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Background: Pulmonary tuberculosis and anemia are both prevalent in Tanzania. There is limited and inconsistent literature on the association between anemia and sputum conversion following tuberculosis treatment. Methods: Newly diagnosed sputum smear positive pulmonary tuberculosis patients aged ≥15 years initiating on standard anti tuberculosis therapy were recruited from 14 of 54 tuberculosis clinics in Dar es Salaam. Patients were receiving medication according to the recommended short course Directly Observed Therapy (DOT) strategy and were followed up prospectively until completion of treatment (six months). Patients were evaluated before initiation of TB treatment by performing the following; clinical history, physical examination, complete blood counts, serum biochemistry and sputum microscopy. Sputum smears were re-examined at two months of anti-tuberculosis therapy for presence of acid fast bacilli. Anemia was defined as hemoglobin <13 g/dl (males) or <12 g/dl (females). Log-binomial regression was used to assess the association between anemia and sputum conversion at two months. Results: Of the 1245 patients included in the study, 86% were anemic and 7% were sputum smear positive at two months of anti-tuberculosis therapy. Anemic patients were three times more likely to have sputum positive smear as compared to non-anemic patients at two months (RR = 3.05; 95% CI 1.11–8.40) p = 0.03. The risk for sputum positive smear results increased with severity of anemia (P for trend <0.01). Conclusion: Baseline anemia is associated with increased risk for persistent positive sputum smears at two months of tuberculosis treatment. Future studies should evaluate the mechanisms for TB-associated anemia as well as the role of intervention for anemia among TB patients. [ABSTRACT FROM AUTHOR]

Background: Pre-Exposure Prophylaxis (PrEP) has demonstrated efficacy in preventing HIV infection. Female Bar Workers (FBWs) often act as informal sex workers, placing them at risk of HIV infection. Despite expressing interest in PrEP, FBWs face barriers to accessing public-sector clinics where PrEP is delivered. We developed a study to compare the effectiveness of workplace-based PrEP provision to standard-of-care facility-based provision for PrEP initiation, retention and adherence among FBWs. Methods: In this double-randomized intervention study, FBWs aged 15 years and above will be screened, consented and initiated on PrEP (emtricitabine/tenofovir disoproxil), and followed for six months. Participants will be randomized at the bar level and offered PrEP at their workplace or at a health facility. Those who are initiated will be independently individually randomized to either receive or not receive an omni-channel PrEP champion intervention (support from an experienced PrEP user) to improve PrEP adherence. We expect to screen 1,205 FBWs to enroll at least 160 HIV negative women in the study. Follow-up visits will be scheduled monthly. HIV testing will be performed at baseline, month 1, 4 and 6; and TDF testing at months 2 and 6. Primary outcomes for this trial are: (1) initiation on PrEP (proportion of those offered PrEP directly observed to initiate PrEP); and (2) adherence to PrEP (detectable urine TDF drug level at 6-months post-enrollment). The primary outcomes will be analyzed using Intention-to-Treat (ITT) analyses. Discussion: Using a randomized trial design, we will evaluate two interventions aiming to reduce barriers to uptake and retention on PrEP among FBWs, a vulnerable population at risk of HIV acquisition and onward transmission. If these interventions prove effective in promoting PrEP among FBWs, they could assist in abating the HIV epidemic in Africa. Trial registration: Registered with German Clinical Trials Register (www.drks.de) on 29 April 2020; Registration number DRKS00018101. [ABSTRACT FROM AUTHOR]

Background: Worksite-based health programs have shown positive impacts on employee health and have led to significant improvements in cardiovascular risk factor profiles. We aimed to determine the effect of cafeteria intervention on cardio-metabolic risk factors diet in a worksite setting (Dhulikhel Hospital) in Nepal. Methods: In this one-arm pre-post intervention study, we recruited 277 non-pregnant hospital employees aged 18–60 with prediabetes or pre-hypertension. The study was registered in clinicaltrials.gov (NCT03447340; 2018/02/27). All four cafeterias in the hospital premises received cafeteria intervention encouraging healthy foods and discouraging unhealthy foods for six months. We measured blood pressure, fasting glucose level, glycated hemoglobin, cholesterol in the laboratory, and diet intake (in servings per week) using 24-hour recall before and six months after the intervention. The before and after measures were compared using paired-t tests. Results: After six months of cafeteria intervention, the median consumption of whole grains, mono/polyunsaturated fat, fruits, vegetable and nuts servings per week increased by 2.24(p<0.001), 2.88(p<0.001), 0.84(p<0.001) 2.25(p<0.001) and nuts 0.55 (p<0.001) servings per week respectively. The median consumption of refined grains decreased by 5.07 servings per week (p<0.001). Mean systolic and diastolic blood pressure decreased by 2 mmHg (SE = 0.6; p = 0.003) and 0.1 mmHg (SE = 0.6; p = 0.008), respectively. The low-density lipoprotein (LDL) was significantly reduced by 6 mg/dL (SE = 1.4; p<0.001). Conclusion: Overall, we found a decrease in consumption of refined grains and an increase in consumption of whole grains, unsaturated fats, fruits, and nuts observed a modest reduction in blood pressure and LDL cholesterol following a 6-month cafeteria-based worksite intervention incorporating access to healthy foods. [ABSTRACT FROM AUTHOR]

Background: Further improvements in population health in low- and middle-income countries demand high-quality care to address an increasingly complex burden of disease. Health facility surveys provide an important but costly source of information on readiness to provide care. To improve the efficiency of health system measurement, we applied unsupervised machine learning methods to assess the performance of the service readiness index (SRI) defined by the World Health Organization and compared it to empirically derived indices. Methods: We drew data from nationally representative Service Provision Assessment surveys conducted in 10 countries between 2007 and 2015. We extracted 649 items in domains such as infrastructure, medication, and management to calculate an index using all available information and classified facilities into quintiles. We compared three approaches against the full item set: the SRI, a new index based on sequential backward selection, and an enriched SRI that added empirically selected items to the SRI. We evaluated index performance with a cross-validated kappa statistic comparing classification using the candidate index against the 649-item index. Results: 9238 facilities were assessed. The 49-item SRI performed poorly against the index using all 649 items, with a kappa value of 0.35. New empirically derived indices with 50 and 100 items captured much more information, with cross-validated kappa statistics of 0.71 and 0.80, respectively. Items varied across the indices and in sensitivity analyses. A 100-item enriched SRI reliably captured the information from the full index: 83% of the facilities were classified into correct quintiles of service readiness based on the full index. Conclusion: A facility readiness measure developed by global health experts performed poorly in capturing the totality of readiness information collected during facility surveys. Using a machine learning approach with sequential selection and cross-validation to identify the most informative items dramatically improved performance. Such approaches can make assessment of health facility readiness more efficient. Further improvements in measurement will require identification of external criteria—such as patient outcomes—to guide and validate measure development. [ABSTRACT FROM AUTHOR]

Background: Cervical cancer ranks as the most common cancer among Nepalese women with a high incidence and mortality. Despite evidence that effective screening programs reduce disease burden, screening services are under-utilized. Cancer stigma can be a major barrier to cervical cancer screening uptake among Nepalese women. Objectives: This study assessed the association between cancer stigma and cervical cancer screening uptake among women residing in semi-urban areas of Kavrepalanchok district (Dhulikhel and Banepa), Nepal. Methods: We conducted a cross-sectional study among 426 women aged 30–60 years using telephone interview method from 15th June to 15th October 2021. A validated Cancer Stigma Scale (CASS) was used to measure cancer stigma and categorized women as presence of cancer stigma if the mean total score was greater than three. We obtained information on cervical cancer screening uptake through self-reported responses. Univariable and multivariable logistic regression were performed to assess the association between cancer stigma and cervical cancer screening uptake. We adjusted socio-demographic: age, ethnicity, occupation, religion and education, and reproductive health variables: parity, family planning user, age of menarche and age at first sexual intercourse during multivariable logistic regression. Results: Twenty-three percent of women had cancer stigma and 27 percent reported that they had ever been screened for cervical cancer. The odds of being screened was 0.23 times lower among women who had stigma compared to those who had no stigma (95% CI: 0.11–0.49) after adjusting for confounders: age, ethnicity, occupation, religion, education, parity, contraceptive use, age of menarche and age at first sexual intercourse. Conclusion: Women residing in semi-urban areas of Nepal and had cancer stigma were less likely to have been screened for cervical cancer. De-stigmatizing interventions may alleviate cancer stigma and contribute to higher uptake of cervical cancer screening. [ABSTRACT FROM AUTHOR]

Background: Stakeholder engagement is important from the management point of view to capture knowledge, increase ownership, reduce conflict, encourage partnership, as well as to develop an ethical perspective that facilitates inclusive decision making and promotes equity. However, there is dearth of literature in the process of stakeholder engagement. The purpose of this paper is to describe the process of increasing stakeholder engagement and highlight the lessons learnt on stakeholder engagement while designing, implementing, and monitoring a study on diabetes and hypertension prevention in workplace settings in Nepal. Methodology: We identified the stakeholders based on the 7P framework: Patients and public (clients), providers, payers, policy makers, product makers, principal investigators, and purchasers. The identified stakeholders were engaged in prioritization of the research questions, planning data collection, designing, implementing, and monitoring the intervention. Stakeholders were engaged through focus group discussions, in-depth interviews, participatory workshops, individual consultation, information sessions and representation in study team and implementation committees. Results: The views of the stakeholders were synthesized in each step of the research process, from designing to interpreting the results. Stakeholder engagement helped to shape the methods and plan, and process for participant's recruitment and data collection. In addition, it enhanced adherence to intervention, mutual learning, and smooth intervention adoption. The major challenges were the time-consuming nature of the process, language barriers, and the differences in health and food beliefs between researchers and stakeholders. Conclusion: It was possible to engage and benefit from stakeholder's engagement on the design, implementation and monitoring of a workplace-based hypertension and diabetes management research program in Nepal. [ABSTRACT FROM AUTHOR]

Background: Home delivery and late and infrequent attendance at antenatal care (ANC) are responsible for substantial avoidable maternal and pediatric morbidity and mortality in sub-Saharan Africa. This cluster-randomized trial aimed to determine the impact of a community health worker (CHW) intervention on the proportion of women who (i) visit ANC fewer than 4 times during their pregnancy and (ii) deliver at home.Methods and Findings: As part of a 2-by-2 factorial design, we conducted a cluster-randomized trial of a home-based CHW intervention in 2 of 3 districts of Dar es Salaam from 18 June 2012 to 15 January 2014. Thirty-six wards (geographical areas) in the 2 districts were randomized to the CHW intervention, and 24 wards to the standard of care. In the standard-of-care arm, CHWs visited women enrolled in prevention of mother-to-child HIV transmission (PMTCT) care and provided information and counseling. The intervention arm included additional CHW supervision and the following additional CHW tasks, which were targeted at all pregnant women regardless of HIV status: (i) conducting home visits to identify pregnant women and refer them to ANC, (ii) counseling pregnant women on maternal health, and (iii) providing home visits to women who missed an ANC or PMTCT appointment. The primary endpoints of this trial were the proportion of pregnant women (i) not making at least 4 ANC visits and (ii) delivering at home. The outcomes were assessed through a population-based household survey at the end of the trial period. We did not collect data on adverse events. A random sample of 2,329 pregnant women and new mothers living in the study area were interviewed during home visits. At the time of the survey, the mean age of participants was 27.3 years, and 34.5% (804/2,329) were pregnant. The proportion of women who reported having attended fewer than 4 ANC visits did not differ significantly between the intervention and standard-of-care arms (59.1% versus 60.7%, respectively; risk ratio [RR]: 0.97; 95% CI: 0.82-1.15; p = 0.754). Similarly, the proportion reporting that they had attended ANC in the first trimester did not differ significantly between study arms. However, women in intervention wards were significantly less likely to report having delivered at home (3.9% versus 7.3%; RR: 0.54; 95% CI: 0.30-0.95; p = 0.034). Mixed-methods analyses of additional data collected as part of this trial suggest that an important reason for the lack of effect on ANC outcomes was the perceived high economic burden and inconvenience of attending ANC. The main limitations of this trial were that (i) the outcomes were ascertained through self-report, (ii) the study was stopped 4 months early due to a change in the standard of care in the other trial that was part of the 2-by-2 factorial design, and (iii) the sample size of the household survey was not prespecified.Conclusions: A home-based CHW intervention in urban Tanzania significantly reduced the proportion of women who reported having delivered at home, in an area that already has very high uptake of facility-based delivery. The intervention did not affect self-reported ANC attendance. Policy makers should consider piloting, evaluating, and scaling interventions to lessen the economic burden and inconvenience of ANC.Trial Registration: ClinicalTrials.gov NCT01932138. [ABSTRACT FROM AUTHOR]

There is widespread vitamin and mineral deficiency problem in Tanzania with known deficiencies of at least vitamin A, iron, folate and zinc, resulting in lasting negative consequences especially on maternal health, cognitive development and thus the nation’s economic potential. Folate deficiency is associated with significant adverse health effects among women of reproductive age, including a higher risk of neural tube defects. Several countries, including Tanzania, have implemented mandatory fortification of wheat and maize flour but evidence on the effectiveness of these programs in developing countries remains limited. We evaluated the effectiveness of Tanzania’s food fortification program by examining folate levels for women of reproductive age, 18–49 years. A prospective cohort study with 600 non-pregnant women enrolled concurrent with the initiation of food fortification and followed up for 1 year thereafter. Blood samples, dietary intake and fortified foods consumption data were collected at baseline, and at 6 and 12 months. Plasma folate levels were determined using a competitive assay with folate binding protein. Using univariate and multivariate linear regression, we compared the change in plasma folate levels at six and twelve months of the program from baseline. We also assessed the relative risk of folate deficiency during follow-up using log-binomial regression. The mean (±SE) pre–fortification plasma folate level for the women was 5.44-ng/ml (±2.30) at baseline. These levels improved significantly at six months [difference: 4.57ng/ml (±2.89)] and 12 months [difference: 4.27ng/ml (±4.18)]. Based on plasma folate cut-off level of 4 ng/ml, the prevalence of folate deficiency was 26.9% at baseline, and 5% at twelve months. One ng/ml increase in plasma folate from baseline was associated with a 25% decreased risk of folate deficiency at 12 months [(RR = 0.75; 95% CI = 0.67–0.85, P<0.001]. In a setting where folate deficiency is high, food fortification program with folic acid resulted in significant improvements in folate status among women of reproductive age. [ABSTRACT FROM AUTHOR]

Background: While food pricing is a promising strategy to improve diet, the prospective impact of food pricing on diet has not been systematically quantified. Objective: To quantify the prospective effect of changes in food prices on dietary consumption. Design: We systematically searched online databases for interventional or prospective observational studies of price change and diet; we also searched for studies evaluating adiposity as a secondary outcome. Studies were excluded if price data were collected before 1990. Data were extracted independently and in duplicate. Findings were pooled using DerSimonian-Laird's random effects model. Pre-specified sources of heterogeneity were analyzed using meta-regression; and potential for publication bias, by funnel plots, Begg's and Egger's tests. Results: From 3,163 identified abstracts, 23 interventional studies and 7 prospective cohorts with 37 intervention arms met inclusion criteria. In pooled analyses, a 10% decrease in price (i.e., subsidy) increased consumption of healthful foods by 12% (95%CI = 10–15%; N = 22 studies/intervention arms) whereas a 10% increase price (i.e. tax) decreased consumption of unhealthful foods by 6% (95%CI = 4–8%; N = 15). By food group, subsidies increased intake of fruits and vegetables by 14% (95%CI = 11–17%; N = 9); and other healthful foods, by 16% (95%CI = 10–23%; N = 10); without significant effects on more healthful beverages (-3%; 95%CI = -16-11%; N = 3). Each 10% price increase reduced sugar-sweetened beverage intake by 7% (95%CI = 3–10%; N = 5); fast foods, by 3% (95%CI = 1–5%; N = 3); and other unhealthful foods, by 9% (95%CI = 6–12%; N = 3). Changes in price of fruits and vegetables reduced body mass index (-0.04 kg/m2 per 10% price decrease, 95%CI = -0.08–0 kg/m2; N = 4); price changes for sugar-sweetened beverages or fast foods did not significantly alter body mass index, based on 4 studies. Meta-regression identified direction of price change (tax vs. subsidy), number of intervention components, intervention duration, and study quality score as significant sources of heterogeneity (P-heterogeneity<0.05 each). Evidence for publication bias was not observed. Conclusions: These prospective results, largely from interventional studies, support efficacy of subsidies to increase consumption of healthful foods; and taxation to reduce intake of unhealthful beverages and foods. Use of subsidies and combined multicomponent interventions appear most effective. [ABSTRACT FROM AUTHOR]

Background: Plant-based diets have been recommended to reduce the risk of type 2 diabetes (T2D). However, not all plant foods are necessarily beneficial. We examined the association of an overall plant-based diet and hypothesized healthful and unhealthful versions of a plant-based diet with T2D incidence in three prospective cohort studies in the US.Methods and Findings: We included 69,949 women from the Nurses' Health Study (1984-2012), 90,239 women from the Nurses' Health Study 2 (1991-2011), and 40,539 men from the Health Professionals Follow-Up Study (1986-2010), free of chronic diseases at baseline. Dietary data were collected every 2-4 y using a semi-quantitative food frequency questionnaire. Using these data, we created an overall plant-based diet index (PDI), where plant foods received positive scores, while animal foods (animal fats, dairy, eggs, fish/seafood, poultry/red meat, miscellaneous animal-based foods) received reverse scores. We also created a healthful plant-based diet index (hPDI), where healthy plant foods (whole grains, fruits, vegetables, nuts, legumes, vegetable oils, tea/coffee) received positive scores, while less healthy plant foods (fruit juices, sweetened beverages, refined grains, potatoes, sweets/desserts) and animal foods received reverse scores. Lastly, we created an unhealthful plant-based diet index (uPDI) by assigning positive scores to less healthy plant foods and reverse scores to healthy plant foods and animal foods. We documented 16,162 incident T2D cases during 4,102,369 person-years of follow-up. In pooled multivariable-adjusted analysis, both PDI and hPDI were inversely associated with T2D (PDI: hazard ratio [HR] for extreme deciles 0.51, 95% CI 0.47-0.55, p trend < 0.001; hPDI: HR for extreme deciles 0.55, 95% CI 0.51-0.59, p trend < 0.001). The association of T2D with PDI was considerably attenuated when we additionally adjusted for body mass index (BMI) categories (HR 0.80, 95% CI 0.74-0.87, p trend < 0.001), while that with hPDI remained largely unchanged (HR 0.66, 95% CI 0.61-0.72, p trend < 0.001). uPDI was positively associated with T2D even after BMI adjustment (HR for extreme deciles 1.16, 95% CI 1.08-1.25, p trend < 0.001). Limitations of the study include self-reported diet assessment, with the possibility of measurement error, and the potential for residual or unmeasured confounding given the observational nature of the study design.Conclusions: Our study suggests that plant-based diets, especially when rich in high-quality plant foods, are associated with substantially lower risk of developing T2D. This supports current recommendations to shift to diets rich in healthy plant foods, with lower intake of less healthy plant and animal foods. [ABSTRACT FROM AUTHOR]

Objective: Women’s nutritional status during conception and early pregnancy can influence maternal and infant outcomes. This study examined the efficacy of pre-pregnancy supplementation with iron and multivitamins to reduce the prevalence of anemia during the periconceptional period among rural Tanzanian women and adolescent girls. Design: A double-blind, randomized controlled trial was conducted in which participants were individually randomized to receive daily oral supplements of folic acid alone, folic acid and iron, or folic acid, iron, and vitamins A, B-complex, C, and E at approximately single recommended dietary allowance (RDA) doses for six months. Setting: Rural Rufiji District, Tanzania. Subjects: Non-pregnant women and adolescent girls aged 15–29 years (n = 802). Results: The study arms were comparable in demographic and socioeconomic characteristics, food security, nutritional status, pregnancy history, and compliance with the regimen (p>0.05). In total, 561 participants (70%) completed the study and were included in the intention-to-treat analysis. Hemoglobin levels were not different across treatments (median: 11.1 g/dL, Q1-Q3: 10.0–12.4 g/dL, p = 0.65). However, compared with the folic acid arm (28%), there was a significant reduction in the risk of hypochromic microcytic anemia in the folic acid and iron arm (17%, RR: 0.61, 95% CI: 0.42–0.90, p = 0.01) and the folic acid, iron, and multivitamin arm (19%, RR: 0.66, 95% CI: 0.45–0.96, p = 0.03). Inverse probability of treatment weighting (IPTW) to adjust for potential selection bias due to loss to follow-up did not materially change these results. The effect of the regimens was not modified by frequency of household meat consumption, baseline underweight status, parity, breastfeeding status, or level of compliance (in all cases, p for interaction>0.2). Conclusions: Daily oral supplementation with iron and folic acid among women and adolescents prior to pregnancy reduces risk of anemia. The potential benefits of supplementation on the risk of periconceptional anemia and adverse pregnancy outcomes warrant investigation in larger studies. Trial Registration: ClinicalTrials.gov [ABSTRACT FROM AUTHOR]

Background: Experimental data suggest a role for iron in the course of tuberculosis (TB) infection, but there is limited evidence on the potential effects of iron deficiency or iron overload on the progression of TB disease in humans. The aim of the present analysis was to examine the association of iron status with the risk of TB progression and death. Methodology/Principal Findings: We analyzed plasma samples and data collected as part a randomized micronutrient supplementation trial (not including iron) among HIV-infected and HIV-uninfected TB patients in Dar es Salaam, Tanzania. We prospectively related baseline plasma ferritin concentrations from 705 subjects (362 HIV-infected and 343 HIVuninfected) to the risk of treatment failure at one month after initiation, TB recurrence and death using binomial and Cox regression analyses. Overall, low (plasma ferritin<30 аg/L) and high (plasma ferritin>150 аg/L for women and>200 аg/L for men) iron status were seen in 9% and 48% of patients, respectively. Compared with normal levels, low plasma ferritin predicted an independent increased risk of treatment failure overall (adjusted RR = 1.95, 95% CI: 1.07 to 3.52) and of TB recurrence among HIV-infected patients (adjusted RR = 4.21, 95% CI: 1.22 to 14.55). High plasma ferritin, independent of Creactive protein concentrations, was associated with an increased risk of overall mortality (adjusted RR = 3.02, 95% CI: 1.95 to 4.67). Conclusions/Significance: Both iron deficiency and overload exist in TB patients and may contribute to disease progression and poor clinical outcomes. Strategies to maintain normal iron status in TB patients could be helpful to reduce TB morbidity and mortality. [ABSTRACT FROM AUTHOR]

Background: Vitamin D has a potential role in slowing HIV disease progression and preventing mortality based on its extensive involvement in the immune system; however, this relationship has not been examined in large studies or in resource-limited settings. Methodology/Principal Findings: Vitamin D levels were assessed in 884 HIV-infected pregnant women at enrollment in a trial of multivitamin supplementation (not including vitamin D) in Tanzania. Women were followed up for a median of 69.5 months, and information on hemoglobin levels, HIV disease progression, and mortality was recorded. Proportional hazard models and generalized estimating equations were used to assess the relationship of these outcomes with vitamin D status. Conclusions/Significance: Low vitamin D status (serum 25-hydroxyvitamin D<32ng/mL) was significantly associated with progression to WHO HIV disease stage III or greater in multivariate models (incidence rate ratio [RR]: 1.25; 95% confidence intervals [CI]: 1.05, 1.50). No significant relationship was observed between vitamin D status and T-cell counts during followup. Women with low vitamin D status had 46% higher risk of developing severe anemia during follow-up, compared to women with adequate vitamin D levels (RR: 1.46; 95% CI: 1.09, 1.96). Women in the highest vitamin D quintile had a 42% lower risk of all-cause mortality, compared to the lowest quintile (RR: 0.58; 95% CI: 0.40, 0.84). Vitamin D status had a protective association with HIV disease progression, all-cause mortality, and development of anemia during follow-up in HIV-infected women. If confirmed in randomized trials, vitamin D supplementation could represent a simple and inexpensive method to prolonging the time to initiation of antiretroviral therapy in HIV-infected patients, particularly in resource-limited settings. [ABSTRACT FROM AUTHOR]

Background: The CpG island methylator phenotype (CIMP) is a distinct phenotype associated with microsatellite instability (MSI) and BRAF mutation in colon cancer. Recent investigations have selected 5 promoters (CACNA1G, IGF2, NEUROG1, RUNX3 and SOCS1) as surrogate markers for CIMP-high. However, no study has comprehensively evaluated an expanded set of methylation markers (including these 5 markers) using a large number of tumors, or deciphered the complex clinical and molecular associations with CIMP-high determined by the validated marker panel. Metholodology/Principal Findings: DNA methylation at 16 CpG islands [the above 5 plus CDKN2A (p16), CHFR, CRABP1, HIC1, IGFBP3, MGMT, MINT1, MINT31, MLH1, p14 (CDKN2A/ARF) and WRN] was quantified in 904 colorectal cancers by realtime PCR (MethyLight). In unsupervised hierarchical clustering analysis, the 5 markers (CACNA1G, IGF2, NEUROG1, RUNX3 and SOCS1), CDKN2A, CRABP1, MINT31, MLH1, p14 and WRN were generally clustered with each other and with MSI and BRAF mutation. KRAS mutation was not clustered with any methylation marker, suggesting its association with a random methylation pattern in CIMP-low tumors. Utilizing the validated CIMP marker panel (including the 5 markers), multivariate logistic regression demonstrated that CIMP-high was independently associated with older age, proximal location, poor differentiation, MSI-high, BRAF mutation, and inversely with LINE-1 hypomethylation and β-catenin (CTNNB1) activation. Mucinous feature, signet ring cells, and p53-negativity were associated with CIMP-high in only univariate analysis. In stratified analyses, the relations of CIMP-high with poor differentiation, KRAS mutation and LINE-1 hypomethylation significantly differed according to MSI status. Conclusions: Our study provides valuable data for standardization of the use of CIMP-high-specific methylation markers. CIMP-high is independently associated with clinical and key molecular features in colorectal cancer. Our data also suggest that KRAS mutation is related with a random CpG island methylation pattern which may lead to CIMP-low tumors. [ABSTRACT FROM AUTHOR]