HR for ≥5 versus <1 serving/week = 0.44, 95% CI: 0.26-0.75 and 0.70, 95% CI: 0.55-0.89, respectively).

Conclusions: Higher post-diagnosis intake of SSBs and sugars may be associated with higher CRC-specific mortality, but only up to 5 years from diagnosis, when more deaths were due to CRC. The inverse association between ASBs and CRC-specific mortality warrants further examination.
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http://dx.doi.org/10.1038/s41416-021-01487-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8476625PMC
September 2021

Smoking and Incidence of Colorectal Cancer Subclassified by Tumor-Associated Macrophage Infiltrates.

J Natl Cancer Inst 2021 Jul 15. Epub 2021 Jul 15.

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

Background: Biological evidence indicates that smoking can influence macrophage functions and polarization, thereby promoting tumor evolution. We hypothesized that the association of smoking with colorectal cancer incidence might differ by macrophage infiltrates.

Methods: Utilizing the Nurses' Health Study and the Health Professionals Follow-up Study, we examined the association of smoking with incidence of colorectal cancer subclassified by macrophage counts. Multiplexed immunofluorescence [for CD68, CD86, IRF5, MAF, and MRC1 (CD206)] combined with digital image analysis and machine learning was used to identify overall, M1-polarized, and M2-polarized macrophages in tumor. We used inverse-probability-weighted multivariable Cox proportional hazards regression models to control for potential confounders and selection bias due to tissue data availability. All statistical tests were 2-sided.

Results: During follow-up of 131,144 participants (3,648,370 person-years), we documented 3,092 incident colorectal cancer cases including 871 cases with available macrophage data. The association of pack-years smoked with colorectal cancer incidence differed by stromal macrophage densities (Pheterogeneity=.003). Compared to never smoking, multivariable-adjusted hazard ratios (95% confidence interval) for tumors with low macrophage densities were 1.32 (0.97 to 1.79) for 1-19 pack-years, 1.31 (0.92 to 1.85) for 20-39 pack-years, and 1.74 (1.26 to 2.41) for ≥40 pack-years (Ptrend=.004). In contrast, pack-years smoked were not statistically significantly associated with the incidence of tumors having intermediate or high macrophage densities (Ptrend>.009, with the α level of 0.005). No statistically significant differential association was found for colorectal cancer subclassified by M1-like or M2-like macrophages.

Conclusions: The association of smoking with colorectal cancer incidence is stronger for tumors with lower stromal macrophage counts. Our findings suggest an interplay of smoking and macrophages in colorectal carcinogenesis.
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http://dx.doi.org/10.1093/jnci/djab142DOI Listing
July 2021

CoSMeD: a user-friendly web server to estimate 5-year survival probability of left-sided and right-sided colorectal cancer patients using molecular data.

Bioinformatics 2021 Jul 14. Epub 2021 Jul 14.

Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.

Summary: Colorectal cancer is a heterogeneous disease with diverse prognoses between left-sided and right-sided patients; therefore, it is necessary to precisely evaluate the survival probability of side-specific colorectal cancer patients. Here, we collected multi-omics data from The Cancer Genome Atlas (TCGA) program, including gene expression, DNA methylation, and microRNA (miRNA) expression. Specificity measure (SPM) and robust likelihood-based survival analysis were used to identify 6 left-sided and 28 right-sided prognostic biomarkers. Compared to the performance of clinical prognostic models, the addition of these biomarkers could significantly improve the discriminatory ability and calibration in predicting side-specific 5-year survival for colorectal cancer. Additional dataset derived from Gene Expression Omnibus (GEO) was used to validate the prognostic value of side-specific genes. Finally, we constructed colorectal cancer side-specific molecular database (CoSMeD), a user-friendly interface for estimating side-specific colorectal cancer 5-year survival probability, which can lay the basis for personalized management of left-sided and right-sided colorectal cancer patients.

Availability And Implementation: CoSMeD is freely available at https://mulongdu.shinyapps.io/cosmed.

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btab523DOI Listing
July 2021

Total Vitamin D Intake and Risks of Early-Onset Colorectal Cancer and Precursors.

Gastroenterology 2021 Oct 7;161(4):1208-1217.e9. Epub 2021 Jul 7.

Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. Electronic address:

Background & Aims: Vitamin D has been implicated in colorectal cancer (CRC) pathogenesis, but it remains unknown whether total vitamin D intake is associated with early-onset CRC and precursors diagnosed before age 50.

Methods: We prospectively examined the association between total vitamin D intake and risks of early-onset CRC and precursors among women enrolled in the Nurses' Health Study II. Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for early-onset CRC were estimated with Cox proportional hazards model. Multivariable-adjusted odds ratios (ORs) and 95% CIs for early-onset conventional adenoma and serrated polyp were estimated with logistic regression model.

Results: We documented 111 incident cases of early-onset CRC during 1,250,560 person-years of follow-up (1991 to 2015). Higher total vitamin D intake was significantly associated with a reduced risk of early-onset CRC (HR for ≥450 IU/day vs <300 IU/day, 0.49; 95% CI, 0.26-0.93; P for trend = .01). The HR per 400 IU/day increase was 0.46 (95% CI, 0.26-0.83). The inverse association was significant and appeared more evident for dietary sources of vitamin D (HR per 400 IU/day increase, 0.34; 95% CI, 0.15-0.79) than supplemental vitamin D (HR per 400 IU/day increase, 0.77; 95% CI, 0.37-1.62). For CRC precursors, the ORs per 400 IU/day increase were 0.76 (95% CI, 0.65-0.88) for conventional adenoma (n = 1,439) and 0.85 (95% CI, 0.75-0.97) for serrated polyp (n = 1,878).

Conclusions: In a cohort of younger women, higher total vitamin D intake was associated with decreased risks of early-onset CRC and precursors.
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http://dx.doi.org/10.1053/j.gastro.2021.07.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8463427PMC
October 2021

Statistical methods for analysis of combined biomarker data from multiple nested case-control studies.

Stat Methods Med Res 2021 08 7;30(8):1944-1959. Epub 2021 Jul 7.

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

By combining data across multiple studies, researchers increase sample size, statistical power, and precision for pooled analyses of biomarker-disease associations. However, researchers must adjust for between-study variability in biomarker measurements. Previous research often treats the biomarker measurements from a reference laboratory as a gold standard, even though those measurements are certainly not equal to their true values. This paper addresses measurement error and bias arising from both the reference and study-specific laboratories. We develop two calibration methods, the exact calibration method and approximate calibration method, for pooling biomarker data drawn from nested or matched case-control studies, where the calibration subset is obtained by randomly selecting controls from each contributing study. Simulation studies are conducted to evaluate the empirical performance of the proposed methods. We apply the proposed methods to a pooling project of nested case-control studies to evaluate the association between circulating 25-hydroxyvitamin D (25(OH)D) and colorectal cancer risk.
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http://dx.doi.org/10.1177/09622802211025992DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8454258PMC
August 2021

Adolescent animal product intake in relation to later prostate cancer risk and mortality in the NIH-AARP Diet and Health Study.

Br J Cancer 2021 Oct 16;125(8):1158-1167. Epub 2021 Jun 16.

Division of Public Health Sciences, Department of Surgery; and the Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA.

Background: Adolescent intake of animal products has been proposed to contribute to prostate cancer (PCa) development because of its potentially carcinogenic constituents and influence on hormone levels during adolescence.

Methods: We used data from 159,482 participants in the NIH-AARP Diet and Health Study to investigate associations for recalled adolescent intake of red meat (unprocessed beef and processed red meat), poultry, egg, canned tuna, animal fat and animal protein at ages 12-13 years with subsequent PCa risk and mortality over 14 years of follow-up. Cox proportional hazard regression was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) of total (n = 17,349), advanced (n = 2,297) and fatal (n = 804) PCa.

Results: Suggestive inverse trends were observed for adolescent unprocessed beef intake with risks of total, advanced and fatal PCa (multivariable-adjusted P-trends = 0.01, 0.02 and 0.04, respectively). No consistent patterns of association were observed for other animal products by PCa outcome.

Conclusion: We found evidence to suggest that adolescent unprocessed beef intake, or possibly a correlate of beef intake, such as early-life socioeconomic status, may be associated with reduced risk and mortality from PCa. Additional studies with further early-life exposure information are warranted to better understand this association.
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http://dx.doi.org/10.1038/s41416-021-01463-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8505417PMC
October 2021

Osteoporosis, bisphosphonate use, and risk of moderate or worse hearing loss in women.

J Am Geriatr Soc 2021 Nov 24;69(11):3103-3113. Epub 2021 May 24.

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

Background: Osteoporosis and low bone density (LBD) may be associated with higher risk of hearing loss, but findings are inconsistent and longitudinal data are scarce. Bisphosphonates may influence risk, but the relation has not been studied in humans. We longitudinally investigated associations of osteoporosis and LBD, bisphosphonate use, vertebral fracture (VF), hip fracture (HF), and risk of self-reported moderate or worse hearing loss.

Design: Longitudinal cohort study.

Setting: The Nurses' Health Study (NHS) (1982-2016) and Nurses' Health Study II (NHS II) (1995-2017).

Participants: Participants included 60,821 NHS women, aged 36-61 years at baseline, and 83,078 NHS II women, aged 31-48 years at baseline (total n = 143,899).

Measurements: Information on osteoporosis, LBD, bisphosphonate use, VF, HF, and hearing status was obtained from validated biennial questionnaires. In a subcohort (n = 3749), objective hearing thresholds were obtained by audiometry. Multivariable-adjusted Cox proportional hazards models were used to examine independent associations between osteoporosis (NHS), osteoporosis/LBD (NHS II), and risk of hearing loss.

Results: The multivariable-adjusted relative risk (MVRR, 95% confidence interval) of moderate or worse hearing loss was higher among women with osteoporosis or LBD in both cohorts. In NHS, compared with women without osteoporosis, the MVRR was 1.14 (1.09, 1.19) among women with osteoporosis; in NHS II, the MVRR was 1.30 (1.21, 1.40) among women with osteoporosis/LBD. The magnitude of the elevated risk was similar among women who did and did not use bisphosphonates. VF was associated with higher risk (NHS: 1.31 [1.16, 1.49]; NHS II: 1.39 [1.13, 1.71]), but HF was not (NHS: 1.00 [0.86, 1.16];NHS II: 1.15 [0.75,1.74]). Among participants with audiometric measurements, compared with women without osteoporosis/LBD, the mean multivariable-adjusted hearing thresholds were higher (i.e., worse) among those with osteoporosis/LBD who used bisphosphonates.

Conclusion: Osteoporosis and LBD may be important contributors to aging-related hearing loss. Among women with osteoporosis, the risk of hearing loss was not influenced by bisphosphonate use.
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http://dx.doi.org/10.1111/jgs.17275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8595486PMC
November 2021

Prospective study of sleep duration and glioma risk.

Cancer Causes Control 2021 Sep 20;32(9):1039-1042. Epub 2021 May 20.

Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL, 33612, USA.

Purpose: Both long and short sleep duration have been linked with risk of some cancers, but evidence for glioma is lacking.

Methods: Using prospective data from the UK Biobank (UKB), the Nurses' Health Study (NHS), and the Health Professionals Follow-Up Study (HPFS), we examined the association between self-reported hours of sleep and incident glioma in multivariable-adjusted Cox proportional hazards models.

Results: In the UKB, compared to 7 h, sleep durations of < 7 h (HR = 0.90; 95% CI 0.70-1.16) or > 7 h (HR = 1.05; 95% CI 0.85-1.30) were not significantly associated with glioma risk. Likewise, no significant associations were found between sleep duration and glioma risk in the NHS/HPFS for either < 7 h (HR = 0.93; 95% CI 0.69-1.26) or > 7 h (HR = 1.22; 95% CI 0.94-1.57), compared to 7 h. Results were similar for low-grade and high-grade glioma, did not materially change after lagging 2 years, or after accounting for factors known to disrupt sleep.

Conclusion: Sleep duration was not associated with incident glioma in either the UKB or the NHS/HPFS cohorts.
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http://dx.doi.org/10.1007/s10552-021-01447-9DOI Listing
September 2021

Dairy foods, calcium, and risk of breast cancer overall and for subtypes defined by estrogen receptor status: a pooled analysis of 21 cohort studies.

Am J Clin Nutr 2021 08;114(2):450-461

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

Background: Epidemiologic studies examining the relations between dairy product and calcium intakes and breast cancer have been inconclusive, especially for tumor subtypes.

Objective: To evaluate the associations between intakes of specific dairy products and calcium and risk of breast cancer overall and for subtypes defined by estrogen receptor (ER) status.

Method: We pooled the individual-level data of over 1 million women who were followed for a maximum of 8-20 years across studies. Associations were evaluated for dairy product and calcium intakes and risk of incident invasive breast cancer overall (n = 37,861 cases) and by subtypes defined by ER status. Study-specific multivariable hazard ratios (HRs) were estimated and then combined using random-effects models.

Results: Overall, no clear association was observed between the consumption of specific dairy foods, dietary (from foods only) calcium, and total (from foods and supplements) calcium, and risk of overall breast cancer. Although each dairy product showed a null or very weak inverse association with risk of overall breast cancer (P, test for trend >0.05 for all), differences by ER status were suggested for yogurt and cottage/ricotta cheese with associations observed for ER-negative tumors only (pooled HR = 0.90, 95% CI: 0.83, 0.98 comparing ≥60 g/d with <1 g/d of yogurt and 0.85, 95% CI: 0.76, 0.95 comparing ≥25 g/d with <1 g/d of cottage/ricotta cheese). Dietary calcium intake was only weakly associated with breast cancer risk (pooled HR = 0.98, 95% CI: 0.97, 0.99 per 350 mg/d).

Conclusion: Our study shows that adult dairy or calcium consumption is unlikely to associate with a higher risk of breast cancer and that higher yogurt and cottage/ricotta cheese intakes were inversely associated with the risk of ER-negative breast cancer, a less hormonally dependent subtype with poor prognosis. Future studies on fermented dairy products, earlier life exposures, ER-negative breast cancer, and different racial/ethnic populations may further elucidate the relation.
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http://dx.doi.org/10.1093/ajcn/nqab097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8326053PMC
August 2021

Pre-diagnostic circulating concentrations of fat-soluble vitamins and risk of glioma in three cohort studies.

Sci Rep 2021 04 29;11(1):9318. Epub 2021 Apr 29.

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

Few prospective studies have evaluated the relation between fat-soluble vitamins and glioma risk. Using three cohorts-UK Biobank (UKB), Nurses' Health Study (NHS), and Health Professionals Follow-Up Study (HPFS), we investigated associations of pre-diagnostic concentrations of fat-soluble vitamins D, A, and E with incident glioma. In 346,785 participants (444 cases) in UKB, associations with vitamin D (25-hydroxyvitamin D [25(OH)D]) were evaluated by Cox proportional hazards regression. In NHS (52 cases, 104 controls) and HPFS (32 cases, 64 controls), associations with 25(OH)D, vitamin A (retinol), and vitamin E (α- and γ-tocopherol) were assessed using conditional logistic regression. Our results suggested plasma concentrations of 25(OH)D and retinol were not associated with glioma risk. Comparing the highest to lowest tertile, the multivariable hazard ratio (MVHR) for 25(OH)D was 0.87 (95% confidence interval [CI] 0.68-1.11) in UKB and the multivariable risk ratio (MVRR) was 0.97 (95% CI 0.51-1.85) in NHS and HPFS. In NHS and HPFS, the MVRR for the same comparison for retinol was 1.16 (95% CI 0.56-2.38). Nonsignificant associations were observed for α-tocopherol (MVRR = 0.61, 95% CI 0.29-1.32) and γ-tocopherol (MVRR  = 1.30, 95% CI 0.63-2.69) that became stronger in 4-year lagged analyses. Further investigation is warranted on a potential association between α- and γ-tocopherol and glioma risk.
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http://dx.doi.org/10.1038/s41598-021-88485-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084971PMC
April 2021

Exposure misclassification in propensity score-based time-to-event data analysis.

Stat Methods Med Res 2021 05 7;30(5):1347-1357. Epub 2021 Apr 7.

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

In epidemiology, identifying the effect of exposure variables in relation to a time-to-event outcome is a classical research area of practical importance. Incorporating propensity score in the Cox regression model, as a measure to control for confounding, has certain advantages when outcome is rare. However, in situations involving exposure measured with moderate to substantial error, identifying the exposure effect using propensity score in Cox models remains a challenging yet unresolved problem. In this paper, we propose an estimating equation method to correct for the exposure misclassification-caused bias in the estimation of exposure-outcome associations. We also discuss the asymptotic properties and derive the asymptotic variances of the proposed estimators. We conduct a simulation study to evaluate the performance of the proposed estimators in various settings. As an illustration, we apply our method to correct for the misclassification-caused bias in estimating the association of PM2.5 level with lung cancer mortality using a nationwide prospective cohort, the Nurses' Health Study. The proposed methodology can be applied using our user-friendly R program published online.
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http://dx.doi.org/10.1177/0962280221998410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8311974PMC
May 2021

Sleep Duration and Snoring at Midlife in Relation to Healthy Aging in Women 70 Years of Age or Older.

Nat Sci Sleep 2021 17;13:411-422. Epub 2021 Mar 17.

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

Purpose: Both short and long sleep durations are associated with higher mortality. This study examined the association between sleep duration and overall health among those who survive to older ages.

Participants And Methods: In the Nurses' Health Study, participants without major chronic diseases in 1986 and survived to age 70 years or older in 1995-2001 were included. Habitual sleep duration and snoring were self-reported in 1986. Healthy aging was defined as being free of 11 major chronic diseases and having no cognitive impairment, physical impairment, or mental health limitations. Logistic regression was used to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) for healthy aging.

Results: Of the 12,304 participants, 1354 (11.0%) achieved healthy aging. We observed a non-linear association between sleep duration and the odds of achieving healthy aging. Compared with women sleeping 7 hours per day, women with longer sleep duration were less likely to achieve healthy aging; there was also a suggestion of lower odds of healthy aging for shorter sleepers, although the associations did not reach statistical significance: the multivariate-adjusted ORs (95% CIs) of healthy aging for those sleeping ≤5, 6, 8, and ≥9 hours were 0.94 (0.70, 1.27), 0.88 (0.76, 1.02), 0.83 (0.72, 0.96), and 0.60 (0.43, 0.84), respectively. Similar non-linear associations were consistently observed for individual dimensions of healthy aging. Regular snoring was associated with 31% lower odds of healthy aging (95% CI: 0.54, 0.88), which was primarily due to lower odds of having no major chronic diseases.

Conclusion: Both short and long sleep durations as well as regular snoring at midlife were associated with lower odds of healthy aging in later life.
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http://dx.doi.org/10.2147/NSS.S302452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982569PMC
March 2021

CUL4B renders breast cancer cells tamoxifen-resistant via miR-32-5p/ER-α36 axis.

J Pathol 2021 Jun 9;254(2):185-198. Epub 2021 Apr 9.

Key Laboratory of Experimental Teratology, Ministry of Education, Institute of Molecular Medicine and Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, PR China.

Tamoxifen (TAM) resistance is a significant clinical challenge in endocrine therapies for estrogen receptor (ER)-positive breast cancer patients. Cullin 4B (CUL4B), which acts as a scaffold protein in CUL4B-RING ubiquitin ligase complexes (CRL4B), is frequently overexpressed in cancer and represses tumor suppressors through diverse epigenetic mechanisms. However, the role and the underlying mechanisms of CUL4B in regulating drug resistance remain unknown. Here, we showed that CUL4B promotes TAM resistance in breast cancer cells through a miR-32-5p/ER-α36 axis. We found that upregulation of CUL4B correlated with decreased TAM sensitivity of breast cancer cells, and knockdown of CUL4B or expression of a dominant-negative CUL4B mutant restored the response to TAM in TAM-resistant MCF7-TAM and T47D-TAM cells. Mechanistically, we demonstrated that CUL4B renders breast cancer cells TAM-resistant by upregulating ER-α36 expression, which was mediated by downregulation of miR-32-5p. We further showed that CRL4B epigenetically represses the transcription of miR-32-5p by catalyzing monoubiquitination at H2AK119 and coordinating with PRC2 and HDAC complexes to promote trimethylation at H3K27 at the promoter of miR-32-5p. Pharmacologic or genetic inhibition of CRL4B/PRC2/HDAC complexes significantly increased TAM sensitivity in breast cancer cells in vitro and in vivo. Taken together, our findings thus establish a critical role for the CUL4B-miR-32-5p-ER-α36 axis in the regulation of TAM resistance and have important therapeutic implications for combined application of TAM and the inhibitors of CRL4B/PRC2/HDAC complex in breast cancer treatment. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/path.5657DOI Listing
June 2021

STATISTICAL METHODS FOR ANALYSIS OF COMBINED CATEGORICAL BIOMARKER DATA FROM MULTIPLE STUDIES.

Ann Appl Stat 2020 Sep 18;14(3):1146-1163. Epub 2020 Sep 18.

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

In the analysis of pooled data from multiple studies involving a biomarker exposure, the biomarker measurements can vary across laboratories and usually require calibration to a reference assay prior to pooling. Previous researches consider the measurements from a reference laboratory as the gold standard, even though measurements in the reference laboratory are not necessarily closer to the underlying truth in reality. In this paper we do not treat any laboratory measurements as the gold standard, and we develop two statistical methods, the exact calibration and cut-off calibration methods, for the analysis of aggregated categorical biomarker data. We compare the performance of both methods for estimating the biomarker-disease relationship under a random sample or controls-only calibration design. Our findings include: (1) the exact calibration method provides significantly less biased estimates and more accurate confidence intervals than the other method; (2) the cut-off calibration method could yield estimates with minimal bias and valid confidence intervals under small measurement errors and/or small exposure effects; (3) controls-only calibration design can result in additional bias, but the bias is minimal if the exposure effects and/or disease prevalences are small. Finally, we illustrate the methods in an application evaluating the relationship between circulating vitamin D levels and colorectal cancer risk in a pooling project.
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http://dx.doi.org/10.1214/20-aoas1337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903924PMC
September 2020

Prenatal dietary diversity may influence underweight in infants in a Ugandan birth-cohort.

Matern Child Nutr 2021 07 17;17(3):e13127. Epub 2021 Feb 17.

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

Growth faltering in early childhood is prevalent in many low resource countries. Poor maternal dietary diversity during pregnancy has been linked with increased risk of fetal growth failure and adverse birth outcomes but may also influence subsequent infant growth. Our aim is to assess the role of prenatal maternal dietary diversity in infant growth in rural Uganda. Data from 3291 women and infant pairs enrolled in a birth cohort from 2014 to 2016 were analysed (NCT04233944). Maternal diets were assessed using dietary recall in the second or third trimesters of pregnancy. Maternal dietary diversity scores (DDS) were calculated using the FAO Minimum Dietary Diversity for Women (MDD-W). Cox regression models were used to evaluate associations of the DDS with the incidence of underweight, stunting and wasting in infants from 3 to 12 months, adjusting for confounding factors. The median DDS for women was low, at 3.0 (interquartile range 3.0-4.0), relative to the threshold of consuming five or more food groups daily. Infants of women in highest quartile of DDS (diverse diets) were less likely to be underweight (adjusted hazard ratio: 0.70, 95% confidence interval: 0.61, 0.80) compared with infants of women in Quartile 1 (p for trend <0.001) in models controlling for maternal factors. There was no significant association between DDS and stunting or wasting. Our findings suggest a relationship between higher maternal dietary diversity and lower risk of underweight in infancy. These findings suggest that programmes to improve infant growth could additionally consider strengthening prenatal dietary diversity to improve child outcomes globally.
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http://dx.doi.org/10.1111/mcn.13127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8189249PMC
July 2021

Tinnitus and 3-Year Change in Audiometric Hearing Thresholds.

Ear Hear 2021 Jul-Aug 01;42(4):886-895

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

Objectives: Tinnitus and hearing loss commonly coexist, however, the temporal relation between tinnitus and hearing loss is complex and not fully understood. Our objective was to examine the longitudinal association between persistent tinnitus, bothersome tinnitus, and 3-year elevation of audiometric hearing thresholds.

Design: We conducted a longitudinal cohort study among 3106 women (mean age 59 years) who were participants in the Nurses' Health Study II (2012-2018). Information on tinnitus was obtained from biennial questionnaires. Longitudinal changes in air conduction thresholds (0.5 to 8 kHz) were assessed by pure-tone audiometry conducted by licensed audiologists at 19 audiology testing sites across the United States. Logistic regression was used to estimate multivariable-adjusted odds ratios (MVORs, 95% confidence interval [CI]) and evaluate the relations of persistent tinnitus (several days per week or more), bothersome tinnitus (interferes with work, sleep, or daily activities), and risk of 3-year elevation of hearing thresholds.

Results: Persistent tinnitus was associated with higher risk of 3-year elevation of hearing thresholds across a broad range of frequencies. Compared with women without tinnitus, the MVORs (95% CI) for ≥5-dB threshold elevation among women with persistent tinnitus were 1.01 (0.81, 1.25) at 0.5 kHz, 1.45 (1.17, 1.81) at 1 kHz, 1.25 (1.00, 1.56) at 2 kHz, 1.34 (1.07, 1.69) at 3 kHz, 1.34 (1.06, 1.70) at 4 kHz, 1.49 (1.16, 1.91) at 6 kHz, and 1.63 (1.25, 2.12) at 8 kHz. The magnitudes of the associations for ≥10-dB threshold elevation were similar. The magnitudes of the associations were substantially greater among women with bothersome tinnitus. For example, compared with women without tinnitus, the MVORs (95% CI) for a ≥5- and ≥10-dB elevation of hearing thresholds at 4 kHz were 2.97 (1.50, 5.89) and 2.79 (1.38, 5.65), respectively. The risk was elevated even among women with tinnitus who had clinically normal hearing thresholds at baseline. In analyses that examined the association of tinnitus and elevation of low-, mid- and high-frequency pure-tone average (PTA) hearing thresholds, the results were similar. Compared with women without tinnitus, the MVORs (95% CI) for ≥5-dB PTA elevation among women with persistent tinnitus were 1.29 (0.99,1.67) for LPTA(0.5,1,2 kHz); 1.44 (1.16, 1.78) for MPTA(3,4 kHz); and 1.38 (1.11, 1.71) for HPTA(6,8 kHz). For ≥10-dB elevation, the MVORs were 2.85 (1.55, 5.23), 1.52 (1.10, 2.09), and 1.41 (1.10, 1.82), respectively.

Conclusion: Persistent tinnitus was associated with substantially higher risk of 3-year hearing threshold elevation, even among women with clinically normal baseline hearing. The magnitudes of the associations were greater among those with bothersome tinnitus. Monitoring hearing sensitivities may be indicated in patients with tinnitus, including those without audiometric evidence of hearing impairment.
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http://dx.doi.org/10.1097/AUD.0000000000000990DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8222055PMC
August 2021

Methodological approaches to imputing early-pregnancy weight based on weight measures collected during pregnancy.

BMC Med Res Methodol 2021 02 5;21(1):24. Epub 2021 Feb 5.

Department of Epidemiology, Harvard T.H. Chan School of Public Health, 677 Huntington Ave, Boston, MA, 02215, USA.

Background: Early pregnancy weights are needed to quantify gestational weight gain accurately. Different methods have been used in previous studies to impute early-pregnancy weights. However, no studies have systematically compared imputed weight accuracy across different imputation techniques. This study aimed to compare four methodological approaches to imputing early-pregnancy weight, using repeated measures of pregnancy weights collected from two pregnancy cohorts in Tanzania.

Methods: The mean gestational ages at enrollment were 17.8 weeks for Study I and 10.0 weeks for Study II. Given the gestational age distributions at enrollment, early-pregnancy weights were extrapolated for Study I and interpolated for Study II. The four imputation approaches included: (i) simple imputation based on the nearest measure, (ii) simple arithmetic imputation based on the nearest two measures, (iii) mixed-effects models, and (iv) marginal models with generalized estimating equations. For the mixed-effects model and the marginal model with generalized estimating equation methods, imputation accuracy was further compared across varying degrees of model flexibility by fitting splines and polynomial terms. Additional analyses included dropping third-trimester weights, adding covariate to the models, and log-transforming weight before imputation. Mean absolute error was used to quantify imputation accuracy.

Results: Study I included 1472 women with 6272 weight measures; Study II included 2131 individuals with 11,775 weight measures. Among the four imputation approaches, mixed-effects models had the highest accuracy (smallest mean absolute error: 1.99 kg and 1.60 kg for Studies I and II, respectively), while the other three approaches showed similar degrees of accuracy. Depending on the underlying data structure, allowing appropriate degree of model flexibility and dropping remote pregnancy weight measures may further improve the imputation performance.

Conclusions: Mixed-effects models had superior performance in imputing early-pregnancy weight compared to other commonly used strategies.
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http://dx.doi.org/10.1186/s12874-021-01210-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7863454PMC
February 2021
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