Patterns of fish and whale consumption in relation to methylmercury in hair among residents of Western Canadian Arctic communities.

BACKGROUND: Methylmercury contamination of the environment represents a substantial environmental health concern. Human exposure to methylmercury occurs primarily through consumption of fish and marine mammals. Heavily exposed subgroups include sport or subsistence fishers residing in Arctic communities. We aimed to estimate the association of fish/whale consumption patterns of Canadian Arctic subsistence fishers with the internal dose of methylmercury as measured in hair. METHODS: This research was conducted within ongoing community projects led by the CANHelp Working Group in Aklavik and Fort McPherson, Northwest Territories and Old Crow, Yukon. We interviewed each participant using a fish-focused food-frequency questionnaire during September-November 2016 and collected hair samples concurrently. Methylmercury was measured in the full-length of each hair sample using gas chromatography inductively-coupled plasma-mass spectrometry. Multivariable linear regression estimated beta-coefficients and 95% confidence intervals (CIs) for the effect of fish/whale consumption on hair-methylmercury concentrations. RESULTS: Among 101 participants who provided hair samples and diet data, the mean number of fish/whale species eaten was 3.5 (SD:1.9). The mean hair-methylmercury concentration was 0.60 µg/g (SD:0.47). Fish/whale consumption was positively associated with hair-methylmercury concentration, after adjusting for sex, hair length and use of permanent hair treatments. Hair-methylmercury concentrations among participants who consumed the most fish/whale in each season ranged from 0.30-0.50 µg/g higher than those who consumed < 1 meal/week. CONCLUSIONS: In this population of Canadian Arctic subsistence fishers, hair-methylmercury concentration increased with fish/whale consumption, but the maximum concentrations were below Health Canada's 6.0 µg/g threshold for safe exposure.

Regional Variability in Survival for Patients Diagnosed with Selected Central Nervous System Tumours in Canada.

Canada's decentralized healthcare system may lead to regional disparities in survival among Canadians diagnosed with central nervous system (CNS) tumours. We identified 50,670 patients diagnosed with a first-ever primary CNS tumour between 2008 and 2017 with follow-up until 31 December 2017. We selected the four highest incidence histologies and used proportional hazard regression to estimate hazard ratios (HRs) for five regions (British Columbia, Prairie Provinces, Ontario, Atlantic Provinces and the Territories), adjusting for sex, tumour behaviour and patient age. Ontario had the best survival profile for all histologies investigated. The Atlantic Provinces had the highest HR for glioblastoma (HR = 1.26, 95% CI: 1.18-1.35) and malignant glioma not otherwise specified (NOS) (Overall: HR = 1.87, 95% CI:1.43-2.43; Pediatric population: HR = 2.86, 95% CI: 1.28-6.39). For meningioma, the Territories had the highest HR (HR = 2.44, 95% CI: 1.09-5.45) followed by the Prairie Provinces (HR = 1.52, 95% CI: 1.38-1.67). For malignant unclassified tumours, the highest HRs were in British Columbia (HR = 1.45, 95% CI: 1.22-1.71) and the Atlantic Provinces (HR = 1.40, 95% CI: 1.13-1.74). There are regional differences in the survival of CNS patients at the population level for all four specific histological types of CNS tumours investigated. Factors contributing to these observed regional survival differences are unknown and warrant further investigation.

Diagnostic utility of DNA methylation analysis in genetically unsolved pediatric epilepsies and CHD2 episignature refinement.

Sequence-based genetic testing identifies causative variants in ~ 50% of individuals with developmental and epileptic encephalopathies (DEEs). Aberrant changes in DNA methylation are implicated in various neurodevelopmental disorders but remain unstudied in DEEs. We interrogate the diagnostic utility of genome-wide DNA methylation array analysis on peripheral blood samples from 582 individuals with genetically unsolved DEEs. We identify rare differentially methylated regions (DMRs) and explanatory episignatures to uncover causative and candidate genetic etiologies in 12 individuals. Using long-read sequencing, we identify DNA variants underlying rare DMRs, including one balanced translocation, three CG-rich repeat expansions, and four copy number variants. We also identify pathogenic variants associated with episignatures. Finally, we refine the CHD2 episignature using an 850 K methylation array and bisulfite sequencing to investigate potential insights into CHD2 pathophysiology. Our study demonstrates the diagnostic yield of genome-wide DNA methylation analysis to identify causal and candidate variants as 2% (12/582) for unsolved DEE cases.

Incidence and survival of primary central nervous system tumors diagnosed in 4 Canadian provinces from 2010 to 2015.

Background: The Brain Tumor Registry of Canada was established in 2016 to enhance infrastructure for surveillance and clinical research on Central Nervous System (CNS) tumors. We present information on primary CNS tumors diagnosed among residents of Canada from 2010 to 2015. Methods: Data from 4 provincial cancer registries were analyzed representing approximately 67% of the Canadian population. Age-standardized incidence rates (ASIR) and 95% confidence intervals (CI) were calculated using the 2011 Canadian population age distribution. Net survival was estimated using the Pohar-Perme method. Results: A total of 31 644 primary tumors were identified for an ASIR of 22.8 per 100 000 person-years. Nonmalignant tumors made up 47.1% of all classified tumors, with mixed behaviors present in over half of histology groupings. Unclassified were 19.5% of all tumors. The most common histological subtypes are meningiomas (ASIR = 5.5 per 100 000 person-years); followed by glioblastomas (ASIR 4.0 per 100 000 person-years). The overall 5-year net survival rate for CNS tumors was 65.5%; females 70.2% and males 60.4%. GBMs continue to be the most lethal CNS tumors for all sex and age groups. Conclusions: The low annual frequency of most CNS tumor subtypes emphasizes the value of population-based data on all primary CNS tumors diagnosed among Canadians. The large number of histological categories including mixed behaviors and the proportion of unclassified tumors emphasizes the need for complete reporting. Variation in incidence and survival across histological groups by sex and age highlights the need for comprehensive and histology-specific reporting. These data can be used to better inform research and health system planning.

The Incidence and Prevalence of Primary Central Nervous System (CNS) Tumours in Canada (2010-2017), and the Survival of Patients Diagnosed with CNS Tumours (2008-2017).

Primary central nervous system (CNS) tumours are heterogeneous, with different treatment pathways and prognoses depending on their histological and molecular classification. Due to their anatomical location, all CNS tumours, regardless of malignancy, can be debilitating. We used vital statistics linked to Canadian Cancer Registry data to estimate the age-standardized incidence rates (ASIR), Kaplan-Meier survival rates (SR), and limited-duration prevalence proportions (PP) of 25 histology-specific CNS tumour groups that were classified based on site and histology. During 2010-2017, 45,115 patients were diagnosed with 47,085 primary CNS tumours, of which 19.0% were unclassified. The average annual ASIR was 21.48/100,000 person-years and did not vary by sex. The ASIR increased with age, particularly for meningioma, unclassified tumours, and glioblastoma. The eight-year PP was 102.1/100,000 persons (index date 1 January 2018). The most common histology was meningioma (ASIR: 5.19; PP: 31.6). The overall five-year SR among 51,310 patients diagnosed during 2008-2017 was 57.2% (95% CI: 56.8-57.7%). SRs varied by tumour behaviour, histology, and patient age, with the lowest SR among glioblastoma patients (5-year SRs ranged from 1.3-25.7%). For non-malignant tumours, the 5-year SRs ranged from 37.4-100%. We provide the most up-to-date histology-specific surveillance estimates for primary CNS tumours in Canada.

Diagnostic Utility of Genome-wide DNA Methylation Analysis in Genetically Unsolved Developmental and Epileptic Encephalopathies and Refinement of a CHD2 Episignature.

Sequence-based genetic testing currently identifies causative genetic variants in ∼50% of individuals with developmental and epileptic encephalopathies (DEEs). Aberrant changes in DNA methylation are implicated in various neurodevelopmental disorders but remain unstudied in DEEs. Rare epigenetic variations ("epivariants") can drive disease by modulating gene expression at single loci, whereas genome-wide DNA methylation changes can result in distinct "episignature" biomarkers for monogenic disorders in a growing number of rare diseases. Here, we interrogate the diagnostic utility of genome-wide DNA methylation array analysis on peripheral blood samples from 516 individuals with genetically unsolved DEEs who had previously undergone extensive genetic testing. We identified rare differentially methylated regions (DMRs) and explanatory episignatures to discover causative and candidate genetic etiologies in 10 individuals. We then used long-read sequencing to identify DNA variants underlying rare DMRs, including one balanced translocation, three CG-rich repeat expansions, and two copy number variants. We also identify pathogenic sequence variants associated with episignatures; some had been missed by previous exome sequencing. Although most DEE genes lack known episignatures, the increase in diagnostic yield for DNA methylation analysis in DEEs is comparable to the added yield of genome sequencing. Finally, we refine an episignature for CHD2 using an 850K methylation array which was further refined at higher CpG resolution using bisulfite sequencing to investigate potential insights into CHD2 pathophysiology. Our study demonstrates the diagnostic yield of genome-wide DNA methylation analysis to identify causal and candidate genetic causes as ∼2% (10/516) for unsolved DEE cases.

Brain Metastases among Cancer Patients Diagnosed from 2010-2017 in Canada: Incidence Proportion at Diagnosis and Estimated Lifetime Incidence.

The incidence of BM among Canadian cancer patients is unknown. We aimed to estimate IP of BM at the time of cancer diagnosis and during the lifetime of patients with selected primary cancers. Data on BM at diagnosis from 2010-2017 was obtained from the CCR. Site-specific IPs of BM were estimated from provincial registries containing ≥90% complete data on BM. The CCR IP estimates and the IP estimates from literature were applied to the total diagnosed primary cancers to estimate the number of concurrent BM and lifetime BM from 2010-2017 in Canada, respectively. The annual average number of patients with BM at diagnosis from all cancer sites was approximately 3227. The site-specific IPs of BM at diagnosis were: lung (9.42%; 95% CI: 9.16-9.68%), esophageal (1.58%; 95% CI: 1.15-2.02%), kidney/renal pelvis (1.33%; 95% CI: 1.12-1.54%), skin melanoma (0.73%; 95% CI: 0.61-0.84%), colorectal (0.22%; 95% CI: 0.18-0.26%), and breast (0.21%; 95% CI: 0.17-0.24%). Approximately 76,546 lifetime BM cases (or 5.70% of selected fifteen primary cancers sites) were estimated to have occurred from the 2010-2017 cancer patient cohort. These findings reflect results of population analyses in the US and Denmark. We recommend improved standardization of the collection of BM data within the CCR.

Community-driven research in the canadian arctic: dietary exposure to methylmercury and gastric health outcomes.

Indigenous Arctic Canadians have a higher prevalence of gastric neoplasms relative to North Americans of European ancestry. We investigated the hypothesis that low-dose methylmercury exposure from eating fish/whale increases the risk of gastric cancer in Arctic communities. We used intermediate endpoints from an established model of gastric carcinogenesis: intestinal metaplasia, atrophy, and severe chronic gastritis. During 2008-2012, we obtained gastric biopsies from participants of community-driven projects in 3 communities. In 2016, we collected hair samples to measure methylmercury levels and interviewed them about diet. In cross-sectional analysis, logistic regression estimated odds ratios for the estimated effect of hair-methylmercury concentration on the prevalence of each pathology outcome stratified by selenium intake. Among 80 participants, prevalence of intestinal metaplasia, atrophy and severe chronic gastritis was 17, 29 and 38%, respectively. Adjusted Odds of severe chronic gastritis and atrophy were highest at hair-methylmercury concentrations ≥1µg/g when estimated selenium intake was 0, and approached 0 for all methylmercury levels as estimated selenium intake increased. Gastric pathology increased with methylmercury exposure when selenium intake was low. Though limited by small numbers, these findings suggest selenium ingested by eating fish/whale may counter harmful effects of methylmercury exposure in Arctic populations.

The Importance of Cancer Registry Linkage for Studying Rare Cancers in Prospective Cohorts.

Large prospective cohort studies may offer an opportunity to study the etiology and natural history of rare cancers. Cancer diagnoses in observational cohort studies are often self-reported. Little information exists on the validity of self-reported cancer diagnosis, especially rare cancers, in Canada. This study evaluated the validity of self-reported cancer diagnosis in Alberta's Tomorrow Project (ATP), a provincial cohort in Canada. ATP data were linked to the Alberta Cancer Registry (ACR). The first instance of self-reported cancer in a follow-up survey was compared to the first cancer diagnosis in the ACR after enrollment. The sensitivity and positive predictive value (PPV) were estimated for the reporting of cancer status, reporting of common or rare cancer, and reporting of site-specific cancer. Logistic regression analysis explored factors associated with false positive, false negative, and incorrect cancer site reporting. In the 30,843 ATP participants who consented to registry linkage, there were 810 primary cancer diagnoses in the ACR and 959 self-reports of first cancer post-enrollment, for a cancer status sensitivity of 92.1% (95% CI: 90.0-93.9) and PPV of 77.8% (95% CI: 75.0-80.4). Compared to common cancers, rare cancers had a lower sensitivity (62.8% vs. 89.6%) and PPV (35.8% vs. 84.5%). Participants with a rare cancer were more likely to report an incorrect site than those with a common cancer. Rare cancers were less likely to be captured by active follow-up than common cancers. While rare cancer research may be feasible in large cohort studies, registry linkage is necessary to capture rare cancer diagnoses completely and accurately.

Malignant primary brain and other central nervous system tumors diagnosed in Canada from 2009 to 2013.

BACKGROUND: We present a national surveillance report on malignant primary brain and other central nervous system (CNS) tumors diagnosed in the Canadian population in 2009-2013. METHODS: Patients were identified through the Canadian Cancer Registry, an administrative dataset that includes cancer incidence data from all provinces/territories in Canada. Tumor types were classified by site and histology using the definitions from the Central Brain Tumor Registry of the United States (CBTRUS). Incidence rates (IRs) and 95% confidence intervals (CIs) were calculated per 100000 person-years (py) and age-standardized to the 2011 Canadian population for comparisons within Canada and to the 2000 United States population for comparisons with the US. RESULTS: Overall, 12515 malignant brain and other CNS tumors were diagnosed in the Canadian population in 2009-2013 (IR: 8.71/100000 py; 95% CI: 8.56, 8.86); 7085 were among males (IR: 10.06/100000 py; 95% CI: 9.82, 10.29) and 5430 among females (IR: 7.41/100000 py; 95% CI: 7.22, 7.61). Of these, 12115 were classifiable according to histological subgroups defined by CBTRUS. The most common histology was glioblastoma (IR: 4.06/100000 py; 95% CI: 3.95, 4.16). Among those aged 0-19 years, 1130 malignant brain and CNS tumors were diagnosed in 2009-2013 (IR: 3.36/100000 py; 95% CI: 3.16, 3.56). The most common histology among the pediatric population was embryonal tumor (IR: 0.74/100000 py; 95% CI: 0.65, 0.84). CONCLUSIONS: These data represent an initial detailed report on the frequency and distribution of primary malignant brain and other CNS tumors diagnosed in the Canadian population in 2009-2013. The reported distributions of tumor diagnoses by sex and age reflected expected patterns based on the literature from similar populations. A report incorporating data on nonmalignant primary brain tumors is forthcoming.

Noninvasive Fecal Immunochemical Testing and Fecal Calprotectin Predict Mucosal Healing in Inflammatory Bowel Disease: A Prospective Cohort Study.

BACKGROUND: The noninvasive biomarkers fecal immunochemical testing (FIT) and fecal calprotectin (FCP) are sensitive for prediction of mucosal inflammation in inflammatory bowel disease. However, neither test has yet been shown to independently and accurately predict mucosal healing (MH). We aimed to assess the specificity of noninvasive FIT and FCP for MH prediction. METHODS: In this prospective cohort study of adult inflammatory bowel disease outpatients presenting for colonoscopy, stool samples for FIT and FCP were collected 48 hours before endoscopy. Using MH defined by Simple Endoscopic Score for Crohn's disease (SES-CD = 0), Rutgeert's score (i0), and the Ulcerative Colitis Endoscopic Index of Severity (UCEIS = 3), receiver operator characteristic curves were plotted, and sensitivity, specificity, positive and negative predictive values, and areas under the curve were calculated. Multivariate logistic regression analysis was used to develop a clinical model for noninvasively predicting MH. RESULTS: Eighty patients (40 Crohn's disease and 40 ulcerative colitis) were enrolled. The specificities of FIT <100 ng/mL and FCP <250 µg/g for MH were 0.57 (95% confidence interval, 0.38-0.74) and 0.77 (0.57-0.89), respectively. Positive predictive values for MH for FIT <100 ng/mL and FCP <250 µg/g were 0.78 (0.64-0.87) and 0.77 (0.58-0.90), respectively. In multivariate modeling, combining FIT, FCP, and clinical symptomatic remission improved specificity for MH to 0.90 (0.72-0.97) with positive predictive values of 0.84 (0.60-0.96). Areas under the curve for FIT was higher for patients with ulcerative colitis (0.88) than for patients with Crohn's disease (0.69, P = 0.05). CONCLUSIONS: FIT and FCP have similar performance characteristics for identifying MH. Combined, low FIT, low FCP, and clinical remission are specific for MH.