Laboratory performance of genome-wide cfDNA for copy number variants as compared to prenatal microarray.

BACKGROUND: Noninvasive prenatal testing (NIPT) allows for screening of fetal aneuploidy and copy number variants (CNVs) from cell-free DNA (cfDNA) in maternal plasma. Professional societies have not yet embraced NIPT for fetal CNVs, citing a need for additional performance data. A clinically available genome-wide cfDNA test screens for fetal aneuploidy and CNVs larger than 7 megabases (Mb). RESULTS: This study reviews 701 pregnancies with "high risk" indications for fetal aneuploidy which underwent both genome-wide cfDNA and prenatal microarray. For aneuploidies and CNVs considered 'in-scope' for the cfDNA test (CNVs ≥ 7 Mb and select microdeletions), sensitivity and specificity was 93.8% and 97.3% respectively, with positive and negative predictive values of 63.8% and 99.7% as compared to microarray. When including 'out-of-scope' CNVs on array as false negatives, the sensitivity of cfDNA falls to 48.3%. If only pathogenic out-of-scope CNVs are treated as false negatives, the sensitivity is 63.8%. Of the out-of-scope CNVs identified by array smaller than 7 Mb, 50% were classified as variants of uncertain significance (VUS), with an overall VUS rate in the study of 2.29%. CONCLUSIONS: While microarray provides the most robust assessment of fetal CNVs, this study suggests that genome-wide cfDNA can reliably screen for large CNVs in a high-risk cohort. Informed consent and adequate pretest counseling are essential to ensuring patients understand the benefits and limitations of all prenatal testing and screening options.

Modified multiple marker aneuploidy screening as a primary screening test for preeclampsia.

BACKGROUND: Abnormal levels of maternal biochemical markers used in multiple marker aneuploidy screening have been associated with adverse pregnancy outcomes. This study aims to assess if a combination of maternal characteristics and biochemical markers in the first and second trimesters can be used to screen for preeclampsia (PE). The secondary aim was to assess this combination in identifying pregnancies at risk for gestational hypertension and preterm birth. METHODS: This case-control study used information on maternal characteristics and residual blood samples from pregnant women who have undergone multiple marker aneuploidy screening. The median multiple of the median (MoM) of first and second trimester biochemical markers in cases (women with PE, gestational hypertension and preterm birth) and controls were compared. Biochemical markers included pregnancy-associated plasma protein A (PAPP-A), placental growth factor (PlGF), human chorionic gonadotropin (hCG), alpha feto-protein (AFP), unconjugated estriol (uE3) and Inhibin A. Logistic regression analysis was used to estimate screening performance using different marker combinations. Screening performance was defined as detection rate (DR) and false positive rate (FPR). Preterm and early-onset preeclampsia PE were defined as women with PE who delivered at < 37 and < 34 weeks of gestation, respectively. RESULTS: There were 147 pregnancies with PE (81 term, 49 preterm and 17 early-onset), 295 with gestational hypertension, and 166 preterm birth. Compared to controls, PE cases had significantly lower median MoM of PAPP-A (0.77 vs 1.10, p < 0.0001), PlGF (0.76 vs 1.01, p < 0.0001) and free-ß hCG (0.81 vs. 0.98, p < 0.001) in the first trimester along with PAPP-A (0.82 vs 0.99, p < 0.01) and PlGF (0.75 vs 1.02, p < 0.0001) in the second trimester. The lowest first trimester PAPP-A, PlGF and free ß-hCG were seen in those with preterm and early-onset PE. At a 20% FPR, 67% of preterm and 76% of early-onset PE cases can be predicted using a combination of maternal characteristics with PAPP-A and PlGF in the first trimester. The corresponding DR was 58% for gestational hypertension and 36% for preterm birth cases. CONCLUSIONS: Maternal characteristics with first trimester PAPP-A and PlGF measured for aneuploidy screening provided reasonable accuracy in identifying women at risk of developing early onset PE, allowing triage of high-risk women for further investigation and risk-reducing therapy. This combination was less accurate in predicting women who have gestational hypertension or preterm birth.

Building the What Comes Next Cohort for BRCA1 and BRCA2 testing: a descriptive analysis.

BACKGROUND: Our understanding of how testing for and mutations of the BRCA1 and BRCA2 genes affect cancer risk and the use of risk-reduction strategies comes largely from studies of women recruited from specialized genetics clinics. Our aim was to assemble a generalizable cohort of women who underwent BRCA1/BRCA2 testing (the What Comes Next Cohort), irrespective of test result, to enable study of health care utilization and outcomes after testing. METHODS: This descriptive study included adult women (≥ 18 yr) who met at least 1 of 13 provincial criteria for BRCA1/BRCA2 testing and who underwent genetic testing at sites in Ontario, Canada, from 2007 to 2016. Most of the women were tested at 1 of 2 main sites, which together capture about 70% of all BRCA1/BRCA2 testing in the province. We collected detailed demographic, genetic testing and family history data through chart review for linkage with data from administrative health databases providing information on cancer history before and after testing. We followed all women to September 2019, evaluating the demographic characteristics of the cohort, indications for testing and test results. RESULTS: We identified 15 986 women (mean age 52.5 [standard deviation 13.9] yr) who underwent BRCA1/BRCA2 testing. Of these, 2033 women had positive results, 1175 women had variants of uncertain significance, and 12 778 women had negative results. Positive yields were 41.0% (955/2329) for predictive testing (for familial variants), 10.4% (216/2072) for Ashkenazi Jewish founder testing and 7.4% (862/11 585) for complete gene analysis. Six of the 13 provincial testing criteria had less than 10% positive yield. Among 403 women who tested negative for Ashkenazi Jewish founder mutations and subsequently underwent complete gene analysis, 12 (3.0%) tested positive for alternate pathogenic or likely pathogenic variants in the BRCA1 or BRCA2 gene. INTERPRETATION: Several provincial eligibility criteria for BRCA1/BRCA2 testing led to positive results in less than 10% of cases. How testing influences women's health care behaviours, particularly those with negative results and those found to carry variants of uncertain significance, is unknown; the What Comes Next Cohort will be instrumental in the study of long-term implications of BRCA1/BRCA2 testing.

Risk of Severe Maternal Morbidity or Death in Relation to Prenatal Biochemical Screening: Population-Based Cohort Study.

OBJECTIVE: This study aimed to examine whether prenatal biochemical screening analytes are associated with an increased risk of severe maternal morbidity (SMM) or maternal mortality. STUDY DESIGN: This population-based cohort study includes all women in Ontario, Canada, who underwent prenatal screening from 2001 to 2011. Increasing fifth percentiles of the multiple of the median (MoM) for alphafetoprotein (AFP), total human chorionic gonadotropin, unconjugated estriol (uE3), dimeric inhibin-A (DIA), and pregnancy-associated plasma protein A were evaluated. An abnormally high concentration (>95th percentile MoM) for each analyte, individually and combined, was also evaluated. The main outcome assessed was the adjusted relative risk (aRR) of SMM or maternal mortality from 20 weeks' gestation up to 26 weeks thereafter. RESULTS: Among 748,972 pregnancies, 11,177 resulted in SMM or maternal mortality (1.5%). Except for uE3, the aRR of SMM or maternal mortality increased in association with increasing fifth percentiles of the MoM for all analytes. AFP (aRR: 2.10; 95% confidence interval [CI]: 1.97-2.25) and DIA (aRR: 2.33; 95% CI: 1.98-2.74) > 95th versus ≤ 5th percentile of the MoM were especially associated with SMM or death. CONCLUSION: Women with abnormally high concentrations of certain prenatal biochemical analytes may be at a higher risk of SMM or death in pregnancy or postpartum.

Prenatal screening for trisomy 21: a comparative performance and cost analysis of different screening strategies.

BACKGROUND: Prenatal screening for chromosome aneuploidies have constantly been evolving, especially with the introduction of cell-free fetal DNA (cfDNA) screening in the most recent years. This study compares the performance, costs and timing of test results of three cfDNA screening implementation strategies: contingent, reflex and primary. METHODS: We modelled enhanced first trimester screening (eFTS) as the first-tier test in contingent or reflex strategies. cfDNA test was performed contingent on or reflex from eFTS results. A comparison was made between cfDNA screening using sequencing technology and Rolling Circle Amplification (RCA)/imaging solution. All model assumptions were based on results from previous publications or information from the Ontario prenatal screening population. RESULTS: At an eFTS risk cut-off of ≥1/1000, contingent and reflex cfDNA screening have the same detection rate (DR) (94%) for trisomy 21. Reflex cfDNA screening using RCA/Imaging solution provided the lowest false positive rate and cost. The number of women requiring genetic counselling and diagnostic testing was significantly reduced and women received their cfDNA screening result 9 days sooner compared with the contingent model. While primary cfDNA screening improved the trisomy 21 DR by 3-5%, it was more costly and more women required diagnostic testing. CONCLUSION: Reflex cfDNA screening is the most cost-effective prenatal screening strategy. It can improve the efficiency of prenatal aneuploidy screening by reducing the number of patient visits and providing more timely results.

Cognitive markers of dementia risk in middle-aged women with bilateral salpingo-oophorectomy prior to menopause.

Oophorectomy prior to menopause is associated with late-life dementia. Memory decline may start within 6 months after oophorectomy in middle-aged women, suggested by lower verbal and working memory performance. Unknown is whether such changes persist beyond 6 months, and whether they are reversed by estradiol. Short-term benefits of estradiol on verbal memory following oophorectomy were observed in one study, but longer term effects remain unknown. In the present study, middle-aged BRCA1/2 mutation carriers with early oophorectomy at least 1 year prior to study onset were tested on verbal and working memory with results stratified by (1) current estradiol use (n = 22) or (2) no history of estradiol use (n = 24), and compared to age-matched premenopausal controls (n = 25). Both memory abilities were adversely affected by oophorectomy, but only working memory was maintained by estradiol. Estrogen metabolite levels correlated with working memory, suggesting a role for estradiol in preserving this ability. Memory decline appears to persist after early oophorectomy, particularly for women who do not take estradiol.

Prenatal Biochemical Screening and a Woman's Long-Term Risk of Cancer: A Population-Based Cohort Study.

BACKGROUND: Some hormones measured in pregnancy are linked to certain hormone-sensitive cancers. We investigated whether routine serum screening in pregnancy is associated with a woman's subsequent risk of hormone-sensitive cancer. METHODS: This population-based cohort study included women aged 12-55 years who underwent prenatal screening between 11 weeks + 0 days of gestation to 20 weeks + 6 days of gestation in Ontario, Canada, 1993-2011, where universal health care is available. The hazard ratio of newly diagnosed breast, ovarian, endometrial, and thyroid cancer-arising at 21 weeks + 0 days of gestation or thereafter-was estimated in association with an abnormally low (≤5th) or high (>95th) percentile multiple of the median (MoM) for alpha-fetoprotein (AFP), total human chorionic gonadotropin (hCG), unconjugated estriol, pregnancy-associated plasma protein A, and dimeric inhibin A. RESULTS: Among 677 247 pregnant women followed for a median of 11.0 years (interquartile range = 7.5-16.1), 7231 (1.07%) developed breast cancer, 515 (0.08%) ovarian cancer, 508 (0.08%) endometrial cancer, and 4105 (0.61%) thyroid cancer. In multivariable adjusted models, abnormally high hCG greater than the 95th percentile MoM was associated with a doubling in the risk of endometrial cancer (adjusted hazard ratio [aHR] = 1.98, 95% confidence interval [CI] = 1.33 to 2.95), and abnormally low AFP at the fifth percentile or less MoM conferred a moderately greater risk of thyroid cancer (aHR = 1.21, 95% CI = 1.07 to 1.38). Abnormally low pregnancy-associated plasma protein A at the fifth percentile or less MoM was not statistically significantly associated with breast cancer after multivariable adjustment (aHR = 1.19, 95% CI = 0.98 to 1.36). CONCLUSIONS: Women with abnormally high levels of serum hCG or low AFP in early pregnancy may be at a greater future risk of certain types of hormone-sensitive cancers.

De novo TBR1 variants cause a neurocognitive phenotype with ID and autistic traits: report of 25 new individuals and review of the literature.

TBR1, a T-box transcription factor expressed in the cerebral cortex, regulates the expression of several candidate genes for autism spectrum disorders (ASD). Although TBR1 has been reported as a high-confidence risk gene for ASD and intellectual disability (ID) in functional and clinical reports since 2011, TBR1 has only recently been recorded as a human disease gene in the OMIM database. Currently, the neurodevelopmental disorders and structural brain anomalies associated with TBR1 variants are not well characterized. Through international data sharing, we collected data from 25 unreported individuals and compared them with data from the literature. We evaluated structural brain anomalies in seven individuals by analysis of MRI images, and compared these with anomalies observed in TBR1 mutant mice. The phenotype included ID in all individuals, associated to autistic traits in 76% of them. No recognizable facial phenotype could be identified. MRI analysis revealed a reduction of the anterior commissure and suggested new features including dysplastic hippocampus and subtle neocortical dysgenesis. This report supports the role of TBR1 in ID associated with autistic traits and suggests new structural brain malformations in humans. We hope this work will help geneticists to interpret TBR1 variants and diagnose ASD probands.

New insights into DNA methylation signatures: SMARCA2 variants in Nicolaides-Baraitser syndrome.

BACKGROUND: Nicolaides-Baraitser syndrome (NCBRS) is a neurodevelopmental disorder caused by pathogenic sequence variants in SMARCA2 which encodes the catalytic component of the chromatin remodeling BAF complex. Pathogenic variants in genes that encode epigenetic regulators have been associated with genome-wide changes in DNA methylation (DNAm) in affected individuals termed DNAm signatures. METHODS: Genome-wide DNAm was assessed in whole-blood samples from the individuals with pathogenic SMARCA2 variants and NCBRS diagnosis (n = 8) compared to neurotypical controls (n = 23) using the Illumina MethylationEPIC array. Differential methylated CpGs between groups (DNAm signature) were identified and used to generate a model enabling classification variants of uncertain significance (VUS; n = 9) in SMARCA2 as "pathogenic" or "benign". A validation cohort of NCBRS cases (n = 8) and controls (n = 96) demonstrated 100% model sensitivity and specificity. RESULTS: We identified a DNAm signature of 429 differentially methylated CpG sites in individuals with NCBRS. The genes to which these CpG sites map are involved in cell differentiation, calcium signaling, and neuronal function consistent with NCBRS pathophysiology. DNAm model classifications of VUS were concordant with the clinical phenotype; those within the SMARCA2 ATPase/helicase domain classified as "pathogenic". A patient with a mild neurodevelopmental NCBRS phenotype and a VUS distal to the ATPase/helicase domain did not score as pathogenic, clustering away from cases and controls. She demonstrated an intermediate DNAm profile consisting of one subset of signature CpGs with methylation levels characteristic of controls and another characteristic of NCBRS cases; each mapped to genes with ontologies consistent with the patient's unique clinical presentation. CONCLUSIONS: Here we find that a DNAm signature of SMARCA2 pathogenic variants in NCBRS maps to CpGs relevant to disorder pathophysiology, classifies VUS, and is sensitive to the position of the variant in SMARCA2. The patient with an intermediate model score demonstrating a unique genotype-epigenotype-phenotype correlation underscores the potential utility of this signature as a functionally relevant VUS classification system scalable beyond binary "benign" versus "pathogenic" scoring. This is a novel feature of DNAm signatures that could enable phenotypic predictions from genotype data. Our findings also demonstrate that DNAm signatures can be domain-specific, highlighting the precision with which they can reflect genotypic variation.

International trends in the uptake of cancer risk reduction strategies in women with a BRCA1 or BRCA2 mutation.

BACKGROUND: Women with a BRCA1 or BRCA2 mutation face high risks of breast and ovarian cancer. In the current study, we report on uptake of cancer screening and risk-reduction options in a cohort of BRCA mutation carriers from ten countries over two time periods (1995 to 2008 and 2009 to 2017). METHODS: Eligible subjects were identified from an international database of female BRCA mutation carriers and included women from 59 centres from ten countries. Subjects completed a questionnaire at the time of genetic testing, which included past use of cancer prevention options and screening tests. Biennial follow-up questionnaires were administered. RESULTS: Six-thousand two-hundred and twenty-three women were followed for a mean of 7.5 years. The mean age at last follow-up was 52.1 years (27-96 years) and 42.3% of the women had a prior diagnosis of breast cancer. In all, 27.8% had a prophylactic bilateral mastectomy and  64.7% had a BSO. Screening with breast MRI increased from 70% before 2009 to 81% at or after 2009. There were significant differences in uptake of all options by country. CONCLUSION: For women who received genetic testing more recently, uptake of prophylactic mastectomy and breast MRI is significantly higher than those who received genetic testing more than 10 years ago. However, uptake of both BSO and breast MRI is not optimal, and interventions to increase uptake are needed.

Hormone Levels in Pregnancy and Subsequent Risk of Maternal Breast and Ovarian Cancer: A Systematic Review.

OBJECTIVE: Some maternal hormone levels in pregnancy are associated with a higher risk of breast and ovarian cancer. This study systematically assessed the association between blood hormone levels measured in pregnancy and future risk of these cancers. METHODS: Two reviewers independently conducted a literature search of MEDLINE and EMBASE databases from January 1970 to August 2017. Studies were included that measured one or more serum hormone levels in pregnancy and later assessed for cancer. Cancer outcomes were considered by cancer type, each in relation to a specific maternal hormone. RESULTS: Eleven studies were included, comprising a total of 57 967 women. The interval between pregnancy and cancer onset varied from 4.1 to 20.5 years. Elevated serum chorionic gonadotropin (two of four studies) and alpha fetoprotein (two of three studies) were each associated with a lower risk of maternal breast cancer, whereas elevated estrone levels suggested a higher risk (one of three studies). Elevated testosterone (one of one study) and androstenedione (one of one study) were each associated with a significantly greater risk of sex-cord stromal ovarian tumours. Higher serum 17-hydroxyprogesterone was associated with an increased risk of sex-cord stromal (one of one study) and epithelial (one of one study) ovarian cancer. CONCLUSION: Observational studies suggest some degree of association between serum hormones measured in pregnancy and a woman's future risk of breast and ovarian cancer. More data are needed to determine sufficiently whether certain blood hormone levels measured in pregnancy are predictive of future cancer risk.

BAFopathies' DNA methylation epi-signatures demonstrate diagnostic utility and functional continuum of Coffin-Siris and Nicolaides-Baraitser syndromes.

Coffin-Siris and Nicolaides-Baraitser syndromes (CSS and NCBRS) are Mendelian disorders caused by mutations in subunits of the BAF chromatin remodeling complex. We report overlapping peripheral blood DNA methylation epi-signatures in individuals with various subtypes of CSS (ARID1B, SMARCB1, and SMARCA4) and NCBRS (SMARCA2). We demonstrate that the degree of similarity in the epi-signatures of some CSS subtypes and NCBRS can be greater than that within CSS, indicating a link in the functional basis of the two syndromes. We show that chromosome 6q25 microdeletion syndrome, harboring ARID1B deletions, exhibits a similar CSS/NCBRS methylation profile. Specificity of this epi-signature was confirmed across a wide range of neurodevelopmental conditions including other chromatin remodeling and epigenetic machinery disorders. We demonstrate that a machine-learning model trained on this DNA methylation profile can resolve ambiguous clinical cases, reclassify those with variants of unknown significance, and identify previously undiagnosed subjects through targeted population screening.

Real-world health services utilisation and outcomes after BRCA1 and BRCA2 testing in Ontario, Canada: the What Comes Next Cohort Study protocol.

INTRODUCTION: Women who have pathogenic mutations in the BRCA1 and BRCA2 genes are at greatly increased risks for breast and ovarian cancers. Although risk-reduction strategies can be undertaken by these women, knowledge regarding the uptake of these strategies is limited. Additionally, the healthcare behaviours of women who receive inconclusive test results are not known. This study protocol describes the creation of a retrospective cohort of women who have undergone genetic testing for BRCA1 and BRCA2, linking genetic test results with administrative data to quantify the uptake of risk-reduction strategies and to assess long-term cancer and non-cancer outcomes after genetic testing. METHODS AND ANALYSIS: Approximately two-thirds of BRCA1 and BRCA2 testing in Ontario, Canada is performed at North York General Hospital (NYGH) and Mount Sinai Hospital (MSH), Toronto. We will use registries at these sites to assemble a cohort of approximately 17 000 adult women who underwent BRCA1 and BRCA2 testing from January 2007 to April 2016. Trained chart abstractors will obtain detailed information for all women tested over this period, including demographics, personal and family cancer histories and genetic test results. We will link these data to provincial administrative databases, enabling assessment of healthcare utilisation and long-term outcomes after testing. Study outcomes will include the uptake of breast cancer screening and prophylactic breast and ovarian surgery, cancer incidence and mortality and incidence of non-cancer health outcomes, including cardiovascular, osteoporotic and neurodegenerative disease. ETHICS AND DISSEMINATION: This study has been approved by the Research Ethics Boards at NYGH (no 16-0035), MSH (no 13-0124) and Sunnybrook Health Sciences Centre (no 275-2016). We plan to disseminate research findings through peer-reviewed publications and presentations at national and international meetings.

Prenatal biochemical screening and long term risk of maternal cardiovascular disease: population based cohort study.

OBJECTIVE: To examine whether abnormal prenatal biochemical screening results are associated with an increased risk of premature cardiovascular disease after pregnancy. DESIGN: Population based cohort study. SETTING: The entire province of Ontario, Canada, where healthcare is universally available. PARTICIPANTS: Women aged 12-55 years, without pre-existing cardiovascular disease, who underwent prenatal screening between 1993 and 2011. One pregnancy per woman was randomly selected. EXPOSURES: Low (≤5th centile multiple of the median) serum total chorionic gonadotropin, unconjugated estriol, and pregnancy associated plasma protein A and high (≥95th centile multiple of the median) alphafetoprotein and dimeric inhibin-A. MAIN OUTCOME MEASURES: Composite of hospital admission or revascularisation for coronary artery, cerebrovascular, or peripheral arterial disease or hospital admission for heart failure or dysrhythmia at least 365 days after pregnancy. RESULTS: Among 855 536 pregnancies, and after a median of 11.4 (interquartile range 6.8-17.5) years of follow-up, 6209 women developed the main cardiovascular disease outcome. Abnormal results for each of the five prenatal biochemical screening analytes, especially dimeric inhibin-A, were associated with a higher risk of cardiovascular disease. Women with an abnormally high dimeric inhibin-A (≥95th centile) had the highest rate of cardiovascular disease (30 events or 8.3 per 10 000 person years versus 251 events or 3.8 per 10 000 person years for those <95th centile; multivariable adjusted hazard ratio 2.0, 95% confidence interval 1.4 to 3.0). Compared with women without any abnormal biochemical measure, the hazard ratio for the cardiovascular disease composite outcome was 1.2-1.3 times higher with one abnormal analyte and 1.5-2.0 times higher with two or more abnormal analytes. CONCLUSIONS: Women with abnormal prenatal biochemical screening results, especially for dimeric inhibin-A, may be at higher risk of cardiovascular disease. If these findings are replicated elsewhere, a massive amount of data exists that could aid in identifying women at higher risk of premature cardiovascular disease and that could be conveyed to them or their healthcare providers.

Evolution of genetic assessment for BRCA-associated gynaecologic malignancies: a Canadian multisociety roadmap.

The landscape of genetic testing in ovarian cancer patients has changed dramatically in recent years. The therapeutic benefits of poly ADP-ribose polymerase (PARP) inhibitors in treatment of BRCA1/2-related ovarian cancers has resulted in an increased demand and urgency for genetic testing results, while technological developments have led to widespread use of multi-gene cancer panels and development of tumour testing protocols. Traditional genetic counselling models are no longer sustainable and must evolve to match the rapid evolution of genetic testing technologies and developments in personalized medicine. Recently, representatives from oncology, clinical genetics, molecular genetics, pathology, and patient advocacy came together to create a national multi-disciplinary Canadian consortium. By aligning stakeholder interests, the BRCA Testing to Treatment (BRCA TtoT) Community of Practice aims to develop a national strategy for tumour and germline BRCA1/2 testing and genetic counselling in women with ovarian cancer. This article serves to provide an overview of the recent evolution of genetic assessment for BRCA1/2-associated gynecologic malignancies and outline a Canadian roadmap to facilitate change, improve genetic testing rates, and ultimately improve outcomes for hereditary ovarian cancer patients and their families.

Enhanced First Trimester Aneuploidy Screening with Placental Growth Factor and Alpha Feto-Protein: Detection of Trisomies 18 and 13.

OBJECTIVES: To assess the performance of first trimester combined screening (FTS) when enhanced with placental growth factor and alpha feto-protein in the detection of trisomies 18 and 13. METHODS: A retrospective case-control study. Marker parameters were derived using frozen serum samples. Multivariate Gaussian modelling predicted the detection rate (DR) and false-positive rate (FPR) for trisomies 18 and 13 with FTS and enhanced first trimester screening (eFTS) using the risk of trisomy 21 alone and an additional risk cut-off for trisomy 18, or trisomies 18 or 13. RESULTS: There were 83 trisomy 18, 22 trisomy 13, and 588 controls. The median placental growth factor levels in trisomies 18 and 13 were 0.75 and 0.65 multiple of the median of controls, respectively (both P < 0.0001). There were no statistically significant differences in alpha feto-protein levels. Modelling predicts that using a trisomy 21 risk cut-off alone, at FPR of 3%, eFTS increases the DR for trisomies 18 and 13 by 0.6-0.8% compared with FTS. Additionally using a trisomy 18 risk cut-off, at an extra FPR of 0.2%, eFTS increased the DR by 0.6-0.9% over FTS; using a trisomy 18 or 13 risk cut-off did not further increase detection for FTS or eFTS. The increase in DR was greater at higher FPR. CONCLUSION: eFTS increases the detection of trisomies 18 and 13 to a small extent.

Physical activity during adolescence and young adulthood and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers.

BACKGROUND: Physical activity is inversely associated with the risk of breast cancer among women in the general population. It is not clear whether or not physical activity is associated with the risk of BRCA-associated breast cancer. METHODS: We conducted a case-control study of 443 matched pairs of BRCA mutation carriers to evaluate the association between physical activity and breast cancer risk. Moderate and vigorous physical activities at ages 12-13, ages 14-17, ages 18-22, ages 23-29 and ages 30-34 were determined using the Nurses' Health Study II Physical Activity Questionnaire. We estimated mean metabolic equivalent task hours/week for moderate, vigorous and total physical activities overall (ages 12-34), during adolescence (ages 12-17) and during early adulthood (ages 18-34). Logistic regression analysis was used to estimate the odds ratios (OR) and 95% confidence intervals (CI) for total, moderate and strenuous recreational physical activities and breast cancer risk, by menopausal status. RESULTS: Overall, there was no significant association between total physical activity and subsequent breast cancer risk (ORQ4 vs. Q1 = 1.01, 95% CI 0.69-1.47; P-trend = 0.72). Moderate physical activity between ages 12-17 was associated with a 38% decreased risk of premenopausal breast cancer (ORQ4 vs. Q1 = 0.62; 95% CI 0.40-0.96; P-trend = 0.01). We found no association between exercise and breast cancer diagnosed after menopause. CONCLUSIONS: These findings suggest that early-life physical activity is associated with a reduced risk of premenopausal breast cancer among BRCA mutation carriers. IMPACT: Future prospective analyses, complemented by mechanistic evidence, are warranted in this high-risk population.

Genetic assessment wait time indicators in the High Risk Ontario Breast Screening Program.

BACKGROUND: The Ontario Breast Screening Program (OBSP) expanded in July 2011 to screen high-risk women aged 30-69 with annual MRI and mammography. This study evaluated wait time (WT) indicators along the genetic assessment (GA) pathway for women referred to the High Risk OBSP. METHODS: Information was collected for 27,170 women referred to the High Risk OBSP from July 2011 to June 2015 and followed for GA until June 2016. Median duration (days), interquartile range (IQR) were measured for each WT indicator by program year, age, prior breast cancer, and risk criteria. RESULTS: Among 24,811 women who completed GA, 16,367 (66.0%) had genetic counseling only, 8,444 (34.0%) had counseling and testing and 8,027 (32.4%) met the high risk criteria. Median WT from physician visit to first screen was longer for women having genetic counseling only compared to those having counseling and testing (244 vs. 197 days). Women having counseling only also experienced the longest WT from physician visit to genetic counseling (88 days; IQR = 10-174), which increased by year from 71 to 100 days (p < .0001). Among women having counseling and testing, WT from physician visit to counseling was shortest for mutation carriers (39 days; IQR = 4-100). Median WT from testing to laboratory report issue was 41 days (IQR = 22-70) and 17 days to disclosure of test results (IQR = 7-33). Both WTs decreased with year and were shorter for mutation carriers (33 days, IQR = 19-58; 15 days, IQR = 7-28, respectively). CONCLUSIONS: After implementation of the High Risk OBSP, women received timely genetic counseling, in particular those having counseling and testing. Effective triage models for physicians could reduce WT to GA after physician referral.

Enhanced First Trimester Screening for Trisomy 21 with Contingent Cell-Free Fetal DNA: A Comparative Performance and Cost Analysis.

OBJECTIVE: Prenatal screening for trisomy 21 is a standard of care. Emerging cell-free fetal DNA (cffDNA) technologies can improve screening performance, but they are expensive. This study was conducted to propose a contingent screening model that would incorporate cffDNA technology, would remain affordable, and could be applied equitably in a publically funded system. METHODS: Using performance and cost parameters from published literature, four prenatal screening strategies were compared. Scenario 1 modelled integrated prenatal screening (first trimester nuchal translucency and biochemical markers from both the first and second trimesters) with no cffDNA. Scenarios 2 and 3 modelled first trimester combined screening (FTS) and "enhanced FTS" (adding serum placental growth factor and alpha fetoprotein to FTS), respectively, with contingent cffDNA following a positive result. Scenario 4 modelled cffDNA as the primary screening test. RESULTS: Scenario 1 provides a known detection rate (DR) of 88%, with a false positive rate (FPR) of 3.3%. Scenarios 2 and 3 result in a DR of 94% and overall FPR of 0.59% and 0.33%, respectively, comparable to the DR of 96% and FPR of 0.1% with primary cffDNA (assuming the published test failure rate of 3%). The total cost, cost per woman screened, and cost per case of trisomy 21 detected were lower with scenario 3 (enhanced FTS with contingent cffDNA) compared with primary cffDNA or scenario 2 (FTS with contingent cffDNA). CONCLUSION: Enhanced FTS with contingent cffDNA following a positive result provides a similar performance to that of primary cffDNA at a substantially lower cost.

Feasibility of computerized working memory training in individuals with Huntington disease.

OBJECTIVES: Huntington disease (HD) is associated with a variety of cognitive deficits, with prominent difficulties in working memory (WM). WM deficits are notably compromised in early-onset and prodromal HD patients. This study aimed to determine the feasibility of a computerized WM training program (Cogmed QM), novel to the HD population. METHODS: Nine patients, aged 26-62, with early stage HD underwent a 25-session (5 days/week for 5 weeks) WM training program (Cogmed QM). Training exercises involved the manipulation and storage of verbal and visuospatial information, with difficulty adapted as a function of individual performance. Neuropsychological testing was conducted before and after training, and performance on criterion WM measures (Digit Span and Spatial Span), near-transfer WM measures (Symbol Span and Auditory WM), and control measures were evaluated. Post-training interviews about patient experience were thematically analyzed using NVivo software. RESULTS: Seven of nine patients demonstrated adherence to the training and completed all sessions within the recommended timeframe of 5 weeks. All adherent patients showed improvement on the Cogmed tasks as defined by the Improvement Index (M = 22.17, SD = 8.84, range = 13-36). All adherent patients reported that they found training helpful (n = 7), and almost all felt that their memory improved (n = 6). Participants also expressed that the training was difficult, sometimes frustrating, and time consuming. CONCLUSIONS: This pilot study provides support for feasibility of computerized WM training in early-stage patients with HD. Results suggest that HD patients perceive benefits of intensive WM training, though a full-scale and controlled intervention project is needed to understand the size of the effect and reliability of changes over time. TRIAL REGISTRATION: ClinicalTrials.gov, Registry number NCT02926820.