Performance of a universal prenatal screening program incorporating cell-free fetal DNA analysis in Ontario, Canada.

BACKGROUND: The emergence of cell-free fetal DNA (cfDNA) testing technology has disrupted the landscape of prenatal screening for trisomies 21 (T21) and 18 (T18). Publicly funded systems around the world are grappling with how to best integrate this more accurate but costly technology, as there is limited evidence about its incremental value in real-world conditions. The objectives of this study were to describe the population-based performance of Ontario's prenatal screening program, which incorporates publicly funded cfDNA screening for specific indications, and the effect of cfDNA testing on the screening and diagnostic choices made by pregnant people. METHODS: We conducted a retrospective, descriptive cohort study using routinely collected data from Better Outcomes & Registry Network (BORN) Ontario, which captures linked population data for prenatal and neonatal health encounters across Ontario. We included all singleton pregnancies with an estimated due date between Sept. 1, 2016, and Mar. 31, 2019, that underwent publicly funded prenatal screening in Ontario, and a comparison cohort from Apr. 1, 2012, and Mar. 31, 2013. We assessed performance of the screening program for the detection of T21 or T18 by calculating sensitivity, specificity, positive predictive value and negative predictive value against diagnostic cytogenetic results or birth outcomes. We assessed the impact of the program by calculating the proportion of T21 screen-positive pregnancies undergoing subsequent cfDNA screening and invasive prenatal diagnostic testing. RESULTS: The study cohort included 373 682 pregnancies. The prenatal screening program had an uptake of 69.9%, a screen-positive rate and sensitivity of 1.6% and 89.9% for T21, and 0.2% and 80.5% for T18, respectively. The test failure rate for cfDNA screening was 2.2%. Invasive prenatal diagnostic testing decreased from 4.4% in 2012-2013 to 2.4% over the study period; 65.2% of pregnant people who received a screen-positive result from cfDNA testing went on to have invasive prenatal diagnostic testing. INTERPRETATION: This publicly funded screening program, incorporating cfDNA analysis for common aneuploidies, showed robust performance, a substantial reduction in invasive prenatal diagnostic testing and that pregnant people exercise autonomy in their choices about prenatal screening and diagnosis.

New Diagnostic Approaches for Undiagnosed Rare Genetic Diseases.

Accurate diagnosis is the cornerstone of medicine; it is essential for informed care and promoting patient and family well-being. However, families with a rare genetic disease (RGD) often spend more than five years on a diagnostic odyssey of specialist visits and invasive testing that is lengthy, costly, and often futile, as 50% of patients do not receive a molecular diagnosis. The current diagnostic paradigm is not well designed for RGDs, especially for patients who remain undiagnosed after the initial set of investigations, and thus requires an expansion of approaches in the clinic. Leveraging opportunities to participate in research programs that utilize new technologies to understand RGDs is an important path forward for patients seeking a diagnosis. Given recent advancements in such technologies and international initiatives, the prospect of identifying a molecular diagnosis for all patients with RGDs has never been so attainable, but achieving this goal will require global cooperation at an unprecedented scale.

The Canadian Rare Diseases Models and Mechanisms (RDMM) Network: Connecting Understudied Genes to Model Organisms.

Advances in genomics have transformed our ability to identify the genetic causes of rare diseases (RDs), yet we have a limited understanding of the mechanistic roles of most genes in health and disease. When a novel RD gene is first discovered, there is minimal insight into its biological function, the pathogenic mechanisms of disease-causing variants, and how therapy might be approached. To address this gap, the Canadian Rare Diseases Models and Mechanisms (RDMM) Network was established to connect clinicians discovering new disease genes with Canadian scientists able to study equivalent genes and pathways in model organisms (MOs). The Network is built around a registry of more than 500 Canadian MO scientists, representing expertise for over 7,500 human genes. RDMM uses a committee process to identify and evaluate clinician-MO scientist collaborations and approve 25,000 Canadian dollars in catalyst funding. To date, we have made 85 clinician-MO scientist connections and funded 105 projects. These collaborations help confirm variant pathogenicity and unravel the molecular mechanisms of RD, and also test novel therapies and lead to long-term collaborations. To expand the impact and reach of this model, we made the RDMM Registry open-source, portable, and customizable, and we freely share our committee structures and processes. We are currently working with emerging networks in Europe, Australia, and Japan to link international RDMM networks and registries and enable matches across borders. We will continue to create meaningful collaborations, generate knowledge, and advance RD research locally and globally for the benefit of patients and families living with RD.

Nablus syndrome: Easy to diagnose yet difficult to solve.

Nablus syndrome was first described by the late Ahmad Teebi in 2000, and 13 individuals have been reported to date. Nablus syndrome can be clinically diagnosed based on striking facial features, including tight glistening skin with reduced facial expression, blepharophimosis, telecanthus, bulky nasal tip, abnormal external ear architecture, upswept frontal hairline, and sparse eyebrows. However, the precise genetic etiology for this rare condition remains elusive. Comparative microarray analyses of individuals with Nablus syndrome (including two mother-son pairs) reveal an overlapping 8q22.1 microdeletion, with a minimal critical region of 1.84 Mb (94.43-96.27 Mb). Whereas this deletion is present in all affected individuals, 13 individuals without Nablus syndrome (including two mother-child pairs) also have the 8q22.1 microdeletion that partially or fully overlaps the minimal critical region. Thus, the 8q22.1 microdeletion is necessary but not sufficient to cause the clinical features characteristic of Nablus syndrome. We discuss possible explanations for Nablus syndrome, including one-locus, two-locus, epigenetic, and environmental mechanisms. We performed exome sequencing for five individuals with Nablus syndrome. Although we failed to identify any deleterious rare coding variants in the critical region that were shared between individuals, we did identify one common SNP in an intronic region that was shared. Clearly, unraveling the genetic mechanism(s) of Nablus syndrome will require additional investigation, including genomic and RNA sequencing of a larger cohort of affected individuals. If successful, it will provide important insights into fundamental concepts such as variable expressivity, incomplete penetrance, and complex disease relevant to both Mendelian and non-Mendelian disorders.

Clinical management recommendations for surveillance and risk-reduction strategies for hereditary breast and ovarian cancer among individuals carrying a deleterious BRCA1 or BRCA2 mutation.

BACKGROUND: In Canada, there are wide variations in services for patients at risk for hereditary breast and ovarian cancer (HBOC), and clinical interventions and recommendations differ between regions and/or provinces. National strategies for the clinical management of HBOC exist in the United Kingdom, France, and Australia, and clinical programs in Canada would benefit from similar national recommendations and a consistent approach to clinical management. The National Hereditary Cancer Task Force developed recommendations to address the clinical management of patients at high risk of HBOC and related cancers. These recommendations are based on current practice in high-risk cancer clinics that provide care for individuals with known BRCA1 or BRCA2 mutations. METHODS: Canadian consensus recommendations were generated by the National Hereditary Cancer Task Force and compared mainly with two recently published guidance documents on the clinical management of women with increased risk of HBOC, one from the United Kingdom and the other from France. After review of these documents and the associated supporting scientific evidence, the Canadian consensus recommendations were modified and rated using predefined criteria. CONCLUSIONS: These recommendations pertain to (1) surveillance options including breast self-examination, clinical breast examination, breast surveillance by imaging, ovarian cancer surveillance, and surveillance for men; (2) risk-reduction strategies including prophylactic mastectomy, prophylactic salpingo-oophorectomy, and pharmacoprevention; and (3) the use of exogenous hormones. Regular updates should occur as new evidence becomes available.

Pelvic magnetic resonance venography reveals high rate of pelvic vein thrombosis after cesarean section.

In the run-in phase of a thromboprophylactic trial in women at moderate to high risk of deep vein thrombosis postcesarean section, we used magnetic resonance venography and found a surprisingly high rate of pelvic deep vein thrombosis (46% overall). Pelvic magnetic resonance venography may be a useful surrogate outcome in obstetric thromboprophylaxis studies but the clinical significance is not known.

The interobserver reliability of pretest probability assessment in patients with suspected pulmonary embolism.

INTRODUCTION: Pretest probability assessment and objective testing are combined to appropriately manage patients with suspected pulmonary embolism (PE). However, the interobserver reliability of pretest probability assessment has not been investigated. We sought to determine (for patients with suspected PE) the interobserver reliability of pretest probability assessment (by overall impression (gestalt) versus an explicit clinical model). MATERIALS AND METHODS: A prospective cohort study was conducted at an urban university hospital. For patients referred for ventilation and perfusion (V/Q) scanning for suspected PE, structured assessments (11 history and 4 physical examination parameters) were performed by a referring physician and a designated thrombosis physician. The referring and thrombosis physicians also assigned a pretest probability for PE (low, moderate, or high) by gestalt. An explicit seven-point clinical model for suspected PE was later applied to each structured assessment to determine the pretest probability. Assessments were performed independently and prior to diagnostic test results. Interobserver reliability (two rater unweighted Kappa (kappa) statistic) was determined for each parameter on the structured assessment and the pretest probability assessments (gestalt vs. explicit clinical model). RESULTS: One hundred and ten patients with suspected PE received duplicate assessments. Historical features demonstrated substantial to almost perfect interobserver reliability (kappa=0.60-0.95). For the physical findings, only heart rate had substantial interobserver reliability (kappa=0.60). Pretest probability assessment was not reliable when using physician's gestalt (kappa=0.33), but produced substantial interobserver reliability using the explicit clinical model (kappa=0.62). CONCLUSIONS: Given the inadequate interobserver reliability of pretest probability assessment by overall impression (or gestalt), physicians should use explicit clinical models in the diagnostic management of patients with suspected pulmonary embolism.

A systematic review of the association between factor V Leiden or prothrombin gene variant and intrauterine growth restriction.

OBJECTIVE: The purpose of this study was to conduct a systematic review of the literature of studies that examined the association between factor V Leiden and/or prothrombin gene variant and intrauterine growth restriction. STUDY DESIGN: This systematic review of studies assesses the association between factor V Leiden and/or prothrombin gene variant and intrauterine growth restriction. RESULTS: Ten case-control studies fulfilled the selection criteria for inclusion in the meta-analysis. There was a significant association between factor V Leiden and intrauterine growth restriction (odds ratio, 2.7; 95% CI, 1.3-5.5) and prothrombin gene variant and intrauterine growth restriction (odds ratio, 2.5; 95% CI, 1.3-5.0). Five cohort studies were identified in the systematic review; 3 studies were prospective (2 full publications), and 2 studies were retrospective (1 full publication). Combining the 2 full publication prospective studies yields a summary relative risk of 0.99 (95% CI, 0.5-1.9). CONCLUSION: This meta-analysis of case-control studies suggests that the factor V Leiden and prothrombin gene variant both confer an increased risk of giving birth to an intrauterine growth restricted infant, although this may be driven by small, poor-quality studies that demonstrated extreme associations. Large well-conducted prospective cohort studies are required to determine definitively whether an association between thrombophilia and intrauterine growth restriction is present.

The outpatient treatment of deep vein thrombosis delivers cost savings to patients and their families, compared to inpatient therapy.

BACKGROUND: The outpatient treatment of deep vein thrombosis (DVT) with low-molecular-weight heparin (LMWH) has been shown to be cost-effective from the perspective of a third party payer. The aim of this study is to determine if some or all of these cost savings to third party payers are shifted to patients and their families. METHODS: A prospective cohort study with micro-costing of patient/family costs was conducted at the thrombosis units of The Ottawa Hospital. Costs were determined by administering a questionnaire at the end of the patients' heparin therapy. Over a period of 4 months, consecutive patients presenting at the thrombosis units were approached at the initiation of their heparin therapy; 44 patients consented to participate and completed questionnaires were obtained for 41. RESULTS: The mean patient/family costs associated with outpatient therapy were significantly less than those associated with inpatient therapy (219.42 dollars versus 402.93 dollars, p=0.003); a savings of 190.91 dollars per patient. Even when lost income to patients/families was ignored, mean patient/family costs remained significantly less for outpatient therapy (72.00 dollars versus 134.29 dollars, p=0.004); a savings of 62.30 dollars per patient. Furthermore, patients preferred outpatient to inpatient therapy by almost 3:1 (30 versus 11, respectively). INTERPRETATION: The outpatient treatment of DVT does not result in any net shifting of costs to patients and their families, and further, brings about cost savings. Given the cost savings associated with and the preference of patients for outpatient care, this study further supports the shift of DVT therapy from the inpatient unit to the outpatient clinic.