Lowering Fecal Immunochemical Test Positivity Threshold vs Multitarget Stool RNA Testing for Colorectal Cancer Screening.

This analysis uses data from 2 studies to explore whether lowering the threshold for fecal immunochemical test positivity can achieve comparable levels of sensitivity and specificity as multitarget stool RNA testing for colorectal cancer screening.

Excess Weight, Polygenic Risk Score, and Findings of Colorectal Neoplasms at Screening Colonoscopy.

INTRODUCTION: Excess weight is an established risk factor of colorectal cancer (CRC). However, evidence is lacking on how its impact varies by polygenic risk at different stages of colorectal carcinogenesis. METHODS: We assessed the individual and joint associations of body mass index (BMI) and polygenic risk scores (PRSs) with findings of colorectal neoplasms among 4,784 participants of screening colonoscopy. Adjusted odds ratios (aORs) for excess weight derived by multiple logistic regression were converted to genetic risk equivalents (GREs) to quantify the impact of excess weight compared with genetic predisposition. RESULTS: Overweight and obesity (BMI 25-<30 and ≥30 kg/m 2 ) were associated with increased risk of any colorectal neoplasm (aOR [95% confidence interval, CI] 1.26 [1.09-1.45] and 1.47 [1.24-1.75]). Obesity was associated with increased risk of advanced colorectal neoplasm (aOR [95% CI] 1.46 [1.16-1.84]). Dose-response relationships were seen for the PRS (stronger for advanced neoplasms than any neoplasms), with no interaction with BMI, suggesting multiplicative effects of both factors. Obese participants with a PRS in the highest tertile had a 2.3-fold (95% CI 1.7-3.1) and 2.9-fold (95% CI 1.9-4.3) increased risk of any colorectal neoplasm and advanced colorectal neoplasm, respectively. The aOR of obesity translated into a GRE of 38, meaning that its impact was estimated to be equivalent to the risk caused by 38 percentiles higher PRS for colorectal neoplasm. DISCUSSION: Excess weight and polygenic risk are associated with increased risk of colorectal neoplasms in a multiplicative manner. Maintaining normal weight is estimated to have an equivalent effect as having 38 percentiles lower PRS.

The underestimated impact of excess body weight on colorectal cancer risk: Evidence from the UK Biobank cohort.

BACKGROUND: The association between excess weight and colorectal cancer (CRC) risk may have been underestimated due to potential weight loss during pre-clinical sojourn time of CRC. We aimed to investigate this association and the corresponding population attributable fraction (PAF), accounting for prediagnostic weight loss. METHODS: Data from the UK Biobank prospective cohort were used. Multivariable adjusted hazard ratios (HR) and their 95% confidence intervals (CI) for various periods of follow-up and the corresponding PAF of excess weight were calculated. RESULTS: During a median of 10.0 years of follow-up, of 453,049 participants, 4794 developed CRC. The excess weight-CRC association became substantially stronger with including increasing lengths of follow-up in the analyses and further excluding the initial years of follow-up. HRs (95% CIs) for overweight and obesity were 1.06 (0.97-1.16) and 1.14 (1.03-1.26) after 7 years of follow-up, 1.13 (1.05-1.21) and 1.23 (1.14-1.33) when including complete follow-up length, and 1.26 (1.12-1.43) and 1.42 (1.24-1.63) when excluding the initial 7 years of follow-up. The corresponding PAFs of excess weight were estimated as 6.8%, 11.3%, and 19.0%, respectively. CONCLUSIONS: Comprehensive consideration of the potential effect of prediagnostic weight loss discloses a much stronger impact of excess body weight on CRC risk than previously assumed.

Association of Overweight, Obesity, and Recent Weight Loss With Colorectal Cancer Risk.

Importance: Overweight and obesity, conditions with rising prevalence in many countries, are associated with increased colorectal cancer (CRC) risk. However, many patients with CRC lose weight before diagnosis, which may lead the association to be underestimated. Objective: To evaluate the association of body mass index (BMI) and weight change with CRC risk when considering BMI at different time frames, with the intention to account for prediagnostic weight loss. Design, Setting, and Participants: This population-based case-control study was conducted in southwestern Germany between 2003 and 2021. Cases with a first diagnosis of CRC and controls (frequency matched by age, sex, and county) with comprehensive risk factor information and self-reported weight at different time points were included. Data were analyzed between October 2022 and March 2023. Exposure: BMI and weight change at different time frames before the time of diagnosis (cases) or recruitment (controls). Main Outcomes and Measures: Association of BMI and weight change at various points in time before and up to diagnosis with CRC, assessed by multivariable logistic regression with comprehensive confounder adjustment. Results: A total of 11 887 participants (6434 CRC cases, 5453 controls; median [IQR] age, 69 [61-77] years; 7173 male [60.3%]) were included. At the time of diagnosis, 3998 cases (62.1%) and 3601 controls (66.0%) were overweight or obese, suggesting an inverse association between excess weight and CRC risk. Conversely, we found significant positive associations of overweight (adjusted odds ratio [aOR], 1.27; 95% CI, 1.03-1.56), obesity (aOR, 2.09; 95% CI, 1.61-2.70), and a 5-unit increase in BMI (aOR, 1.35; 95% CI, 1.21-1.50) with CRC risk when using BMI measured 8 to 10 years before diagnosis. High BMI as a risk factor for CRC was increased as earlier periods before diagnosis were examined, with the association being particularly pronounced using BMI at least 8 years before diagnosis. An opposite trend was found for the association of weight loss (at or exceeding 2 kg) with CRC, with the greatest effect sizes occurring for weight loss within 2 years before diagnosis (aOR, 7.52; 95% CI, 5.61-10.09), and gradually decreased for earlier intervals. Conclusions and Relevance: In this population-based case-control study, accounting for substantial prediagnostic weight loss further highlighted the association of overweight and obesity with CRC risk.

Impact of Reducing Intake of Red and Processed Meat on Colorectal Cancer Incidence in Germany 2020 to 2050-A Simulation Study.

BACKGROUND: According to the International Agency for Research on Cancer (IARC), there is sufficient evidence for the carcinogenicity of processed meat consumption in humans, specifically regarding colorectal cancer (CRC) risk. Evidence for the carcinogenicity of red meat consumption is more limited but points in the same direction. METHODS: A macro-simulation approach was used to calculate age- and sex-specific potential impact fractions in a 30-year period (2020-2050). AIMS: We estimated numbers and proportions of future CRC cases preventable under different scenarios of reducing the intake of processed and red meat in the German population. RESULTS: Eliminating processed meat intake could reduce the burden of CRC by approximately 205,000 cases in Germany (9.6%) in 2020-2050, 2/3 among males (145,000) and 1/3 among females (60,000). Without red meat intake, approximately 63,000 CRC cases could be avoided (2.9%), 39,000 among males and 24,000 among females. Reductions in the mean consumption of both processed and red meat by one or two servings (each 11 or 22 g) per day would be expected to reduce CRC case numbers by 68,000 (3.1%) and 140,000 (6.5%), respectively. CONCLUSION: A reduction in red and processed meat intake might substantially reduce the incidence of CRC in Germany. The means of achieving such a reduction might include price and taxation policies, food labeling, and clearer risk communication aiming to reduce individual intake.

Prevalence of Colorectal Neoplasia 10 or More Years After a Negative Screening Colonoscopy in 120 000 Repeated Screening Colonoscopies.

Importance: Screening colonoscopy to prevent and early detect colorectal cancer is recommended to be repeated in 10-year intervals, which goes along with high demands of capacities and costs. Evidence of findings at screening colonoscopies conducted 10 or more years after a negative colonoscopy result is sparse, and it remains unclear whether screening colonoscopy intervals could possibly be prolonged. Objective: To assess the prevalence of advanced colorectal neoplasms (ADNs) at least 10 years after a negative screening colonoscopy in a very large cohort of repeated screening colonoscopy participants in Germany. Design, Setting, and Participants: This registry-based cross-sectional study on screening colonoscopy findings reported to the German screening colonoscopy registry during January 2013 to December 2019 included data on screening colonoscopies that were offered to the German general population 55 years or older since 2002; virtually all screening colonoscopies among individuals covered by Statutory Health Insurance (approximately 90% of eligible adults) are reported to the national registry. A total of 120 298 repeat screening colonoscopy participants 65 years or older were identified who had a previous negative screening colonoscopy at least 10 years prior. The findings were compared with all screening colonoscopies conducted at 65 years or older during the same period (1.25 million). The data were analyzed from March to July 2022. Main Outcomes and Measures: Prevalence of colorectal cancers and ADNs (advanced adenomas and cancers). Results: Of 120 298 participants, 72 349 (60.1%) were women. Prevalence of ADN was 3.6% and 5.2% among women and men 10 years after a negative screening colonoscopy and gradually increased to 4.9% and 6.6%, respectively, among those who had a negative colonoscopy 14 years or longer prior compared with 7.1% and 11.6% among all screening colonoscopies. Sex-specific and age-specific prevalence of ADNs at repeated colonoscopies conducted 10 or more years after a negative colonoscopy were consistently at least 40% lower among women than among men, lower at younger vs older ages, and much lower than among all screening colonoscopies (standardized prevalence ratios for cancers: 0.22-0.38 among women, 0.15-0.24 among men; standardized prevalence ratios for ADNs: 0.49-0.62 among women, 0.50-0.56 among men). Conclusions and Relevance: The results of this cross-sectional study suggest that ADN prevalence at screening colonoscopies conducted 10 or more years after a negative screening colonoscopy is low. Extension of the currently recommended 10-year screening intervals may be warranted, especially for female and younger participants without gastrointestinal symptoms.

Is the association of overweight and obesity with colorectal cancer underestimated? An umbrella review of systematic reviews and meta-analyses.

Although high body-mass index (BMI) is associated with increased risk of developing colorectal cancer (CRC), many CRC patients lose weight before diagnosis. BMI is often reported close to diagnosis, which may have led to underestimation or even reversal of direction of the BMI-CRC association. We aimed to assess if and to what extent potential bias from prediagnostic weight loss has been considered in available epidemiological evidence. We searched PubMed and Web of Science until May 2022 for systematic reviews and meta-analyses investigating the BMI-CRC association. Information on design aspects and results was extracted, including if and how the reviews handled prediagnostic weight loss as a potential source of bias. Additionally, we analyzed how individual cohort studies included in the latest systematic review handled the issue. Overall, 18 reviews were identified. None of them thoroughly considered or discussed prediagnostic weight loss as a potential source of bias. The majority (15/21) of cohorts included in the latest review did not exclude any initial years of follow-up from their main analysis. Although the majority of studies reported having conducted sensitivity analyses in which initial years of follow-up were excluded, results were reported very heterogeneously and mostly for additional exclusions of 1-2 years only. Where explicitly reported, effect estimates mostly increased with increasing length of exclusion. The impact of overweight and obesity on CRC risk may be larger than suggested by the existing epidemiological evidence.

Real-world evidence for the effectiveness of vitamin D supplementation in reduction of total and cause-specific mortality.

BACKGROUND: Meta-analyses of randomized controlled trials (RCTs) have demonstrated the efficacy of vitamin D supplementation for reduced cancer mortality, all-cause mortality, and respiratory tract infections. However, whether and to what extent this translates into effectiveness in real-world practice is unknown. METHODS: We assessed the association of vitamin D supplement use (as an over-the-counter drug or as part of a multivitamin product), vitamin D deficiency (25-hydroxyvitamin D, 25[OH]D <30 nmol/L), and insufficiency (25[OH]D 30 to <50 nmol/L) with all-cause and cause-specific mortality in 445,601 participants, aged 40-73 years, from the UK Biobank cohort. RESULTS: A total of 4.3% and a further 20.4% of the study participants reported regularly taking vitamin D or multivitamin supplements, respectively. Still, the majority had either vitamin D deficiency (21.0%) or insufficiency (34.3%). We detected 49 independent determinants of vitamin D deficiency and vitamin D supplement use and used them to adjust Cox regression models for all mortality outcomes. A total of 29,107 (6.5%) participants died during a median follow-up time of 11.8 years. Both vitamin D deficiency and insufficiency were strongly associated with all mortality outcomes. Self-reported vitamin D supplement use (83% over-the-counter/17% prescription drugs) and multivitamin intake were significantly associated with 10% and 5% lower all-cause mortality, respectively. Furthermore, regular vitamin D supplement users had 11%, 11%, and 29% lower cancer, cardiovascular disease, and respiratory disease mortality than nonusers, respectively (not significant for cardiovascular disease mortality). CONCLUSION: This large study suggests that in the real world, the efficacy of vitamin D supplements in reducing mortality may be at least as good as observed in RCTs.

Making colonoscopy-based screening more efficient: A "gateopener" approach.

Screening colonoscopy for early detection and prevention of colorectal cancer (CRC) is mostly used inefficiently. Here, we assessed the potential of an innovative approach to colonoscopy-based screening, by use of a single, low threshold fecal immunochemical test (FIT) as a "gateopener" for screening colonoscopy. Using COSIMO, a validated simulation model, we modeled scenarios including either direct invitation to screening colonoscopy or an alternative approach involving mailing a single ("gateopener") FIT along with an invitation to colonoscopy contingent on a FIT value above a low threshold yielding a 50% positivity rate (ie, every other pretest will be positive). Under plausible assumptions on screening offer adherence, we found that such "gateopener screening" (use of screening colonoscopy contingent on a positive, low threshold gateopener FIT) approximately doubled cancer detection rates vs conventional screening. In those spared from screening colonoscopy due to a negative gateopener FIT pretest, numbers needed to screen were 10-times higher vs those for individuals with a positive FIT, peaking in >2000 and >3800 (hypothetically) needed colonoscopies to detect one case of cancer in men and women, respectively. Gateopener screening resulted in 42%-51% and 59%-65% more prevented CRC cases and deaths, respectively. In summary, by directing colonoscopy capacities to those most likely to benefit, offering screening colonoscopy contingent on a "gateopener" low-threshold FIT would substantially enhance efficiency of colonoscopy screening.

Consistent Inverse Associations of Total, "Bioavailable", Free, and "Non-Bioavailable" Vitamin D with Incidence of Diabetes among Older Adults with Lower Baseline HbA1c (≤6%) Levels.

BACKGROUND: Serum 25-hydroxyvitamin (25(OH)D) levels are inversely associated with risk of diabetes. The "free hormone hypothesis" suggests potential effects to be mainly related to concentrations of "bioavailable" and free rather than total 25(OH)D. We assessed associations of serum concentrations of vitamin D-binding protein (VDBP), as well as total "bioavailable", complementary "non-bioavailable", and free 25(OH)D, with the risk of developing diabetes among non-diabetic older adults in a large population-based cohort study in Germany. METHODS: We included 4841 non-diabetic older adults aged 50-75 years at the baseline exam from the ESTHER cohort conducted in Saarland, Germany, in 2001-2002. Concentrations of "bioavailable" and free 25(OH)D were derived from serum concentrations of VDBP, total 25(OH)D, and albumin. Incidence of diabetes was ascertained during up to 14 years of follow-up. Associations were quantified by multivariable Cox proportional hazards regression models with comprehensive confounder adjustment. RESULTS: During a median follow-up of 10.6 years, 837 non-diabetic participants developed diabetes. We observed similar inverse associations with developing diabetes for VDBP (hazard ratio (HR) for lowest versus highest quintile: 1.37, 95% confidence interval (CI): 1.09, 1.72), total 25(OH)D (HR: 1.31, 95% CI: 1.03, 1.66), and "non-bioavailable" 25(OH)D (HR: 1.30, 95% CI: 1.02, 1.65). Associations were smaller and statistically insignificant for "bioavailable" and free 25(OH)D. However, associations of total "non-bioavailable", "bioavailable", and free 25(OH)D with incidence of diabetes were much stronger among, and essentially restricted to, participants with lower baseline HbA1c (≤6%) levels. CONCLUSIONS: This large prospective cohort study of older Caucasian adults, in agreement with results from randomized trials and Mendelian randomization studies, supports a protective effect of vitamin D against development of diabetes. The "free hormone theory" may not be relevant in this context. However, our results underline the importance of adequate vitamin D status among those who have not yet shown any sign of impaired glucose tolerance.

Assessment of a Serum Microrna Risk Score for Colorectal Cancer among Participants of Screening Colonoscopy at Various Stages of Colorectal Carcinogenesis.

We recently derived and validated a serum-based microRNA risk score (miR-score) which predicted colorectal cancer (CRC) occurrence with very high accuracy within 14 years of follow-up in a large population-based cohort. Here, we aimed to assess and compare the distribution of the miR-score among participants of screening colonoscopy at various stages of colorectal carcinogenesis. MicroRNAs (miRNAs) were profiled by quantitative-real-time-polymerase-chain-reaction in the serum samples of screening colonoscopy participants with CRC (n = 52), advanced colorectal adenoma (AA, n = 100), non-advanced colorectal adenoma (NAA, n = 88), and participants free of colorectal neoplasms (n = 173). The mean values of the miR-score were compared between groups by the Mann-Whitney U test. The associations of the miR-score with risk for colorectal neoplasms were evaluated using logistic regression analyses. MicroRNA risk scores were significantly higher among participants with AA than among those with NAA (p = 0.027) and those with CRC (p = 0.014), whereas no statistically significant difference was seen between those with NAA and those with no colorectal neoplasms (p = 0.127). When comparing adjacent groups, miR-scores were inversely associated with CRC versus AA and positively associated with AA versus NAA [odds ratio (OR), 0.37 (95% confidence interval (CI), 0.16-0.86) and OR, 2.22 (95% CI, 1.06-4.64) for the top versus bottom tertiles, respectively]. Our results are consistent with the hypothesis that a high miR-score may be indicative of an increased CRC risk by an increased tendency of progression from non-advanced to advanced colorectal neoplasms, along with a change of the miR-patterns after CRC manifestation.

Reproductive Factors and Colorectal Cancer Risk: A Population-Based Case-Control Study.

BACKGROUND: Hormone-replacement therapy (HRT) is associated with lower colorectal cancer (CRC) risk among postmenopausal women. However, little is known about the effects of lifetime exposure of women to varying levels of estrogen and progesterone through reproductive factors such as parity, use of oral contraceptives (OC), breastfeeding, and menstruation on CRC risk. METHODS: We assessed associations between reproductive factors and CRC risk among 2650 female CRC patients aged 30+ years and 2175 matched controls in a population-based study in Germany, adjusting for potential confounders by multiple logistic regression. RESULTS: Inverse associations with CRC risk were found for numbers of pregnancies (odds ratio [OR] per pregnancy = 0.91, 95% confidence interval [CI] = 0.86 to 0.97), breastfeeding for 12 months and longer (OR = 0.74, 95% CI = 0.61 to 0.90), and use of either OC or HRT (OR = 0.75, 95% CI = 0.64 to 0.87) or both (OR = 0.58, 95% CI = 0.48 to 0.70). Similar results were found for postmenopausal women only and when adjusting for number of pregnancies and for all reproductive factors analyzed together. Breastfeeding duration of 12 months and longer was associated with lower risk of cancer only in the proximal colon (OR = 0.58, 95% CI = 0.45 to 0.74). CONCLUSIONS: Several reproductive factors were associated with lower CRC risk in women, including number of pregnancies, breastfeeding duration, and use of OC and HRT. This suggests that women's exposure to female reproductive hormones plays a key role in the difference in CRC risk between women and men and in site-specific CRC risk.

Combined Performance of Fecal Immunochemical Tests and a Genetic Risk Score for Advanced Neoplasia Detection.

Fecal immunochemical tests (FITs) are increasingly used as noninvasive screening tests in colorectal cancer-screening programs. Polygenic risk scores (PRS) are increasingly propagated for risk stratification in colorectal cancer screening. We aimed to assess the potential of combining FIT results and PRS to enhance diagnostic accuracy of detecting advanced neoplasia (AN) compared with using FIT results alone. Of 10,362 participants of screening colonoscopy in Southern Germany who conducted either one of two quantitative FITs, genotyping was done in all participants with AN (colorectal cancer or advanced adenoma) and a random subset of controls. Among 5,306 individuals, a PRS was calculated on the basis of the number of risk alleles in 140 SNPs. Partial areas under the receiver operating characteristics (ROC) curves (pAUCs) were computed for FIT and PRS alone and combined, focusing on a specificity range of 100%-80%. Both FITs showed similar performance characteristics with pAUCs of 0.661 (95% confidence interval (CI), 0.625-0.698; Ridascreen Hemoglobin) and 0.682 (95% CI, 0.661-0.701; FOB Gold) for AN detection. PRS alone reached a pAUC of 0.524 (95% CI, 0.499-0.550) and 0.530 (95% CI, 0.516-0.545), respectively, and its addition to FIT did not improve pAUCs (0.659; 95% CI, 0.622-0.697) and 0.667 (95% CI, 0.650-0.687), respectively. This finding was confirmed by investigating sensitivities at fixed specificities at 85%, 90%, and 95%. Partial AUCs also did not improve when adding the weighted PRS to FIT instead of the unweighted PRS. In summary, the combination with PRS did not improve diagnostic accuracy of FIT-based screening in a large asymptomatic colorectal cancer screening population from South-Western Germany. PREVENTION RELEVANCE: In our study, combining polygenic risk score with fecal immunochemical test (FIT) did not improve diagnostic accuracy for advanced colorectal neoplasia detection compared with FIT alone. So far, such a combination cannot be recommended because it would come at extra costs and effort despite no relevant gain in neoplasia detection.

Vitamin D food fortification in European countries: the underused potential to prevent cancer deaths.

BACKGROUND: Meta-analyses of randomized controlled trials have shown that vitamin D supplementation reduces cancer mortality by 13%. Vitamin D fortification of foods may increase vitamin D levels in a similar manner as vitamin D supplementation and could achieve similar reductions in cancer mortality. Whereas some European countries already implemented widespread fortification of foods with vitamin D, in other countries only few or no foods are fortified. In this study, we estimated the reduction in cancer mortality presumably already achieved by current fortification policies in 2017 and the potential for further reductions if all countries had effective fortification. METHODS: We reviewed scientific literature, publicly available information, and contacted health authorities to obtain information on current vitamin D food fortification policies in 34 European countries. Together with country-specific cancer death statistics from Eurostat, information on life expectancy, and country-specific fortification policies, we used data from studies on supplementation and serum 25(OH)D increases and cancer mortality to estimate numbers of probably already prevented cancer deaths and numbers of potentially further preventable deaths and years of life lost. RESULTS: Current vitamin D fortification is estimated to prevent approximately 11,000 in the European Union and 27,000 cancer deaths in all European countries considered per year. If all countries considered here would implement adequate vitamin D fortification of foods, an estimated additional 129,000 cancer deaths (113,000 in the European Union) could be prevented, corresponding to almost 1.2 million prevented years of life lost (1.0 million in the EU) or approximately 9% of cancer deaths (10% in the EU). INTERPRETATION: Systematic fortification of foods might considerably reduce the burden of cancer deaths in Europe.

Vitamin D-binding protein, total, "nonbioavailable," bioavailable, and free 25-hydroxyvitamin D, and mortality in a large population-based cohort of older adults.

BACKGROUND: Epidemiological studies consistently find low concentrations of 25-hydroxyvitamin D (25(OH)D) in blood to be associated with increased mortality, and a recent large-scale Mendelian randomization study strongly supports a causal relationship among individuals with low vitamin D status. Evolving evidence suggested that bioavailable or free 25(OH)D may better predict mortality. We aimed to compare the prognostic values of vitamin D-binding protein (VDBP), total, bioavailable, complementary "nonbioavailable", and free 25(OH)D for total and cause-specific mortality in a large population-based cohort study of older adults from Germany. METHODS: Bioavailable, complementary "nonbioavailable", and free 25(OH)D concentrations were calculated among 5899 participants aged 50-75 years, based on serum concentrations of total 25(OH)D, VDBP, and albumin. The cohort was followed with respect to total and cause-specific mortality from recruitment in 2001-2002 up to the end of 2018. Multivariable Cox proportional hazards regression models were used to assess the associations between various vitamin D biomarkers and mortality, and further stratified by vitamin D status. RESULTS: During a median follow-up of 17.1 years, 1739 participants died, of whom 575, 584, and 94 died of cardiovascular diseases, cancer, and respiratory diseases, respectively. Very similar inverse associations with total mortality (hazard ratio (HR) per standard deviation decrease: 1.17, 95% confidence interval (CI): 1.11, 1.24 for total 25(OH)D; HR: 1.14, 95% CI: 1.08, 1.21 for bioavailable 25(OH)D; HR: 1.12, 95% CI: 1.06, 1.18 for free 25(OH)D) and cause-specific mortalities were seen for all biomarkers of vitamin D status. The strongest associations were consistently seen for respiratory mortality. These inverse associations were strongest among participants with low vitamin D levels (<50 nmol/L). No significant associations were seen between VDBP and mortality. CONCLUSIONS: Total, nonbioavailable, bioavailable, and free 25(OH)D showed very similar inverse associations with total and cause-specific mortality, which were strongest among those with low vitamin D status in this large population-based cohort.

Variation of Positive Predictive Values of Fecal Immunochemical Tests by Polygenic Risk Score in a Large Screening Cohort.

INTRODUCTION: Prevalence of colorectal neoplasms varies by polygenic risk scores (PRS). We aimed to assess to what extent a PRS might be relevant for defining personalized cutoff values for fecal immunochemical tests (FITs) in colorectal cancer screening. METHODS: Among 5,306 participants of screening colonoscopy who provided a stool sample for a quantitative FIT (Ridascreen Hemoglobin or FOB Gold) before colonoscopy, a PRS was determined, based on the number of risk alleles in 140 single nucleotide polymorphisms. Subjects were classified into low, medium, and high genetic risk of colorectal neoplasms according to PRS tertiles. We calculated positive predictive values (PPVs) and numbers needed to scope (NNS) to detect 1 advanced neoplasm (AN) by the risk group, and cutoff variation needed to achieve comparable PPVs across risk groups in the samples tested with Ridascreen (N = 1,271) and FOB Gold (N = 4,035) independently, using cutoffs yielding 85%, 90%, or 95% specificity. RESULTS: Performance of both FITs was very similar within each PRS group. For a given cutoff, PPVs were consistently higher by 11%-15% units in the high-risk PRS group compared with the low-risk group (all P values < 0.05). Correspondingly, NNS to detect 1 advanced neoplasm varied from 2 (high PRS, high cutoff) to 5 (low PRS, low cutoff). Conversely, very different FIT cutoffs would be needed to ensure comparable PPVs across PRS groups. DISCUSSION: PPVs and NNS of FITs varied widely across people with high and low genetic risk score. Further research should evaluate the relevance of these differences for personalized colorectal cancer screening.