Points to consider for laboratories reporting results from diagnostic genomic sequencing.

Although NGS technologies are well-embedded in the clinical setting for identification of genetic causes of disease, guidelines issued by professional bodies are inconsistent regarding some aspects of reporting results. Most recommendations do not give detailed guidance about whether variants of uncertain significance (VUS) should be reported by laboratory personnel to clinicians, and give conflicting messages regarding whether unsolicited findings (UF) should be reported. There are also differences both in their recommendations regarding whether actively searching for secondary findings (SF) is appropriate, and in the extent to which they address the duty (or lack thereof) to reanalyse variants when new information arises. An interdisciplinary working group considered the current guidelines, their own experiences, and data from a recent qualitative study to develop a set of points to consider for laboratories reporting results from diagnostic NGS. These points to consider fall under six categories: (i) Testing approaches and technologies used, (ii) Approaches for VUS; (iii) Approaches for reporting UF, (iv) Approaches regarding SF; (v) Reanalysis of data & re-contact; and vi) Minors. While it is unclear whether uniformity in reporting across all laboratories is desirable, we hope these points to consider will be useful to diagnostic laboratories as they develop their processes for making decisions about reporting VUS and UF from NGS in the diagnostic context.

Cost effectiveness of newborn screening for cystic fibrosis: a simulation study.

BACKGROUND: Early detection of cystic fibrosis (CF) by newborn screening (NBS) reduces the rate of avoidable complications. NBS protocols vary by jurisdiction and the cost effectiveness of these different protocols is debated. OBJECTIVE: To compare the cost effectiveness of various CF NBS options. METHODS: A Markov model was built to simulate the cost effectiveness of various CF-NBS options for a hypothetical CF-NBS program over a 5-year time horizon assuming its integration into an existing universal NBS program. NBS simulated options were based on a combination of tests between the two commonly used immunoreactive trypsinogen (IRT) cutoffs (96th percentile and 99.5th percentile) as first tier tests, and, as a second tier test, either a second IRT, pancreatic-associated protein (PAP) or CFTR mutation panels. CFTR mutation panels were also considered as an eventual third tier test. Data input parameters used were retrieved from a thorough literature search. Outcomes considered were the direct costs borne by the Quebec public health care system and the number of cases of CF detected through each strategy, including the absence of screening option. RESULTS: IRT-PAP with an IRT cutoff at the 96th percentile is the most favorable option with a ratio of CAD$28,432 per CF case detected. The next most favorable alternative is the IRT1-IRT2 option with an IRT1 cutoff at the 96th percentile. The no-screening option is dominated by all NBS screening protocols considered. Results were robust in sensitivity analyses. CONCLUSION: This study suggests that NBS for cystic fibrosis is a cost-effective strategy compared to the absence of NBS. The IRT-PAP newborn screening algorithm with an IRT cutoff at the 96th percentile is the most cost effective NBS approach for Quebec.

Genetics in health care: an overview of current and emerging models.

BACKGROUND: With advances in genetic and genomic medicine, the optimal integration of genetic services into the health care system remains of major concern in many countries. OBJECTIVES: To review the current organisation of genetic services, mostly in Europe, North America and Australia, explore emerging service delivery models, and probe challenges inherent in the transition process. METHODS: We conducted a literature review of genetics in clinical practice: testing, diagnosis, counselling, and treatment. We examined the basic structures of genetic services, examples of integrated networks, and existing professional resources. We investigated services belonging traditionally in medical genetics as well as those developed for more common diseases. RESULTS: Multidisciplinary specialist clinics and coordinated services appeared to be key to delivering proper care in rare genetic disorders. For oncogenetics, neurogenetics and cardiogenetics, interprofessional collaboration between geneticists and other specialists seemed to be favoured. On the other hand, there was also a tendency toward the integration of genetic services directly into primary care. Among the most pressing challenges was the morphing of paediatric care into adult care. CONCLUSION: The coordination of activities between professionals in first-, second-, and third-line medical care is a primary objective calling for the reconfiguration of professional roles and responsibilities. This entails the forging of new relationships as well as an enhanced sharing of expertise and genetic information, including information regarding services. Barriers to overcome include the redistribution of roles, sharing of data and databases, and the lack of preparedness of non-genetics professionals and of the health care system in general.

Debating clinical utility.

The clinical utility of genetic tests is determined by the outcomes following test use. Like other measures of value, it is often contested. Stakeholders may have different views about benefits and risks and about the importance of social versus health outcomes. They also commonly disagree about the evidence needed to determine whether a test is effective in achieving a specific outcome. Questions may be presented as factual disagreements, when they are actually debates about what information matters or how facts should be interpreted and used in clinical decision-making. Defining the different issues at stake is therefore an important element of policy-making. Key issues include evidence standards for test use, and in particular, the circumstances under which prospective controlled data should be required, as well as evidence on feasibility, cost and equitable delivery of testing; the goals of population-based screening programs, and in particular, the role of social outcomes in evaluating test value; and the appropriate uses and funding of tests that inform non-medical actions. Addressing each of these issues requires attention to stakeholder values and methods for effective deliberation that incorporate consumer as well as health professional perspectives.

Assessing the potential success of cystic fibrosis carrier screening: lessons learned from Tay-Sachs disease and beta-thalassemia.

OBJECTIVE: The objective of this study was to identify factors involved in the success of 2 well-established population-based carrier screening programs - Tay-Sachs disease (TSD) in Ashkenazi Jews and beta-thalassemia in Sardinia and Cyprus - and to assess the potential for success of a population-based cystic fibrosis (CF) carrier screening strategy using these factors. METHODS: We performed a literature review and key informant interviews. RESULTS: Factors involved in the success of TSD and beta-thalassemia carrier screening programs include disease characteristics (well-defined population at risk, severe disease with predictable course, availability of effective treatment), test characteristics (high sensitivity, straightforward interpretation of results), and community characteristics (involvement of community, support of families and advocacy groups, consensus in favor of avoiding affected births). Current CF screening strategies include few of the factors listed above. Unlike TSD and beta-thalassemia, the purpose of current CF carrier screening strategies is informed reproductive decision-making, without an explicit goal of reducing disease incidence. CONCLUSION: When compared to TSD and beta-thalassemia, CF is a less favorable candidate for population-based carrier screening. Because of its different purpose, CF carrier screening will require different measures of success than those used for TSD and beta-thalassemia carrier screening, and a consensus on the value or success of CF carrier screening may be difficult to achieve.

Population history and its impact on medical genetics in Quebec.

Knowledge of the genetic demography of Quebec is useful for gene mapping, diagnosis, treatment, community genetics and public health. The French-Canadian population of Quebec, currently about 6 million people, descends from about 8500 French settlers who arrived in Nouvelle-France between 1608 and 1759. The migrations of those settlers and their descendants led to a series of regional founder effects, reflected in the geographical distribution of genetic diseases in Quebec. This review describes elements of population history and clinical genetics pertinent to the treatment of French Canadians and other population groups from Quebec and summarizes the cardinal features of over 30 conditions reported in French Canadians. Some were discovered in French Canadians, such as autosomal recessive ataxia of the Charlevoix-Saguenay (MIM 270550), agenesis of corpus callosum and peripheral neuropathy (MIM 218000) and French-Canadian-type Leigh syndrome (MIM 220111). Other conditions are particularly frequent or have special genetic characteristics in French Canadians, including oculopharyngeal muscular dystrophy, hepatorenal tyrosinaemia, cystic fibrosis, Leber hereditary optic neuropathy and familial hypercholesterolaemia. Three genetic diseases of Quebec First Nations children are also discussed: Cree encephalitis (MIM 608505), Cree leukoencephalopathy (MIM 603896) and North American Indian childhood cirrhosis (MIM 604901).

Structural characterizations of neuropeptide tyrosine (NPY) and its agonist analog [Ahx5-17]NPY by NMR and molecular modeling.

The structures of human NPY and of its centrally truncated agonist analog [Ahx5-17]NPY have been investigated in DMSO-d6 by two-dimensional NMR and by molecular modeling. For both peptides, a complete resonance assignment was achieved and a large number (more than 200) of inter-residue NOE connectivities were observed, including long-range connectivities between the N- and C-terminal ends of the chain. Molecular models were calculated using NOE constraints by distance geometry, simulated annealing and conjugate gradient energy minimization. The results indicate that both peptides are folded in the center of their chain, NPY adopting the hairpin shape, whereas the central portion of [Ahx5-17]NPY is characterized by relatively large loops. In contrast to previous models, practically no alpha-helical structure exists for these peptides under our conditions, but two beta-turns are found in NPY and one in [Ahx5-17]NPY. The proximity of the terminal ends could be the determinant factor for their activity.