Dose-response Meta-analysis Of Cohort Studies Research Articles

Association between protein intake and risk of gestational diabetes mellitus: A systematic review and dose–response meta-analysis of cohort studies

Gestational diabetes mellitus (GDM) is a common condition in pregnancy, the prevalence of which has increased. Identifying modifiable risk factors for GDM, such as dietary factors, could prevent or delay the onset of the condition. Our goal was to perform a comprehensive meta-analysis of cohort studies, to summarize the current evidence on the relationship between total, animal, and plant protein intake during pregnancy, as well as pre-pregnancy protein intake, and the risk of GDM. A literature search was completed using Scopus, PubMed, Web of Science, and Google Scholar up to January 2023 and references of retrieved relevant articles. Observational studies examining the association between the consumption of dietary protein from different sources in pre-pregnancy or/and during pregnancy and the risk of GDM were included. To combine effect sizes for the comparison between the highest and lowest categories of protein intake, a random effects model was utilized. Dose-response relationships were investigated using a 1-stage random-effects model. 8 observational studies were included in the systematic review and 5 prospective cohort studies in the meta-analysis, involving a total of 24,160 participants and 2450 cases of GDM. The analysis revealed a significant association between total protein intake during pregnancy and an elevated risk of GDM (relative risk (RR): 2.24, 95% confidence interval (CI): 1.67-3.00, P=0.000). Conversely, no significant association was found between total protein intake before pregnancy and the risk of GDM. Both animal protein intake before pregnancy (RR: 1.47, 95% CI: 1.06-2.03, P=0.021) and during pregnancy (RR; 2.31, 95% CI: 1.43-3.73, P=0.001) showed a significant association with GDM. Interestingly, there was no significant association between the consumption of plant protein both before and during pregnancy and the risk of GDM. Further analysis revealed that an additional 5% energy from total protein and animal protein per day was associated with a 24% and 32% before and 114% and 67% increased risk of GDM during pregnancy respectively. In conclusion, consumption of animal protein and total protein before pregnancy is associated with an increased risk of GDM, although the association is not significant for total protein. Conversely, plant protein intake is linked to a decreased risk of GDM, however, the results are not significant. The intake of any protein type (plant/animal/total) during pregnancy is associated with an elevated risk of GDM, with this association being statistically insignificant for plant protein. Further cohort studies are required to validate the findings presented in this study. PROSPERO (CRD42023396215).

Association between total and animal proteins with risk of fracture: A systematic review and dose-response meta-analysis of cohort studies.

Previous cohort studies have indicated that consumption of total and animal proteins are related to fracture risk; however, results were inconclusive. This dose-dependent review sought to summarize the earlier evidence regarding the relation between total and animal proteins and fracture risk. We searched Scopus, PubMed, and Web of Science until July 2023 for original research articles examining the association of certain types of proteins and the incidence of all fractures in general adults. Summary relative risks (RRs) were calculated using random effects analysis to examine the relation between each certain amount (g/day) increment of total and animal protein and fracture risk. Twenty cohort studies with serious to moderate risk of bias involving 780,322 individuals were included. There was a non-statistically significant relation between intake of animal proteins and dairy products and all fracture risk. However, 43% and 5% decreased incidence of fracture was obtained with total protein (RR, 0.57; 95%CI, 0.36 to 0.93; per 100g/day) and fish (RR, 0.95; 95%CI, 0.91 to 0.99; per 15g/day) intake. Every 100g/day total and animal protein consumption and every 15g/day fish consumption were linked to 48%, 50%, and 5% lower hip fracture risk. Greater dietary animal protein intake might reduce risk of hip but not fracture at any site. We obtained a lower risk of any or hip fracture with greater total protein (per 100g/day) and fish (per 15g/day) intake. No evidence was obtained that higher intake of dairy could decrease risk of fracture.

Maternal uric acid levels and risk of gestational diabetes mellitus: A systematic review and dose-response meta-analysis of cohort studies including 105,380 participants.

Although the association between uric acid levels and adverse pregnancy outcomes has been investigated, the effects of higher uric acid levels on the risk of gestational diabetes mellitus (GDM) have yet to be established. Therefore, this systematic review and meta-analysis aimed to investigate the relationship between uric acid levels during pregnancy and the risk of GDM. PubMed/Medline, Scopus and Web of Science databases were searched up to April 2022 for relevant observational studies. A random effects model was used to estimate pooled odds ratios (OR) and 95% confidence intervals (95% CI). To assess the heterogeneity of included studies, the I2 index was used. Among the initial 262 studies that were recognized from the databases search, 23 studies including 105,380 participants were eligible. Pooled analysis showed that higher uric acid levels significantly affected the risk of GDM (OR 2.58, 95% CI 1.89-3.52, I2 = 90.8%, P < 0.001). Subgroup analyses based on the gestational week showed that higher uric acid levels before the 20th week of gestation were significantly associated with the risk of GDM (OR 3.26, 95% CI 2.26-4.71, I2 = 89.3%, P < 0.001). Based on the meta-regression analysis, uric acid levels and odds of GDM were significantly correlated with the participants' age, and it was more significant in younger pregnant women. This study showed a positive association between uric acid levels and the risk of GDM. Also, our results indicate that measuring uric acid levels before 20 weeks of gestation can potentially predict GDM, especially in younger women.

Alcohol intake and risk of hypertension: a systematic review and dose-response meta-analysis of cohort studies

Alcohol intake and risk of hypertension: a systematic review and dose-response meta-analysis of cohort studies

Physical activity and risk of lung cancer: A systematic review and dose-response meta-analysis of cohort studies

ObjectiveTo synthesize the knowledge about the association of total physical activity (TPA), leisure-time physical activity (LTPA), occupational physical activity (OPA) and lung cancer risk and explore the dose–response relationship between LTPA level and lung cancer. MethodsPubMed and Web of Science were searched up to 17 November 2021. The summary relative risks (RRs) and 95% confidence intervals (CIs) were calculated by random-effects or fixed-effects model. The dose–response analysis was conducted with restricted cubic splines. ResultsWe identified 25 articles (42 cohort studies) that assessed the physical activity–lung cancer association, including 9,983,295 study participants and 85,988 incident cases of lung cancer. When comparing the highest to the lowest level of TPA and LTPA, lung cancer risk reduced 22% (RR, 0.78; 95% CI: 0.70, 0.86) and 12% (RR, 0.88; 95% CI: 0.83, 0.93), respectively. We found an approximately U-shaped association between LTPA and lung cancer (Pnon-linearity < 0.001), with the lowest risk at 15 metabolic equivalent of task hours per week (h/wk) of LTPA. Compared to participants with sitting occupations, lung cancer risk significantly increased among those being unemployed (RR, 1.33; 95% CI: 1.17, 1.51) or with standing occupations (RR, 1.37; 95% CI: 1.15, 1.63), but not among those with light or high OPA. ConclusionsOur meta-analysis supported a protective effect of TPA and LTPA, but not OPA, on lung cancer risk. The novel finding of a U-shaped association between LTPA and lung cancer risk warrants further investigation.

High-sensitivity cardiac troponin, a cardiac marker predicting death in patients with kidney disease: a dose-response meta-analysis of cohort studies.

Patients with kidney disease are at increased risk of adverse mortality events. Numerous studies have demonstrated the positive association of high-sensitivity cardiac troponin T (hs-cTnT) and I (hs-cTnI) with all-cause and cardiovascular (CV) mortality in patients with kidney disease; however, the dose-response meta-analysis has not been reported. We therefore performed this study to evaluate the dose-response associations of hs-cTn with risk of all-cause and CV mortality to improve risk stratification. We searched three databases (PubMed, Embase and Web of Science) to identify relevant prospective cohort studies published up to 12 January 2021. Random-effects models were used to summarize relative risks (RRs) and 95% confidence intervals (CIs) of all-cause and CV mortality. Restricted cubic splines were used to fit the dose-response associations. For each 10 ng/l increase in hs-cTnT and hs-cTnI, the risk increased by 14% (RR = 1.14, 95% CI, 1.10-1.18) and 19% (RR = 1.19, 95% CI, 1.09-1.31) for all-cause mortality, 25% (RR = 1.25, 95% CI, 1.13-1.38) and 19% (RR = 1.19, 95% CI, 1.10-1.29) for CV mortality. A linear trend was found between hs-cTnT and all-cause mortality, whereas a non-linear trend was found in hs-cTnI. Additionally, both hs-cTnT and hs-cTnI were shown to have linear trends with CV mortality. Our meta-analysis suggests that hs-cTn had high sensitivity in predicting mortality events. All dose-response trends were rising rather than falling, conferring that any increase in the levels of hs-cTn may possibly predict a death prognosis among chronic kidney disease patients.

Serum uric acid level and all-cause and cardiovascular mortality in peritoneal dialysis patients: A systematic review and dose-response meta-analysis of cohort studies.

The association between serum uric acid (SUA) and all-cause and cardiovascular disease (CVD) mortality in peritoneal dialysis (PD) patients is controversial. Therefore, we aimed to determine the relationship between SUA and all-cause and CVD mortality in PD patients. Web of Science, EMBASE, PubMed and the Cochrane Library databases were searched from their inception to 7 April 2021. Effect estimates were presented as hazard ratios (HRs) with 95% confidence intervals (95% CIs) and pooled using random effects model. Thirteen cohort studies with 22418 patients were included in this systematic review, of which 9 were included in the meta-analysis. Before switching the reference group, pooled result for the highest SUA category was significantly greater than the median for all-cause mortality (HR = 2.41, 95% CI: 1.37-4.26). After switching the reference group, the highest SUA category did not demonstrate an increased all-cause (HR = 1.40, 95% CI: 0.95-2.05) or CVD (HR = 1.30, 95% CI: 0.72-2.34) mortality compared with the lowest SUA category. Dose-response analysis suggested a nonlinear association between SUA and all-cause mortality risk (Pnonlinearity = 0.002). This meta-analysis didn't find the relationship between SUA levels and all-cause and CVD mortality risk in PD patients. More rigorously designed studies are warranted in the future.

Anthropometric and adiposity indicators and risk of type 2 diabetes: systematic review and dose-response meta-analysis of cohort studies

ObjectiveTo present a comprehensive review of the association between measures of body weight, waist, and fat, and different ratios of these measures, and the risk of type 2 diabetes.DesignSystematic review...

Dietary intake and biomarkers of alpha linolenic acid and risk of all cause, cardiovascular, and cancer mortality: systematic review and dose-response meta-analysis of cohort studies

ObjectiveTo examine the associations between dietary intake and tissue biomarkers of alpha linolenic acid (ALA) and risk of mortality from all causes, cardiovascular disease (CVD), and cancer.DesignSystematic review and meta-analysis...

Fasting Insulin and Risk of Cancer Related Mortality in Non-diabetic Adults: A Dose-response Meta-analysis of Cohort Studies.

Insulin is known to have direct and indirect effects on cell cycle progression, proliferation and metastatic activities. We performed a dose-response meta-analysis to investigate the association between hyperinsulinemia and all-cause cancer related mortality. A systematic literature search was conducted on MEDLINE and SCOPUS databases to include all published articles up to January 2019. Combined hazard ratios (HRs) with 95% Confidence Intervals (CIs) were estimated using DerSimonian and Laird random-effects models. A dose-response analysis was also conducted to further explore insulin's relationship with cancer-related mortality. We identified seven studies, with a total of 23,990 participants, who reported the association between hyperinsulinemia and cancer-related mortality. Results from the eligible studies indicated that higher fasting insulin levels were not associated with an increased risk of cancer mortality (pooled HR: 1.14, 95% CI: 0.99-1.32), however, significant heterogeneity was present (I2 = 60.3%, P heterogeneity = 0.001). A subgroup analysis based on gender demonstrated a significant association between fasting insulin level and cancer mortality in men (pooled HR: 1.92, 95% CI: 1.23-3.01, P heterogeneity = 0.281). This dose-response meta-analysis showed a direct significant association between fasting insulin level and cancer mortality in men.

睡眠时间与前列腺癌发病风险关系前瞻性研究的Meta分析

睡眠时间与前列腺癌发病风险关系前瞻性研究的Meta分析

Serum uric acid and risk of cardiovascular mortality: a systematic review and dose-response meta-analysis of cohort studies of over a million participants

BackgroundCardiovascular disease (CVD) is the leading cause of death worldwide. Some studies have suggested anassociation between serum uric acid levels and cardiovascular mortality; however, the results have not been summarized in a meta-analysis.MethodsA comprehensive search of all related studies until April 2018was performed in MEDLINE/PubMed and Scopus databases DerSimonianand Laird random-effects models were used to combine hazard ratios (HRs) with 95% confidence intervals (CIs). Dose-response analysis was also carried out.ResultsThirty-two studies containing forty-four arms with 1,134,073 participants reported association between uric acid and risk of CVD mortality were included in our analysis. Pooled results showed a significant positive association between uric acid levels and risk of CVD mortality (HR 1.45, 95% CI 1.33–1.58, I2 = 79%). Sub-group analysis showed this relationshipwasstronger in women compared to men. Moreover, there was a significant non-linear association between uric acid levels and the risk of CVD mortality (r = 0.0709, p = 0.001).ConclusionOur analysis indicates a positive dose-response association between SUA and CVD mortality risk.

Non-linear Relationship between Tacrolimus Blood Concentration and Acute Rejection After Kidney Transplantation: A Systematic Review and Dose-Response Meta-Analysis of Cohort Studies.

Maintaining the exposure of tacrolimus (Tac) after kidney transplantation (KT) must be necessary to prevent acute rejection (AR) and improve graft survival，but there is still no clear consensus on the optimal Tac target blood concentration and concentration-effect relationship is poorly defined. We conducted a dose-response meta-analysis to quantitatively assess the association between Tac blood concentration and (AR) or adverse effects after KT. A comprehensive search of PubMed, Embase and Cochrane library databases was conducted to find eligible studies up to 10th September 2018. Unpublished data from patients receiving KT in West China Hospital (Sichuan University, China) were also collected. Both twostage dose-response and one-stage dose-response meta-analysis models were used to improve the statistical power. A total of 4967 individuals from 10 original studies and 1453 individuals from West China Hospital were eligible for the ultimate analysis. In the two-stage dose-response meta-analysis model, we observed a significant non-linear relationship between Tac blood concentration and AR (P < 0.001) with moderate heterogeneity (I2 = 46.0%, P = 0.08). Tac blood concentration at 8ng/ml was associated with the lowest risk of AR (RR: 0.26, 95%CI: 0.13 - 0.54) by reference to 2ng/ml. Tac concentration at 7.0 - 11.0 ng/ml reduced the risk of AR by at least 70%, 5-14 ng/ml by at least 60%, and 4.5 - 14 ng/ml at least 50%. In the one-stage dose-response model, we also found a strong non-linear relationship between Tac and AR (P < 0.001) with moderate heterogeneity (I2 = 41.2%, P = 0.10). Tac concentration of 7.5 ng/ml was associated with the lowest risk of AR (RR: 0.35, 95%CI: 0.16 - 0.77). The blood concentration at 5.5 - 9.5 ng/ml was associated with the reduced AR by at least 60% and 4.5 - 10.5 ng/ml by at least 50% by reference to 2 ng/ml. Maintaining Tac blood concentration at 5 - 9.5 ng/ml within the first year may prevent AR most effectively.

Effect of Alcohol Use Disorder and Alcohol Intake on Risk of Subsequent Depression: A Dose-Response Meta-Analysis of Cohort Studies

Background: Alcohol misuse is a highly prevalent and attributed to a great burden of public health. Cross-sectional studies reported an association between alcohol misuse and depression. However, whether preceded alcohol misuse is a risk factor for subsequent depression remains undetermined. Moreover, different assessments based on the existence of alcohol use disorder (AUD) and various intake levels of alcohol may lead to different results. We did a dose-response meta-analysis to estimate the longitudinal association between AUD, alcohol intake level and depression. Methods: We searched Pubmed, Embase and PsycINFO for cohort studies investigating alcohol use on risk of subsequent depression up to April 2019. Effect of Alcohol use disorder (AUD) and alcohol intake on depression onset were analyzed separately. In analysis of alcohol intake, we first compared the risk between heavy drinking and non-heavy drinking, following by a qualitative analysis and a dose-response analysis in comparison of different levels of intake versus abstinence. A random-effects model was used to pool the summary RR and 95% confidence intervals (95%CI). Subgroup analysis and meta-regression was performed to trace heterogeneity. Publication bias was evaluated using multiple methods. Findings: Forty-two studies comprising 338426 participants were included in the current analysis. The summary RR of incident depression for AUD was 1.57 (1.41-1.76) compared to non-AUD. Summary RR of depression was 1.14 (1.06, 1.23) on heavy drinking versus non-heavy drinking. In qualitative analysis for various level of alcohol consumption compared to abstinence, light-moderate drinking was inversely associated with depression risk while heavy drinking was found to possibly elevate the risk of depression. Similarity was demonstrated in dose-response analysis, there was a non-linear association between alcohol intake and depression, with a decreased risk observed when consumption approximately between 0 and 29 g/day and an increased but non-significant risk when the intake was >42 g/day. Interpretation: Alcohol use disorder (AUD) is significantly associated with subsequent depression and heavy drinking probably enhanced the risk. Alarm and attention should be sent to alcohol problematic users especially to people with AUD, regardless of the absence of depression yet. Funding: This work was supported by the funding of National Key R&D Program of China (2018YFC1314400 and 2018YFC1314401 to YP). Declaration of Interest: The authors declare that they have no conflict of interest.

Association between total sleep time and all cancer mortality: non-linear dose-response meta-analysis of cohort studies

ObjectiveAppropriate total sleep time is reported to be associated with several important health outcomes. However, the relationship between total sleep time and all cancer mortality is not well defined because of inconsistent results from published studies, and no dose-response meta-analysis was performed to evaluate the exact dose-response relationship. MethodsWe conducted a literature search of PubMed and Web of Science to identify all relevant epidemiological studies published before August 9, 2018. We performed categorical and non-linear dose-response meta-analyses to quantify the association between total sleep time and all cancer mortality. ResultsFinally, we included 14 cohort studies in the present meta-analyses enrolling 866,877 participants with 43,021 cancer deaths. We found that total sleep time less than seven hours was not significantly associated with increased risk of all cancer mortality [relative risk (RR) = 1.02; 95% confidence interval (CI) = 0.99–1.05]. However, four to five hours total sleep time was related to an 8% increased risk of all cancer mortality (RR = 1.08; 95% CI = 1.02–1.13) in dose-response meta-analysis. Furthermore, long total sleep time (≥8 hours) was weakly associated with all cancer mortality (RR = 1.05; 95% CI = 1.02–1.08). However, the increment in total sleep time longer than nine hours was notably associated with an increased risk of cancer mortality. ConclusionThe current meta-analysis provides evidence of a positive association between total sleep time of four to five hours and total sleep time longer than eight hours with the risk of all cancer mortality among the general population. Additional studies are needed to establish causality.

Birth weight and risk of type 2 diabetes: A dose-response meta-analysis of cohort studies.

The association between birth weight and type 2 diabetes mellitus has been debated for several decades. The objective of this systematic review and meta-analysis was to quantitatively clarify the association between birth weight and risk of type 2 diabetes mellitus based on cohort studies. We searched PubMed, Web of Science, and Embase databases for cohort study articles on the association between birth weight and risk of type 2 diabetes mellitus published up to 1 March 2018. Random effects of generalized least square regression models were used to estimate relative risk (RR). Restricted cubic splines were conducted to model the dose-response relationship. We included 21 studies (19 articles) involving 1041879 individuals and 35699 cases of type 2 diabetes mellitus, with follow-up ranged from 6 to 47years. We identified significant decreasing trend for the highest versus lowest category of birth weight for the association with type 2 diabetes mellitus risk: The risk was reduced by 35% (RR, 0.65; 95% confidence interval [CI], 0.53-0.81) and by 12% (RR 0.88; 95% CI, 0.85-0.91) per 500-g increment in birth weight. Our results showed a dose-response relationship between birth weight and diabetes risk, which was nonlinear (Pnonlinearity <0.001) and L-shaped. With increasing birth weight (<5000g), the risk of type 2 diabetes mellitus decreased substantially. The association between birth weight and type 2 diabetes mellitus was curvilinear and L-shaped.

GW29-e0891 Resting heart rate and the risk of hypertension: a dose-response meta-analysis of cohort studies

High resting heart rate is linked with increased risk of hypertesion but it is unclear whether there is a dose-response relationship between resting heart rate and hypertension risk. We conducted a meta-analysis to quantitatively assess this association. We searched PubMed, EmBase and China

Body mass index and incidence of nonaggressive and aggressive prostate cancer: a dose-response meta-analysis of cohort studies.

The relationship between body mass index (BMI) and incidence of prostate cancer is still inconclusive. We performed a dose-response meta-analysis of eligible cohort studies to evaluate potential association of BMI with prostate cancer risk by subtype of prostate cancer (nonaggressive and aggressive). A comprehensive literature search was performed in PubMed and Web of Science databases through March 22, 2017. Linear and non-linear dose-response meta-analyses were carried out to evaluate the effects of BMI on incidence of prostate cancer. A total of 21 cohort or nested case-control studies (17 for nonaggressive and 21 for aggressive prostate cancer) were included in this meta-analysis. For nonaggressive prostate cancer, the pooled relative risk (RR) per 5 kg/m2 increment of BMI with 95% confidence interval (CI) was 0.96 (95% CI 0.92–1.00). Sensitivity analysis indicated that this result was not robust and steady. For aggressive prostate cancer, a significant linear direct relationship with BMI (RR, 1.07; 95% CI 1.03–1.12) for every 5 kg/m2 increase was observed. Statistically significant heterogeneity was detected for nonaggressive prostate cancer (P = 0.020, I2 = 46.1%) but not for aggressive prostate cancer (P = 0.174, I2 = 22.4%). In conclusion, BMI level may be positively associated with aggressive prostate cancer risk. Further large prospective cohort studies are warranted to confirm the findings from our study.

Relationship between initiation time of adjuvant chemotherapy and survival in ovarian cancer patients: a dose-response meta-analysis of cohort studies

Although several studies have previously investigated the association between the initiation time of adjuvant chemotherapy and survival in ovarian cancer, inconsistencies remain about the issue. We searched PubMed and Web of Science through the May 24, 2017 to identify cohort studies that investigated the aforementioned topic. Fourteen studies with 59,569 ovarian cancer patients were included in this meta-analysis. We conducted meta-analyses comparing the longest and shortest initiation time of adjuvant chemotherapy and dose-response analyses to estimate summary hazards ratios (HRs) and 95% confidence intervals (CIs). A random-effects model was used to estimate HRs with 95% CIs. When comparing the longest with the shortest category of initiation time of adjuvant chemotherapy, the summary HR was 1.18 (95% CI: 1.06–1.32; I2 = 17.6; n = 7) for overall survival. Additionally, significant dose-response association for overall survival was observed for each week delay (HR = 1.04; 95% CI: 1.00–1.09; I2 = 9.05; n = 5). Notably, these findings were robust in prospective designed cohort studies as well as studies with advanced stage (FIGO III-IV) patients. No evidence of publication bias was observed. In conclusion, prolonged initiation time of adjuvant chemotherapy is associated with a decreased overall survival rate of ovarian cancer, especially in patients with advanced stage ovarian cancer.

Circulating Vitamin D and Overall Survival in Breast Cancer Patients: A Dose-Response Meta-Analysis of Cohort Studies.

Studies have shown that vitamin D could have a role in breast cancer survival; however, the evidence of the relationship between patients’ vitamin D levels and their survival has been inconsistent. This meta-analysis explores possible dose-response relationships between vitamin D levels and overall survival by allowing for differences in vitamin D levels among populations of the various studies. Studies relating vitamin D (25-OH-D [25-hydroxyvitamin D]) levels in breast cancer patients with their survival were identified by searching PubMed and Embase. A pooled HR (hazard ratio) comparing the highest with the lowest category of circulating 25-OH-D levels were synthesized using the Mantel-Haenszel method under a fixed-effects model. A two-stage fixed-effects dose-response model including both linear (a log-linear dose-response regression) and nonlinear (a restricted cubic spline regression) models were used to further explore possible dose-response relationships. Six studies with a total number of 5984 patients were identified. A pooled HR comparing the highest with the lowest category of circulating 25-OH-D levels under a fixed-effects model was 0.67 (95% confidence interval = 0.56-0.79, P < .001). Utilizing a dose-response meta-analysis, the pooled HR for overall survival in breast cancer patients was 0.994 (per 1 nmol/L), Pfor linear trend < .001. At or above a 23.3 nmol/L threshold, for a 10 nmol/L, 20 nmol/L, or 25 nmol/L increment in circulating 25-OH-D levels, the risk of breast cancer overall mortality decreased by 6%, 12%, and 14%, respectively. There was no significant nonlinearity in the relationship between overall survival and circulating 25-OH-D levels. Our findings suggest that there is a highly significant linear dose-response relationship between circulating 25-OH-D levels and overall survival in patients with breast cancer. However, better designed prospective cohort studies and clinical trials are needed to further confirm these findings.