FORGE Canada Consortium: outcomes of a 2-year national rare-disease gene-discovery project.

Inherited monogenic disease has an enormous impact on the well-being of children and their families. Over half of the children living with one of these conditions are without a molecular diagnosis because of the rarity of the disease, the marked clinical heterogeneity, and the reality that there are thousands of rare diseases for which causative mutations have yet to be identified. It is in this context that in 2010 a Canadian consortium was formed to rapidly identify mutations causing a wide spectrum of pediatric-onset rare diseases by using whole-exome sequencing. The FORGE (Finding of Rare Disease Genes) Canada Consortium brought together clinicians and scientists from 21 genetics centers and three science and technology innovation centers from across Canada. From nation-wide requests for proposals, 264 disorders were selected for study from the 371 submitted; disease-causing variants (including in 67 genes not previously associated with human disease; 41 of these have been genetically or functionally validated, and 26 are currently under study) were identified for 146 disorders over a 2-year period. Here, we present our experience with four strategies employed for gene discovery and discuss FORGE's impact in a number of realms, from clinical diagnostics to the broadening of the phenotypic spectrum of many diseases to the biological insight gained into both disease states and normal human development. Lastly, on the basis of this experience, we discuss the way forward for rare-disease genetic discovery both in Canada and internationally.

Statement of principles on the return of research results and incidental findings in paediatric research: a multi-site consultative process.

This paper proposes a set of recommendations for the return of research results and incidental findings in paediatrics. The Network of Applied Genetic Medicine of Quebec spearheaded the initiative to develop the Statement of Principles on the Return of Research Results and Incidental Findings, which was the result of a consultation process with clinical and research experts in the field. To formulate the Statement of Principles, the authors (i) reviewed empirical and grey literature on the return of research results and incidental findings in Europe and Canada, (ii) conducted a qualitative study of stakeholder groups, (iii) developed, and (iv) validated the recommendations through consultations with the stakeholder groups. The Statement of Principles provides a useful disclosure tool for deciding when, and under what circumstances to return research results and incidental findings. It addresses the issue of return of results in genetic research generally, and has also specific principles for various research contexts, including paediatric research. It delineates ethical issues unique to paediatric research, and provides a framework to guide research ethics committees as well as the research community in addressing these issues.

Expectations and values about expanded newborn screening: a public engagement study.

OBJECTIVES: Newborn bloodspot screening (NBS) panels have expanded to include conditions for which treatment effects are less certain, creating debate about population-based screening criteria. We investigated Canadian public expectations and values regarding the types of conditions that should be included in NBS and whether parents should provide consent. METHODS: Eight focus groups (FG; n = 60) included education, deliberative discussion and pre-/post-questionnaires. Data were analysed quantitatively and qualitatively. RESULTS: Quantitatively, the majority supported NBS for serious disorders for which treatment is not available (95-98, 82%). A majority endorsed screening without explicit consent (77-88%) for treatable disorders, but 62% supported unpressured choice for screening for untreatable disorders. Qualitatively, participants valued treatment-related benefits for infants and informational benefits for families. Concern for anxiety, stigma and unwanted knowledge depended upon disease context and strength of countervailing benefits. CONCLUSIONS: Anticipated benefits of expanded infant screening were prioritized over harms, with information provision perceived as a mechanism for mitigating harms and enabling choice. However, we urge caution around the potential for public enthusiasm to foster unlimited uptake of infant screening technologies.

SOCIO-ETHICAL ISSUES IN PERSONALIZED MEDICINE: A SYSTEMATIC REVIEW OF ENGLISH LANGUAGE HEALTH TECHNOLOGY ASSESSMENTS OF GENE EXPRESSION PROFILING TESTS FOR BREAST CANCER PROGNOSIS.

OBJECTIVES: There have been multiple calls for explicit integration of ethical, legal, and social issues (ELSI) in health technology assessment (HTA) and addressing ELSI has been highlighted as key in optimizing benefits in the Omics/Personalized Medicine field. This study examines HTAs of an early clinical example of Personalized Medicine (gene expression profile tests [GEP] for breast cancer prognosis) aiming to: (i) identify ELSI; (ii) assess whether ELSIs are implicitly or explicitly addressed; and (iii) report methodology used for ELSI integration. METHODS: A systematic search for HTAs (January 2004 to September 2012), followed by descriptive and qualitative content analysis. RESULTS: Seventeen HTAs for GEP were retrieved. Only three (18%) explicitly presented ELSI, and only one reported methodology. However, all of the HTAs included implicit ELSI. Eight themes of implicit and explicit ELSI were identified. "Classical" ELSI including privacy, informed consent, and concerns about limited patient/clinician genetic literacy were always presented explicitly. Some ELSI, including the need to understand how individual patients' risk tolerances affect clinical decision-making after reception of GEP results, were presented both explicitly and implicitly in HTAs. Others, such as concern about evidentiary deficiencies for clinical utility of GEP tests, occurred only implicitly. CONCLUSIONS: Despite a wide variety of important ELSI raised, these were rarely explicitly addressed in HTAs. Explicit treatment would increase their accessibility to decision-makers, and may augment HTA efficiency maximizing their utility. This is particularly important where complex Personalized Medicine applications are rapidly expanding choices for patients, clinicians and healthcare systems.

Attitudes of parents toward the return of targeted and incidental genomic research findings in children.

PURPOSE: We describe parental attitudes toward the return of targeted and incidental genomic research results in the setting of high-risk pediatric cancer and inherited childhood diseases. METHODS: A validated 36-item questionnaire was mailed to participants in three large-scale genome research consortia examining attitudes toward receipt of genomic research results and the influence of certainty, severity, and onset of the condition, in addition to responsibilities to extended family and provision of results even after death of the proband. RESULTS: Of the 563 participants who were sent questionnaires, 362 (64%) responded. Most of them stated a positive right to receive results related to the target condition (97%) or to incidental findings (86%); no difference was found in results between participants with cancer and those with orphan diseases. Furthermore, 92% indicated that genomic research for childhood-onset conditions should occur. The majority wanted incidental results predicting susceptibility even to untreatable fatal conditions (83%), to multiple conditions (87%), or to those with uncertain impact (70%). Most felt sibling genomic results showing serious conditions, whether treatable (93%) or not (88%), and/or results discovered after death of the proband should be shared with family (74%). CONCLUSION: Many parents of children in pediatric genomic research indicated a strong desire to receive a broader range of results than is described in consensus recommendations. Clear delineation of what will be offered should be established at the time of consent.

Returning incidental findings from genetic research to children: views of parents of children affected by rare diseases.

PURPOSE: To explore parental perceptions and experiences regarding the return of genomic incidental research findings in children with rare diseases. METHODS: Parents of children affected by various rare diseases were invited to participate in focus groups or individual telephone interviews in Montreal and Ottawa. Fifteen participants were interviewed and transcriptions were analysed using thematic analysis. RESULTS: Four emergent themes underscored parental enthusiasm for receiving incidental findings concerning their child's health: (1) right to information; (2) perceived benefits and risks; (3) communication practicalities: who, when, and how; and (4) service needs to promote the communication of incidental findings. Parents believed they should be made aware of all results pertaining to their child's health status, and that they are responsible for transmitting this information to their child, irrespective of disease severity. Despite potential negative consequences, respondents generally perceived a favourable risk-benefit ratio in receiving all incidental findings. CONCLUSIONS: Understanding how parents assess the risks and benefits of returning incidental findings is essential to genomic research applications in paediatric medicine. The authors believe the study findings will contribute to establishing future best practices, although further research is needed to evaluate the impact of parental decisions on themselves and their child.

Attitudes of Canadian researchers toward the return to participants of incidental and targeted genomic findings obtained in a pediatric research setting.

PURPOSE: The purpose of this study was to explore the attitudes of genomics researchers in a pediatric setting in the context of regulatory guidance recommending the disclosure of clinically significant research findings. METHODS: A validated 32-item questionnaire was sent to 107 researchers with two large-scale projects (the Canadian Pediatric Cancer Genome Consortium and the Finding of Rare Genes Canada Consortium). We examined researchers' attitudes toward obligations to offer genomic research results (including if the participant was deceased, a relative, or a child), influence of the certainty/severity of the condition on this obligation, and personal experiences. RESULTS: Of the 107 researchers, 74 (69%) responded. Researchers did not feel a strong responsibility to look for meaningful incidental results in the research genomic data set (n = 27, 37%). However, once identified, they felt participants had a strong right to receive them, irrespective of being incidental (n = 50, 68%) or primary targets (n = 64, 87%). There was a high degree of support for informing siblings of genomic results (n = 46, 62%), especially for treatable conditions (n = 56, 76%). Less than half of the participants indicated that their research ethics board required an offer of results (n = 34, 46%) or provided a detailed process (n = 16, 22%). CONCLUSION: Researchers strongly support the offer of targeted and incidental genomic research results to participants. Greater regulatory guidance is needed for a consistent approach.

Cohort profile: the maternal-infant research on environmental chemicals research platform.

BACKGROUND: The Maternal-Infant Research on Environmental Chemicals (MIREC) Study was established to obtain Canadian biomonitoring data for pregnant women and their infants, and to examine potential adverse health effects of prenatal exposure to priority environmental chemicals on pregnancy and infant health. METHODS: Women were recruited during the first trimester from 10 sites across Canada and were followed through delivery. Questionnaires were administered during pregnancy and post-delivery to collect information on demographics, occupation, life style, medical history, environmental exposures and diet. Information on the pregnancy and the infant was abstracted from medical charts. Maternal blood, urine, hair and breast milk, as well as cord blood and infant meconium, were collected and analysed for an extensive list of environmental biomarkers and nutrients. Additional biospecimens were stored in the study's Biobank. The MIREC Research Platform encompasses the main cohort study, the Biobank and follow-up studies. RESULTS: Of the 8716 women approached at early prenatal clinics, 5108 were eligible and 2001 agreed to participate (39%). MIREC participants tended to smoke less (5.9% vs. 10.5%), be older (mean 32.2 vs. 29.4 years) and have a higher education (62.3% vs. 35.1% with a university degree) than women giving birth in Canada. CONCLUSIONS: The MIREC Study, while smaller in number of participants than several of the international cohort studies, has one of the most comprehensive datasets on prenatal exposure to multiple environmental chemicals. The biomonitoring data and biological specimen bank will make this research platform a significant resource for examining potential adverse health effects of prenatal exposure to environmental chemicals.

Emerging issues in paediatric health research consent forms in Canada: working towards best practices.

BACKGROUND: Obtaining a research participant's voluntary and informed consent is the bedrock of sound ethics practice. Greater inclusion of children in research has led to questions about how paediatric consent operates in practice to accord with current and emerging legal and socio-ethical issues, norms, and requirements. METHODS: Employing a qualitative thematic content analysis, we examined paediatric consent forms from major academic centres and public organisations across Canada dated from 2008-2011, which were purposively selected to reflect different types of research ethics boards, participants, and studies. The studies included biobanking, longitudinal studies, and gene-environment studies. Our purpose was to explore the following six emerging issues: (1) whether the scope of parental consent allows for a child's assent, dissent, or future consent; (2) whether the concepts of risk and benefit incorporate the child's psychological and social perspective; (3) whether a child's ability to withdraw is respected and to what extent withdrawal is permitted; (4) whether the return of research results includes individual results and/or incidental findings and the processes involved therein; (5) whether privacy and confidentiality concerns adequately address the child's perspective and whether standard data and/or sample identifiability nomenclature is used; and (6) whether retention of and access to paediatric biological samples and associated medical data are addressed. RESULTS: The review suggests gaps and variability in the consent forms with respect to addressing each of the six issues. Many forms did not discuss the possibility of returning research results, be they individual or general/aggregate results. Forms were also divided in terms of the scope of parental consent (specific versus broad), and none discussed a process for resolving disputes that can arise when either the parents or the child wishes to withdraw from the study. CONCLUSIONS: The analysis provides valuable insight and evidence into how consent forms address current ethical issues. While we do not thoroughly explore the contexts and reasons behind consent form gaps and variability, we do advocate and formulate the development of best practices for drafting paediatric health research consent forms. This can greatly ameliorate current gaps and facilitate harmonised and yet contextualised approaches to paediatric health research ethics.

Paediatric biobanks: what makes them so unique?

Paediatric biobanks store and organise the biological material of children. They are an invaluable resource for the study of the development, health and behaviour of children. International norms for the management of adult biobanks exist, but paediatric biobanks require distinct policies to account for the needs of children, their general incapacity, and their intellectual development throughout the life of the biobank. Because of their particular nature we revisit the issues of consent, the return of research results, and privacy, and discuss how each could be modulated in the paediatric context. We recognize that such modifications entail further financial and logistical complications but maintain that it is essential that paediatric biobanks consider these issues and adapt their biobanks management policies accordingly, rather than extrapolate the current adult-based norms and jeopardise the rights of child participants.

Recruiting terminally ill patients into non-therapeutic oncology studies: views of health professionals.

BACKGROUND: Non-therapeutic trials in which terminally ill cancer patients are asked to undergo procedures such as biopsies or venipunctures for research purposes, have become increasingly important to learn more about how cancer cells work and to realize the full potential of clinical research. Considering that implementing non-therapeutic studies is not likely to result in direct benefits for the patient, some authors are concerned that involving patients in such research may be exploitive of vulnerable patients and should not occur at all, or should be greatly restricted, while some proponents doubt whether such restrictions are appropriate. Our objective was to explore clinician-researcher attitudes and concerns when recruiting patients who are in advanced stages of cancer into non-therapeutic research. METHODS: We conducted a qualitative exploratory study by carrying out open-ended interviews with health professionals, including physicians, research nurses, and study coordinators. Interviews were audio-recorded and transcribed. Analysis was carried out using grounded theory. RESULTS: The analysis of the interviews unveiled three prominent themes: 1) ethical considerations; 2) patient-centered issues; 3) health professional issues. Respondents identified ethical issues surrounding autonomy, respect for persons, beneficence, non-maleficence, discrimination, and confidentiality; bringing to light that patients contribute to science because of a sense of altruism and that they want reassurance before consenting. Several patient-centered and health professional issues are having an impact on the recruitment of patients for non-therapeutic research. Facilitators were most commonly associated with patient-centered issues enhancing communication, whereas barriers in non-therapeutic research were most often professionally based, including the doctor-patient relationship, time constraints, and a lack of education and training in research. CONCLUSIONS: This paper aims to contribute to debates on the overall challenges of recruiting patients to non-therapeutic research. This exploratory study identified general awareness of key ethical issues, as well as key facilitators and barriers to the recruitment of patients to non-therapeutic studies. Due to the important role played by clinicians and clinician-researchers in the recruitment of patients, it is essential to facilitate a greater understanding of the challenges faced; to promote effective communication; and to encourage educational research training programs.

Regulatory approval for new pharmacogenomic tests: a comparative overview.

Pharmacogenomics is the study of how genetic variants affect the way in which an individual or subgroup responds to drugs. This developing field aims to inform individual drug therapy and to minimize adverse drug reactions (ADRs). It also promises great benefits in the drug development process. Innovation in pharmacogenomics and its translation into clinical practice is desirable, but appropriate regulation of the safety and effectiveness of pharmacogenomics testing is necessary. This article will describe the current regulatory framework applicable to pharmacogenomic tests in Canada, the United States and Europe. In particular, it will examine the different regulatory pathways for pharmacogenomic tests marketed as test kits and for laboratory-developed tests (LDTs). Recent and upcoming changes to the regulation of pharmacogenomic tests will also be discussed. For example, FDA's proposal to regulate LDTs could have a major impact on the development and availability of pharmacogenomic tests. This review will lead to an evaluation of the issues raised by the regulatory framework and the impact of regulatory changes in relation to meeting the goals of ensuring public safety and promoting the advancement of pharmacogenomics. Regulatory policies which successfully achieve the dual objectives of ensuring public safety and promoting innovation in health technology are imperative in order to reap the benefits of this emerging field.

Newborn blood spot screening in four countries: stakeholder involvement.

While newborn blood spot screening has historically been viewed as a public health success, the potential harms and benefits are more finely balanced for new conditions being considered for program expansion. We highlight complex issues that must be addressed in policy decisions, which in turn requires a consideration of many stakeholder perspectives. Using national policy documents from the United Kingdom, the United States, Australia, and Canada, we describe the participation of stakeholder organizations in the newborn screening policy process, how such organizations have incorporated stakeholder views into their own policy writing, and their recommendations for inclusiveness. Stakeholder participation in newborn screening decision-making is widely acknowledged as important, and many methods have been endorsed - consultation as well as direct or indirect input into policy development. Differences across organizations and jurisdictions raise questions about the most effective approaches for facilitating inclusiveness, suggesting a need for formal evaluative research.

Evaluation of BRCA1 and BRCA2 mutation prevalence, risk prediction models and a multistep testing approach in French-Canadian families with high risk of breast and ovarian cancer.

BACKGROUND AND OBJECTIVE: In clinical settings with fixed resources allocated to predictive genetic testing for high-risk cancer predisposition genes, optimal strategies for mutation screening programmes are critically important. These depend on the mutation spectrum found in the population under consideration and the frequency of mutations detected as a function of the personal and family history of cancer, which are both affected by the presence of founder mutations and demographic characteristics of the underlying population. The results of multistep genetic testing for mutations in BRCA1 or BRCA2 in a large series of families with breast cancer in the French-Canadian population of Quebec, Canada are reported. METHODS: A total of 256 high-risk families were ascertained from regional familial cancer clinics throughout the province of Quebec. Initially, families were tested for a panel of specific mutations known to occur in this population. Families in which no mutation was identified were then comprehensively tested. Three algorithms to predict the presence of mutations were evaluated, including the prevalence tables provided by Myriad Genetics Laboratories, the Manchester Scoring System and a logistic regression approach based on the data from this study. RESULTS: 8 of the 15 distinct mutations found in 62 BRCA1/BRCA2-positive families had never been previously reported in this population, whereas 82% carried 1 of the 4 mutations currently observed in > or =2 families. In the subset of 191 families in which at least 1 affected individual was tested, 29% carried a mutation. Of these 27 BRCA1-positive and 29 BRCA2-positive families, 48 (86%) were found to harbour a mutation detected by the initial test. Among the remaining 143 inconclusive families, all 8 families found to have a mutation after complete sequencing had Manchester Scores > or =18. The logistic regression and Manchester Scores provided equal predictive power, and both were significantly better than the Myriad Genetics Laboratories prevalence tables (p<0.001). A threshold of Manchester Score > or =18 provided an overall sensitivity of 86% and a specificity of 82%, with a positive predictive value of 66% in this population. CONCLUSION: In this population, a testing strategy with an initial test using a panel of reported recurrent mutations, followed by full sequencing in families with Manchester Scores > or =18, represents an efficient test in terms of overall cost and sensitivity.

An ethical and legal overview of pharmacogenomics: perspectives and issues.

Pharmacogenomics, a field of study at the interface of the disciplines of genomics and pharmacology, strives to understand the interaction between genes and the response to therapeutics. Its introduction into clinical research trials and medical practice promises to optimize the effectiveness of medications, reduce the adverse effects experienced by patients, and improve the research and development of new therapeutics. However, while pharmacogenomics promises tremendous health benefits it is still crucial to critically analyze the ethical, social and legal issues surrounding these developments. First, we present the numerous potential benefits ofpharmacogenomics. Then, using a thorough review of relevant jurisprudence, policies and literature, the main ethical, social and legal issues associated with pharmacogenomics will be identified. The likely new responsibilities for health care professionals and pharmaceutical companies as a result of pharmacogenomic development will also be discussed.

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.

Newborn screening by tandem mass spectrometry: ethical and social issues.

Emerging technologies like Tandem Mass Spectrometry (TMS) enable multiple tests on a single blood sample and allow the expansion of Newborn Screening (NBS) to include various metabolic diseases. Introducing TMS for NBS raises important social and ethical questions: what are the criteria for adding disorders to screening panels? What evidence justifies expansion of screening? How can equity in NBS access and standards be ensured? How can policy standards be set, given the multiplicity of stakeholders? To address emerging issues, policy-makers, patient advocates, clinicians and researchers had a workshop during the 2005 Garrod Symposium. The participants received a summary of the discussion and understood the workshop's goal was to provide a basis for further discussion. This article contributes to this ongoing discussion. Several proposed recommendations assert the centrality of including social and ethical issues in the assessment of whether or not to introduce TMS. The article outlines five key recommendations for advancing the NBS agenda: national public health leadership; transparency; increased national consistency in NBS strategy, including minimum standards; collaboration between the federal and provincial/territorial governments and diverse stakeholders; and supporting research and/or programs based on effectiveness, which integrate ethical and social issues into assessment.