Blood levels of persistent organic pollutants among women in France in the 90's: Main profiles and individual determinants.

CONTEXT AND OBJECTIVES: Persistent organic pollutants (POPs) are a group of organic chemical compounds potentially toxic to human health. The objectives of this study were 1) to describe the levels of POPs biomarkers in blood samples from French women collected during the 1990s and to compare them with levels measured in two more recent French studies, 2) to identify POPs exposure profiles, and 3) to explore their main determinants. METHODS: 73 POPs biomarkers were measured in the blood of 468 women from the French E3N cohort (aged 45-73 years), collected between 1994 and 1999: 28 per- and polyfluoroalkyl substances, 27 organochlorine pesticides, 14 polychlorinated biphenyls and 4 polybrominated diphenyl ethers. POPs biomarker levels were described and compared with levels measured in two more recent French studies conducted by the French National Public Health Agency, the ENNS and Esteban studies. Principal component analysis was performed on POPs quantified in at least 75% of samples to identify the main exposure profiles. Linear regression models were used to estimate the associations between anthropometric, socio-demographic and lifestyle characteristics and exposure to these profiles. RESULTS: Among the 73 biomarkers measured, 41 were quantified in more than 75% of samples. Levels of most pollutants that were also measured in the Esteban of ENNS studies have decreased over time. Six POPs exposure profiles were revealed, explaining 62.1% of the total variance. Most of the characteristics studied were associated with adherence to at least one of these profiles. CONCLUSION: This study highlighted that most of the pollutants for which a comparison was possible decreased over the 10 or 20 years following the E3N blood collection, and identified those which, on the contrary, tended to increase. The health effects of the profiles identified could be assessed in future studies. The determinants identified should be confirmed in larger populations.

3D printing in anatomical lung segmentectomies: A randomized pilot trial.

Objective: This pilot study evaluated the impact of using a 3D printed model of the patient's bronchovascular lung anatomy on the mental workload and fatigue of surgeons during full thoracoscopic segmentectomy. Design: We performed a feasibility pilot study of a prospective randomized controlled trial with 2 parallel arms. All included patients underwent digital 3D visual reconstruction of their bronchovascular anatomy and were randomized into the following two groups: Digital arm (only a virtual 3D model was available) and Digital + Object arm (both virtual and printed 3D models were available). The primary end-point was the surgeons' mental workload measured using the National Aeronautics and Space Administration-Task Load Index (NASA-TLX) score. Setting: Between October 28, 2020 and October 05, 2021, we successively investigated all anatomic segmentectomies performed via thoracoscopy in the Thoracic Department of the Montsouris Mutualiste Institute, except for S6 segmentectomies and S4+5 left bi-segmentectomies. Participants: We assessed 102 patients for anatomical segmentectomy. Among the, 40 were randomly assigned, and 34 were deemed analysable, with 17 patients included in each arm. Results: Comparison of the two groups, each comprising 17 patients, revealed no statistically significant difference in primary or secondary end-points. The consultation of the visual digital model was significantly less frequent when a 3D printed model was available (6 versus 54 consultations, p = 0.001). Notably, both arms exhibited high NASA-TLX scores, particularly in terms of mental demand, temporal demand, and effort scores. Conclusion: In our pilot study, 3D printed models and digital 3D reconstructions for pre-operative planning had an equivalent effect on thoracoscopic anatomic segmentectomy for experienced surgeons. The originality of this study lies in its focus on the impact of 3D printing of bronchovascular anatomy on surgeons, rather than solely on the surgical procedure.

Lower risk of hospitalisation for depression following hospitalisation for COVID-19 versus for another reason.

INTRODUCTION: Although hospitalisation for COVID-19 is associated with a higher post-discharge risk of mood disorders, including major depressive disorder (MDD) and bipolar disorder (BD), this risk has not been compared to that following hospitalisation for a reason other than COVID-19. METHODS: Using data from France's National Health Data System (SNDS) database, we compared patients hospitalised for mood disorders in the 12 months following COVID-19/another reason hospitalisation. RESULTS: 96,313 adult individuals were hospitalised for COVID-19, and 2,979,775 were hospitalised for another reason. In the 12 months post-discharge, 110,976 (3.83 %) patients were hospitalised for mood disorders. In unadjusted analyses, patients initially hospitalised for COVID-19 (versus another reason) were more likely to be subsequently hospitalised for a mood disorder (4.27 % versus 3.82 % versus, respectively, p < 0.0001). These patients were also more likely to have a history of mood disorders, especially depressive disorders (6.45 % versus 5.77 %, respectively, p < 0.0001). Women, older age, lower social deprivation, a history of mood disorders, longer initial hospitalisation (COVID-19 or other), and a higher level of clinical care during initial hospitalisation were all significantly associated with the risk of subsequent hospitalisation for MDD and BD. In contrast, after adjusting for all these factors, persons initially hospitalised for COVID-19 were less likely to be subsequently hospitalised for MDD (OR = 0.902 [0.870-0.935]; p < 0.0001). No difference between both groups was observed for BD. LIMITATIONS: Other reasons were not separately studied. CONCLUSIONS: After adjusting for confounding factors, initial hospitalisation for COVID-19 versus for another reason was associated with a lower risk of hospitalisation for a mood disorder.

Can machine learning provide preoperative predictions of biological hemostasis after extracorporeal circulation for cardiac surgery?

OBJECTIVES: The goal of this study was to improve decision making regarding the transfusion of patients at the end of extracorporeal circulation for cardiac surgery through machine learning predictions of the evolution of platelets counts, prothrombin ratio, and fibrinogen assay. METHODS: Prospective data with information about patient preoperative biology and surgery characteristics were collected at Institut Mutualiste Montsouris Hospital (Paris, France) for 10 months (n = 598). For each outcome of interest, instead of arbitrarily choosing 1 machine learning algorithm, we trained and tested a variety of algorithms together with the super learning algorithm, a state-of-the-art ensemble method that aggregates all the predictions and selects the best performing algorithm (total, 137 algorithms). We considered the top-performing algorithms and compared them to more standard and interpretable multivariable linear regression models. All algorithms were evaluated through their root mean squared error, a measure of the average difference between true and predicted values. RESULTS: The root mean squared error of the top algorithms for predicting the difference between pre- and postoperative platelet counts, prothrombin ratio, and fibrinogen assay were 38.27 × 10e9/L, 8.66%, and 0.44 g/L, respectively. The linear models had similar performances. CONCLUSIONS: Our machine learning algorithms accurately predicted prothrombin ratio and fibrinogen assay and less accurately platelet counts. As such, our models could provide an aid-decision tool for anesthetists in an operating room; future clinical trials addressing this hypothesis are warranted.

Adverse effects of immunotherapies for multiple sclerosis: a network meta-analysis.

BACKGROUND: Multiple sclerosis (MS) is a chronic disease of the central nervous system that affects mainly young adults (two to three times more frequently in women than in men) and causes significant disability after onset. Although it is accepted that immunotherapies for people with MS decrease disease activity, uncertainty regarding their relative safety remains. OBJECTIVES: To compare adverse effects of immunotherapies for people with MS or clinically isolated syndrome (CIS), and to rank these treatments according to their relative risks of adverse effects through network meta-analyses (NMAs). SEARCH METHODS: We searched CENTRAL, PubMed, Embase, two other databases and trials registers up to March 2022, together with reference checking and citation searching to identify additional studies. SELECTION CRITERIA: We included participants 18 years of age or older with a diagnosis of MS or CIS, according to any accepted diagnostic criteria, who were included in randomized controlled trials (RCTs) that examined one or more of the agents used in MS or CIS, and compared them versus placebo or another active agent. We excluded RCTs in which a drug regimen was compared with a different regimen of the same drug without another active agent or placebo as a control arm. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods for data extraction and pairwise meta-analyses. For NMAs, we used the netmeta suite of commands in R to fit random-effects NMAs assuming a common between-study variance. We used the CINeMA platform to GRADE the certainty of the body of evidence in NMAs. We considered a relative risk (RR) of 1.5 as a non-inferiority safety threshold compared to placebo. We assessed the certainty of evidence for primary outcomes within the NMA according to GRADE, as very low, low, moderate or high. MAIN RESULTS: This NMA included 123 trials with 57,682 participants. Serious adverse events (SAEs) Reporting of SAEs was available from 84 studies including 5696 (11%) events in 51,833 (89.9%) participants out of 57,682 participants in all studies. Based on the absolute frequency of SAEs, our non-inferiority threshold (up to a 50% increased risk) meant that no more than 1 in 18 additional people would have a SAE compared to placebo. Low-certainty evidence suggested that three drugs may decrease SAEs compared to placebo (relative risk [RR], 95% confidence interval [CI]): interferon beta-1a (Avonex) (0.78, 0.66 to 0.94); dimethyl fumarate (0.79, 0.67 to 0.93), and glatiramer acetate (0.84, 0.72 to 0.98). Several drugs met our non-inferiority criterion versus placebo: moderate-certainty evidence for teriflunomide (1.08, 0.88 to 1.31); low-certainty evidence for ocrelizumab (0.85, 0.67 to 1.07), ozanimod (0.88, 0.59 to 1.33), interferon beta-1b (0.94, 0.78 to 1.12), interferon beta-1a (Rebif) (0.96, 0.80 to 1.15), natalizumab (0.97, 0.79 to 1.19), fingolimod (1.05, 0.92 to 1.20) and laquinimod (1.06, 0.83 to 1.34); very low-certainty evidence for daclizumab (0.83, 0.68 to 1.02). Non-inferiority with placebo was not met due to imprecision for the other drugs: low-certainty evidence for cladribine (1.10, 0.79 to 1.52), siponimod (1.20, 0.95 to 1.51), ofatumumab (1.26, 0.88 to 1.79) and rituximab (1.01, 0.67 to 1.52); very low-certainty evidence for immunoglobulins (1.05, 0.33 to 3.32), diroximel fumarate (1.05, 0.23 to 4.69), peg-interferon beta-1a (1.07, 0.66 to 1.74), alemtuzumab (1.16, 0.85 to 1.60), interferons (1.62, 0.21 to 12.72) and azathioprine (3.62, 0.76 to 17.19). Withdrawals due to adverse events Reporting of withdrawals due to AEs was available from 105 studies (85.4%) including 3537 (6.39%) events in 55,320 (95.9%) patients out of 57,682 patients in all studies. Based on the absolute frequency of withdrawals, our non-inferiority threshold (up to a 50% increased risk) meant that no more than 1 in 31 additional people would withdraw compared to placebo. No drug reduced withdrawals due to adverse events when compared with placebo. There was very low-certainty evidence (meaning that estimates are not reliable) that two drugs met our non-inferiority criterion versus placebo, assuming an upper 95% CI RR limit of 1.5: diroximel fumarate (0.38, 0.11 to 1.27) and alemtuzumab (0.63, 0.33 to 1.19). Non-inferiority with placebo was not met due to imprecision for the following drugs: low-certainty evidence for ofatumumab (1.50, 0.87 to 2.59); very low-certainty evidence for methotrexate (0.94, 0.02 to 46.70), corticosteroids (1.05, 0.16 to 7.14), ozanimod (1.06, 0.58 to 1.93), natalizumab (1.20, 0.77 to 1.85), ocrelizumab (1.32, 0.81 to 2.14), dimethyl fumarate (1.34, 0.96 to 1.86), siponimod (1.63, 0.96 to 2.79), rituximab (1.63, 0.53 to 5.00), cladribine (1.80, 0.89 to 3.62), mitoxantrone (2.11, 0.50 to 8.87), interferons (3.47, 0.95 to 12.72), and cyclophosphamide (3.86, 0.45 to 33.50). Eleven drugs may have increased withdrawals due to adverse events compared with placebo: low-certainty evidence for teriflunomide (1.37, 1.01 to 1.85), glatiramer acetate (1.76, 1.36 to 2.26), fingolimod (1.79, 1.40 to 2.28), interferon beta-1a (Rebif) (2.15, 1.58 to 2.93), daclizumab (2.19, 1.31 to 3.65) and interferon beta-1b (2.59, 1.87 to 3.77); very low-certainty evidence for laquinimod (1.42, 1.01 to 2.00), interferon beta-1a (Avonex) (1.54, 1.13 to 2.10), immunoglobulins (1.87, 1.01 to 3.45), peg-interferon beta-1a (3.46, 1.44 to 8.33) and azathioprine (6.95, 2.57 to 18.78); however, very low-certainty evidence is unreliable. Sensitivity analyses including only studies with low attrition bias, drug dose above the group median, or only patients with relapsing remitting MS or CIS, and subgroup analyses by prior disease-modifying treatments did not change these figures. Rankings No drug yielded consistent P scores in the upper quartile of the probability of being better than others for primary and secondary outcomes. AUTHORS' CONCLUSIONS: We found mostly low and very low-certainty evidence that drugs used to treat MS may not increase SAEs, but may increase withdrawals compared with placebo. The results suggest that there is no important difference in the occurrence of SAEs between first- and second-line drugs and between oral, injectable, or infused drugs, compared with placebo. Our review, along with other work in the literature, confirms poor-quality reporting of adverse events from RCTs of interventions. At the least, future studies should follow the CONSORT recommendations about reporting harm-related issues. To address adverse effects, future systematic reviews should also include non-randomized studies.

The risk of hospitalization for psychotic disorders following hospitalization for COVID-19: a French nationwide longitudinal study.

COVID-19, like other infectious diseases, may be a risk factor for psychotic disorders. We aimed to compare the proportions of hospitalizations for psychotic disorders in the 12 months following discharge from hospital for either COVID-19 or for another reason in the adult general population in France during the first wave of the pandemic. We conducted a retrospective longitudinal nationwide study using the national French administrative healthcare database. Psychotic disorders were first studied as a whole, and then chronic and acute disorders separately. The role of several adjustment factors, including sociodemographics, a history of psychotic disorder, the duration of the initial hospitalization, and the level of care received during that hospitalization, were also analyzed. Between 1 January 2020 and 30 June 2020, a total of 14,622 patients were hospitalized for psychotic disorders in the 12 months following discharge from hospital for either COVID-19 or another reason. Initial hospitalization for COVID-19 (vs. another reason) was associated with a lower rate of subsequent hospitalization for psychotic disorders (0.31% vs. 0.51%, odds ratio (OR) = 0.60, 95% confidence interval (CI) [0.53-0.67]). This was true for both chronic and acute disorders, even after adjusting for the various study variables. Importantly, a history of psychotic disorder was a major determinant of hospitalization for psychotic disorders (adjusted OR = 126.56, 95% CI [121.85-131.46]). Our results suggest that, in comparison to individuals initially hospitalized for another reason, individuals initially hospitalized for COVID-19 present a lower risk of hospitalization for first episodes of psychotic symptoms/disorders or for psychotic relapse in the 12 months following discharge. This finding contradicts the hypothesis that there is a higher risk of psychotic disorders after a severe COVID-19.

Mediating Role of Lifestyle Behaviors in the Association between Education and Cancer: Results from the European Prospective Investigation into Cancer and Nutrition.

BACKGROUND: Many studies have shown that socioeconomic position (SEP) is associated with the incidence of malignant tumors at different sites. This study aims to estimate the association between educational level (as proxy for SEP) and cancer incidence and to understand whether the observed associations might be partially explained by lifestyle behaviors. METHODS: The analyses were performed on data from the European Prospective Investigation into Cancer and Nutrition (EPIC) study, globally and by sex. We used Cox proportional hazards models together with mediation analysis to disentangle the total effect (TE) of educational level [measured through the Relative Index of Inequality (RII)] on cancer incidence into pure direct (PDE) and total indirect (TIE) effect, unexplained and explained by mediators, respectively. PDE and TIE were then combined to compute the proportions mediated (PM). RESULTS: After an average of 14 years of follow-up, 52,422 malignant tumors were ascertained. Low educated participants showed higher risk of developing stomach, lung, kidney (in women), and bladder (in men) cancers, and, conversely, lower risk of melanoma and breast cancer (in post-menopausal women), when compared with more educated participants. Mediation analyses showed that portions of the TE of RII on cancer could be explained by site-specific related lifestyle behaviors for stomach, lung, and breast (in women). CONCLUSIONS: Cancer incidence in Europe is determined at least in part by a socioeconomically stratified distribution of risk factors. IMPACT: These observational findings support policies to reduce cancer occurrence by altering mediators, such as lifestyle behaviors, particularly focusing on underprivileged strata of the population.

Hospitalization for COVID-19 is associated with a higher risk of subsequent hospitalization for psychiatric disorders: A French nationwide longitudinal study comparing hospitalizations for COVID-19 and for other reasons.

INTRODUCTION: Although COVID-19 has been associated with psychiatric symptoms in patients, no study to date has examined the risk of hospitalization for psychiatric disorders after hospitalization for this disease. OBJECTIVE: We aimed to compare the proportions of hospitalizations for psychiatric disorders in the 12 months following either hospitalization for COVID-19 or hospitalization for another reason in the adult general population in France during the first wave of the current pandemic. METHODS: We conducted a retrospective longitudinal nationwide study based on the national French administrative healthcare database. RESULTS: Among the 2,894,088 adults hospitalized, 96,313 (3.32%) were admitted for COVID-19. The proportion of patients subsequently hospitalized for a psychiatric disorder was higher for COVID-19 patients (11.09 vs. 9.24%, OR = 1.20 95%CI 1.18-1.23). Multivariable analyses provided similar results for a psychiatric disorder of any type and for psychotic and anxiety disorders (respectively, aOR = 1.06 95%CI 1.04-1.09, aOR = 1.09 95%CI 1.02-1.17, and aOR = 1.11 95%CI 1.08-1.14). Initial hospitalization for COVID-19 in intensive care units and psychiatric history were associated with a greater risk of subsequent hospitalization for any psychiatric disorder than initial hospitalization for another reason. DISCUSSION: Compared with hospitalizations for other reasons, hospitalizations for COVID-19 during the first wave of the pandemic in France were associated with a higher risk of hospitalization for a psychiatric disorder during the 12 months following initial discharge. This finding should encourage clinicians to increase the monitoring and assessment of psychiatric symptoms after hospital discharge for COVID-19, and to propose post-hospital care, especially for those treated in intensive care.

Mediation models of anxiety and depression between temperament and drive for thinness and body dissatisfaction in anorexia nervosa.

PURPOSE: Anorexia nervosa (AN) is a life-threatening condition in which temperament, anxiety, depression, and core AN body-related psychopathology (drive for thinness, DT, and body dissatisfaction, BD) are intertwined. This relationship has not been to date disentangled; therefore, we performed a multiple mediation analysis aiming to quantify the effect of each component. METHODS: An innovative multiple mediation statistical method has been applied to data from 184 inpatients with AN completing: Temperament Evaluation of Memphis, Pisa, Paris, and San Diego Autoquestionnaire, Eating Disorders Inventory-2, State-Trait Anxiety Inventory, and Beck Depression Inventory. RESULTS: All affective temperaments but the hyperthymic one were involved in the relationship with DT and BD. Only the anxious temperament had a significant unmediated direct effect on DT after the strictest correction for multiple comparisons, while the depressive temperament had a significant direct effect on DT at a less strict significance level. State anxiety was the strongest mediator of the link between affective temperament and core AN body-related psychopathology. Depression showed intermediate results while trait anxiety was not a significant mediator at all. CONCLUSION: Affective temperaments had a relevant impact on body-related core components of AN; however, a clear direct effect could be identified only for the anxious and depressive temperaments. Also, state anxiety was the strongest mediator thus entailing interesting implications in clinical practice. LEVEL OF EVIDENCE: V, cross-sectional study.

Application of two statistical approaches (Bayesian Kernel Machine Regression and Principal Component Regression) to assess breast cancer risk in association to exposure to mixtures of brominated flame retardants and per- and polyfluorinated alkylated substances in the E3N cohort.

BACKGROUND: Brominated flame retardants (BFR) and per- and polyfluorinated alkylated substances (PFAS) are two groups of substances suspected to act as endocrine disruptors. Such substances could therefore be implicated in the occurrence of breast cancer, nevertheless, previous studies have led to inconstant results. Due to the large correlation between these substances, and the possibly non-linear effects they exert, evaluating their joint impact as mixtures on health remains challenging. This exploratory study aimed to generate hypotheses on the relationship between circulating levels of 7 BFR (6 polybrominated diphenyl ethers and 1 polybrominated biphenyls) and 11 PFAS and the risk of breast cancer in a case-control study nested in the E3N French prospective cohort by performing two methods: Principal Component Regression (PCR) models, and Bayesian Kernel Machine Regression (BKMR) models. METHODS: 194 post-menopausal breast cancer cases and 194 controls were included in the present study. Circulating levels of BFR and PFAS were measured by gas chromatography coupled to high-resolution mass spectrometry and liquid chromatography coupled to tandem mass spectrometry, respectively. The first statistical approach was based on Principal Component Analysis (PCA) followed by logistic regression models that included the identified principal components as main exposure variables. The second approach used BKMR models with hierarchical variable selection, this latter being suitable for highly correlated exposures. Both approaches were also run separately for Estrogen Receptor positive (ER +) and Estrogen Receptor negative (ER-) breast cancer cases. RESULTS: PCA identified four principal components accounting for 67% of the total variance. Component 3 showed a marginal association with ER + breast cancer risk. No clear association between BFR and PFAS mixtures and breast cancer was identified using BKMR models, and the credible intervals obtained were very wide. Finally, the BKMR models suggested a negative cumulative effect of BFR and PFAS on ER- breast cancer risk, and a positive cumulative effect on ER + breast cancer risk. CONCLUSION: Although globally no clear association was identified, both approaches suggested a differential effect of BFR and PFAS mixtures on ER + and ER- breast cancer risk. However, the results for ER- breast cancer should be interpreted carefully due to the small number of ER- cases included in the study. Further studies evaluating mixtures of substances on larger study populations are needed.

Associations between plasma levels of brominated flame retardants and methylation of DNA from peripheral blood: A cross-sectional study in a cohort of French women.

BACKGROUND: Brominated flame retardants (BFRs) are organic compounds that are widespread in the environment. Because of their persistence, they are able to bioaccumulate with major impacts on human health. It has been hypothesized that the effect of BFRs on human health is mediated by alterations of DNA methylation. OBJECTIVE: The aim of this study was to examine the association between methylation of DNA extracted from peripheral blood and circulating levels of BFRs measured in plasma. METHODS: We conducted a methylation wide association study on 336 blood samples from a study within the E3N (Etude Epidémiologique auprès de femmes de l'Education Nationale) cohort, a long-term longitudinal cohort of French women. DNA methylation at more than 850 000 cytosine-guanine dinucleotide (CpG) sites was measured with the Illumina Infinium HumanMethylation - EPIC BeadChip. Circulating levels of seven BFRs (BDE-28, BDE-47, BDE-99, BDE-100, BDE-153, BDE-154 and PBB-153) were measured by gas chromatography coupled to high-resolution mass spectrometry in plasma samples. The association between DNA methylation and BFRs plasma levels was assessed through linear mixed-effects models followed by gene-set enrichment analyses (GSEA). RESULTS: We identified 253 CpG sites whose methylation levels were significantly associated with exposure to BFRs after Bonferroni correction. For 50 of these CpGs the p-values were less than 2.2x10-9 with the strongest association being between BDE-154 and cg23619365 (4.32x10-13). GSEA of CpG sites associated with exposure to BFRs identified significant enrichment of genes involved in hypoxia, glycolysis and adipogenesis. CONCLUSIONS: Exposure to BFRs appears to be related to numerous alterations in DNA methylation. These findings, if replicated in independent studies, provide insights into the biological and health effects of BFRs.

Error rate control for classification rules in multiclass mixture models.

In the context of finite mixture models one considers the problem of classifying as many observations as possible in the classes of interest while controlling the classification error rate in these same classes. Similar to what is done in the framework of statistical test theory, different type I and type II-like classification error rates can be defined, along with their associated optimal rules, where optimality is defined as minimizing type II error rate while controlling type I error rate at some nominal level. It is first shown that finding an optimal classification rule boils down to searching an optimal region in the observation space where to apply the classical Maximum A Posteriori (MAP) rule. Depending on the misclassification rate to be controlled, the shape of the optimal region is provided, along with a heuristic to compute the optimal classification rule in practice. In particular, a multiclass FDR-like optimal rule is defined and compared to the thresholded MAP rules that is used in most applications. It is shown on both simulated and real datasets that the FDR-like optimal rule may be significantly less conservative than the thresholded MAP rule.

Genetic architectures of proximal and distal colorectal cancer are partly distinct.

OBJECTIVE: An understanding of the etiologic heterogeneity of colorectal cancer (CRC) is critical for improving precision prevention, including individualized screening recommendations and the discovery of novel drug targets and repurposable drug candidates for chemoprevention. Known differences in molecular characteristics and environmental risk factors among tumors arising in different locations of the colorectum suggest partly distinct mechanisms of carcinogenesis. The extent to which the contribution of inherited genetic risk factors for CRC differs by anatomical subsite of the primary tumor has not been examined. DESIGN: To identify new anatomical subsite-specific risk loci, we performed genome-wide association study (GWAS) meta-analyses including data of 48 214 CRC cases and 64 159 controls of European ancestry. We characterised effect heterogeneity at CRC risk loci using multinomial modelling. RESULTS: We identified 13 loci that reached genome-wide significance (p<5×10-8) and that were not reported by previous GWASs for overall CRC risk. Multiple lines of evidence support candidate genes at several of these loci. We detected substantial heterogeneity between anatomical subsites. Just over half (61) of 109 known and new risk variants showed no evidence for heterogeneity. In contrast, 22 variants showed association with distal CRC (including rectal cancer), but no evidence for association or an attenuated association with proximal CRC. For two loci, there was strong evidence for effects confined to proximal colon cancer. CONCLUSION: Genetic architectures of proximal and distal CRC are partly distinct. Studies of risk factors and mechanisms of carcinogenesis, and precision prevention strategies should take into consideration the anatomical subsite of the tumour.

Adiposity and Endometrial Cancer Risk in Postmenopausal Women: A Sequential Causal Mediation Analysis.

BACKGROUND: Adiposity increases endometrial cancer risk, possibly through inflammation, hyperinsulinemia, and increasing estrogens. We aimed to quantify the mediating effects of adiponectin (anti-inflammatory adipocytokine); IL6, IL1-receptor antagonist, TNF receptor 1 and 2, and C-reactive protein (inflammatory status biomarkers); C-peptide (hyperinsulinemia biomarker); and free estradiol and estrone (estrogen biomarkers) in the adiposity-endometrial cancer link in postmenopausal women. METHODS: We used data from a case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC). Eligible women did not have cancer, hysterectomy, and diabetes; did not use oral contraceptives or hormone therapy; and were postmenopausal at recruitment. Mediating pathways from adiposity to endometrial cancer were investigated by estimating natural indirect (NIE) and direct (NDE) effects using sequential mediation analysis. RESULTS: The study included 163 cases and 306 controls. The adjusted OR for endometrial cancer for body mass index (BMI) ≥30 versus ≥18.5-<25 kg/m2 was 2.51 (95% confidence interval, 1.26-5.02). The ORsNIE were 1.95 (1.01-3.74) through all biomarkers [72% proportion mediated (PM)] decomposed as: 1.35 (1.06-1.73) through pathways originating with adiponectin (33% PM); 1.13 (0.71-1.80) through inflammation beyond (the potential influence of) adiponectin (13% PM); 1.05 (0.88-1.24) through C-peptide beyond adiponectin and inflammation (5% PM); and 1.22 (0.89-1.67) through estrogens beyond preceding biomarkers (21% PM). The ORNDE not through biomarkers was 1.29 (0.54-3.09). Waist circumference gave similar results. CONCLUSIONS: Reduced adiponectin and increased inflammatory biomarkers, C-peptide, and estrogens mediated approximately 70% of increased odds of endometrial cancer in women with obesity versus normal weight. IMPACT: If replicated, these results could have implications for identifying targets for intervention to reduce endometrial cancer risk in women with obesity.

The impact of lifecourse socio-economic position and individual social mobility on breast cancer risk.

BACKGROUND: Women with an advantaged socioeconomic position (SEP) have a higher risk of developing breast cancer (BC). The reasons for this association do not seem to be limited to reproductive factors and remain to be understood. We aimed to investigate the impact of lifecourse SEP from childhood and social mobility on the risk of BC considering a broad set of potential mediators. METHODS: We used a discovery-replication strategy in two European prospective cohorts, E3N (N = 83,436) and EPIC-Italy (N = 20,530). In E3N, 7877 women were diagnosed with BC during a median 24.4 years of follow-up, while in EPIC-Italy, 893 BC cases were diagnosed within 15.1 years. Hazard ratios (HR) were estimated using Cox proportional hazard models on imputed data. RESULTS: In E3N, women with higher education had a higher risk of BC (HR [95%CI] = 1.21 [1.12, 1.30]). This association was attenuated by adjusting for reproductive factors, in particular age at first childbirth (HR[95%CI] = 1.13 [1.04, 1.22]). Health behaviours, anthropometric variables, and BC screening had a weaker effect on the association. Women who remained in a stable advantaged SEP had a higher risk of BC (HR [95%CI] = 1.24 [1.07; 1.43]) attenuated after adjustment for potential mediators (HR [95%CI] = 1.13 [0.98; 1.31]). These results were replicated in EPIC-Italy. CONCLUSIONS: These results confirm the important role of reproductive factors in the social gradient in BC risk, which does not appear to be fully explained by the large set of potential mediators, including cancer screening, suggesting that further research is needed to identify additional mechanisms.

Causal mediation analysis in presence of multiple mediators uncausally related.

Mediation analysis aims at disentangling the effects of a treatment on an outcome through alternative causal mechanisms and has become a popular practice in biomedical and social science applications. The causal framework based on counterfactuals is currently the standard approach to mediation, with important methodological advances introduced in the literature in the last decade, especially for simple mediation, that is with one mediator at the time. Among a variety of alternative approaches, Imai et al. showed theoretical results and developed an R package to deal with simple mediation as well as with multiple mediation involving multiple mediators conditionally independent given the treatment and baseline covariates. This approach does not allow to consider the often encountered situation in which an unobserved common cause induces a spurious correlation between the mediators. In this context, which we refer to as mediation with uncausally related mediators, we show that, under appropriate hypothesis, the natural direct and joint indirect effects are non-parametrically identifiable. Moreover, we adopt the quasi-Bayesian algorithm developed by Imai et al. and propose a procedure based on the simulation of counterfactual distributions to estimate not only the direct and joint indirect effects but also the indirect effects through individual mediators. We study the properties of the proposed estimators through simulations. As an illustration, we apply our method on a real data set from a large cohort to assess the effect of hormone replacement treatment on breast cancer risk through three mediators, namely dense mammographic area, nondense area and body mass index.

Mediating effect of soluble B-cell activation immune markers on the association between anthropometric and lifestyle factors and lymphoma development.

Sustained B-cell activation is an important mechanism contributing to B-cell lymphoma (BCL). We aimed to validate four previously reported B-cell activation markers predictive of BCL risk (sCD23, sCD27, sCD30, and CXCL13) and to examine their possible mediating effects on the association between anthropometric and lifestyle factors and major BCL subtypes. Pre-diagnostic serum levels were measured for 517 BCL cases and 525 controls in a nested case-control study. The odds ratios of BCL were 6.2 in the highest versus lowest quartile for sCD23, 2.6 for sCD30, 4.2 for sCD27, and 2.6 for CXCL13. Higher levels of all markers were associated with increased risk of chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), and diffuse large B-cell lymphoma (DLBCL). Following mutual adjustment for the other immune markers, sCD23 remained associated with all subtypes and CXCL13 with FL and DLBCL. The associations of sCD23 with CLL and DLBCL and CXCL13 with DLBCL persisted among cases sampled > 9 years before diagnosis. sCD23 showed a good predictive ability (area under the curve = 0.80) for CLL, in particular among older, male participants. sCD23 and CXCL13 showed a mediating effect between body mass index (positive) and DLBCL risk, while CXCL13 contributed to the association between physical activity (inverse) and DLBCL. Our data suggest a role of B-cell activation in BCL development and a mediating role of the immune system for lifestyle factors.

Systematic review with meta-analysis: comparative risk of lymphoma with anti-tumour necrosis factor agents and/or thiopurines in patients with inflammatory bowel disease.

BACKGROUND: The risk of lymphoma in patients with inflammatory bowel disease (IBD) treated with anti-TNF agents remains unclear. AIM: To assess the comparative risk of lymphoma with anti-TNF agents and/or thiopurines in IBD METHODS: We searched PubMed, EMBASE and Cochrane Library to identify studies that evaluated lymphoproliferative disorders associated with anti-TNF agents with or without thiopurines. The risk of lymphoma was assessed through four comparator groups: combination therapy (anti-TNF plus thiopurine), anti-TNF monotherapy, thiopurine monotherapy and control group. Pooled incidence rate ratios (IRR) were estimated through Poisson-normal models. RESULTS: Four observational studies comprising 261 689 patients were included. As compared with patients unexposed to anti-TNF and thiopurines, those exposed to anti-TNF monotherapy, thiopurine monotherapy or combination therapy had pooled IRR (per 1000 patient-years) of lymphoma of 1.52 (95% CI: 1.06-2.19; P = 0.023), 2.23 (95% CI: 1.79-2.79; P < 0.001) and 3.71 (95% CI: 2.30-6.00; P ≤ 0.01), respectively. The risk of lymphoma associated with combination therapy was higher than with thiopurines or anti-TNF alone with pooled IRR of 1.70 (95% CI: 1.03-2.81; P = 0.039) and 2.49 (95% CI: 1.39-4.47; P = 0.002), respectively. The risk did not differ between anti-TNF monotherapy and thiopurine monotherapy with pooled IRR of 0.72 (95% CI: 0.48-1.07; P = 0.107). All observational studies were of high quality according to the Newcastle-Ottawa scale. CONCLUSIONS: There is an increased risk of lymphoma in IBD patients treated with anti-TNF agents, either alone or when combined with thiopurines.

Predicting breast cancer metastasis from whole-blood transcriptomic measurements.

OBJECTIVE: In this exploratory work we investigate whether blood gene expression measurements predict breast cancer metastasis. Early detection of increased metastatic risk could potentially be life-saving. Our data comes from the Norwegian Women and Cancer epidemiological cohort study. The women who contributed to these data provided a blood sample up to a year before receiving a breast cancer diagnosis. We estimate a penalized maximum likelihood logistic regression. We evaluate this in terms of calibration, concordance probability, and stability, all of which we estimate by the bootstrap. RESULTS: We identify a set of 108 candidate predictor genes that exhibit a fold change in average metastasized observation where there is none for the average non-metastasized observation.