The complexity of diagnosing rare disease: An organizing framework for outcomes research and health economics based on real-world evidence.

PURPOSE: To facilitate robust economic analyses of clinical exome and genome sequencing, this study was taken up with the objective of establishing a framework for organizing diagnostic testing trajectories for patients with rare disease. METHODS: We collected diagnostic investigations-related data before exome sequencing from the medical records of 228 cases. Medical geneticist experts participated in a consensus building process to develop the SOLVE Framework for organizing the complex range of observed tests. Experts categorized tests as indicator or nonindicator tests on the basis of their specificity for diagnosing rare diseases. Face validity was assessed using case vignettes. RESULTS: Most cases had symptom onset at birth (42.5%) or during childhood (43.4%) and had intellectual disability (73.3%). On average, the time spent seeking a diagnosis before sequencing was 1989 days (SD = 2137) and included 16 tests (SD = 14). Agreement across experts on test categories ranged from 83% to 96%. The SOLVE Framework comprised observed tests, including 186 indicator and 39 nonindicator tests across cytogenetic/molecular, biochemical, imaging, electrical, and pathology test categories. CONCLUSION: Real-world diagnostic testing data can be ascertained and organized to reflect the complexity of the journey of the patients with rare diseases. SOLVE Framework will improve the accuracy and certainty associated with value-based assessments of genomic sequencing.

The Clinician-reported Genetic testing Utility InDEx (C-GUIDE): Preliminary evidence of validity and reliability.

PURPOSE: Demonstrating the clinical utility of genetic testing is fundamental to clinical adoption and reimbursement, but standardized definitions and measurement strategies for this construct do not exist. The Clinician-reported Genetic testing Utility InDEx (C-GUIDE) offers a novel measure to fill this gap. This study assessed its validity and inter-rater reliability. METHODS: Genetics professionals completed C-GUIDE after disclosure of test results to patients. Construct validity was assessed using regression analysis to measure associations between C-GUIDE and global item scores as well as potentially explanatory variables. Inter-rater reliability was assessed by administering a vignette-based survey to genetics professionals and calculating Krippendorff's α. RESULTS: On average, a 1-point increase in the global item score was associated with an increase of 3.0 in the C-GUIDE score (P < .001). Compared with diagnostic results, partially/potentially diagnostic and nondiagnostic results were associated with a reduction in C-GUIDE score of 9.5 (P < .001) and 10.2 (P < .001), respectively. Across 19 vignettes, Krippendorff's α was 0.68 (95% CI: 0.63-0.72). CONCLUSION: C-GUIDE showed acceptable validity and inter-rater reliability. Although further evaluation is required, C-GUIDE version 1.2 can be useful as a standardized approach to assess the clinical utility of genetic testing.

Health-care providers' perspectives on uncertainty generated by variant forms of newborn screening targets.

PURPOSE: Despite the public health successes of newborn bloodspot screening, uncertainty associated with variant forms of primary screening targets has led to discrepancies in medical management. This study explored health-care providers' approaches to managing atypical forms of inherited metabolic diseases (IMDs) in the absence of evidence-based guidelines. METHODS: Semistructured telephone interviews were conducted with metabolic specialists. 3-Methylcrotonyl CoA deficiency and variant forms of phenylketonuria, biotinidase deficiency, and fatty acid oxidation disorders were considered. Data were analyzed inductively and deductively using a novel taxonomy of uncertainty. RESULTS: Health-care providers (n = 12) navigate diagnostic, prognostic, and therapeutic challenges of uncertainty while interpreting patient and family attitudes, preferences, and ideas in the care of children with these result types. Participants explained the limits of classifying mild and atypical metabolic phenotypes. Participants also described the challenge of finding balance between cautious care and overmedicalization. Developing consistent care plans and honest communication with families were perceived as effective strategies when navigating uncertainty. CONCLUSION: Providers' experiences suggest a need for transparent and accessible guidelines that account for challenges associated with uncertainty generated by screening. Timely consideration of this challenge is warranted with increasing emergence of genotype-first approaches to screening.

Where is the patient in models of patient-centred care: a grounded theory study of total joint replacement patients.

BACKGROUND: Patient-centered care ideally considers patient preferences, values and needs. However, it is unclear if policies such as wait time strategies for hip and knee replacement surgery (TJR) are patient-centred as they focus on an isolated episode of care. This paper describes the accounts of people scheduled to undergo TJR, focusing on their experience of (OA) as a chronic disease that has considerable impact on their everyday lives. METHODS: Semi-structured qualitative interviews were conducted with participants scheduled to undergo TJR who were recruited from the practices of two orthopaedic surgeons. We first used maximum variation and then theoretical sampling based on age, sex and joint replaced. 33 participants (age 38-79 years; 17 female) were included in the analysis. 20 were scheduled for hip replacement and 13 for knee replacement. A constructivist approach to grounded theory guided sampling, data collection and analysis. RESULTS: While a specific hip or knee was the target for surgery, individuals experienced multiple-joint symptoms and comorbidities. Management of their health and daily lives was impacted by these combined experiences. Over time, they struggled to manage symptoms with varying degrees of access to and acceptance of pain medication, which was a source of constant concern. This was a multi-faceted issue with physicians reluctant to prescribe and many patients reluctant to take prescription pain medications due to their side effects. CONCLUSIONS: For patients, TJR surgery is an acute intervention in the experience of chronic disease, OA and other comorbidities. While policy has focused on wait time as patient/surgeon decision for surgery to surgery date, the patient's experience does not begin or end with surgery as they struggle to manage their pain. Our findings suggest that further work is needed to align the medical treatment of OA with the current policy emphasis on patient-centeredness. Patient-centred care may require a paradigm shift that is not always evident in current policy and strategies.

Protocol for a Prospective, Observational Cost-effectiveness Analysis of Returning Secondary Findings of Genome Sequencing for Unexplained Suspected Genetic Conditions.

PURPOSE: Although costly, genome-wide sequencing (GWS) detects an extensive range of variants, enhancing our ability to diagnose and assess risk for an increasing number of diseases. In addition to detecting variants related to the indication for testing, GWS can detect secondary variants in BRCA1, BRCA2, and other genes for which early intervention may improve health. As the list of secondary findings grows, there is increased demand for surveillance and management by multiple specialists, adding pressure to constrained health care budgets. Secondary finding testing is actively debated because some consider it opportunistic screening for future health risks that may not manifest. Given the economic implications of secondary finding testing and follow-up and its unproven clinical utility, the objective is to assess the incremental cost-effectiveness of secondary finding ascertainment per case detected and per unit of improved clinical utility in families of children with unexplained suspected genetic conditions undergoing clinical GWS. METHODS: Those undergoing trio genome or exome sequencing are eligible for the study. Positive secondary finding index cases will be matched to negative controls (1:2) based on age group, primary result(s) type, and clinical indication. During the 2-year study, 71 cases and 142 matched controls are expected. Health service use will be collected in patients and 1 adult family member every 6 months. The per-child and per-dyad total cost will be determined by multiplying use of each resource by a corresponding unit price and summing all cost items. Costs will be estimated from the public and societal payer perspectives. The mean cost per child and per dyad for secondary finding-positive and secondary finding-negative groups will be compared statistically. If important demographic differences are observed between groups, ordinary least-squares regression, log transformation, or other nonparametric technique will be used to compare adjusted mean costs. The ratio of the difference in mean cost to the secondary finding yield will be used to estimate incremental cost-effectiveness. In secondary analyses, effectiveness will be estimated using the number of clinical management changes due to secondary findings or the Clinician-Reported Genetic Testing Utility Index (C-GUIDE) score, a validated measure of clinical utility. Sensitivity analysis will be undertaken to assess the robustness of the findings to variation in key parameters. IMPLICATIONS: This study generates key evidence to inform clinical practice and funding allocation related to secondary finding testing. The inclusion of family members and a new measure of clinical utility represent important advancements in economic evaluation in genomics.

Comparing genome sequencing technologies to improve rare disease diagnostics: a protocol for the evaluation of a pilot project, Genome-wide Sequencing Ontario.

BACKGROUND: Genome-wide sequencing has emerged as a promising strategy for the timely diagnosis of rare diseases, but it is not yet available as a clinical test performed in Canadian diagnostic laboratories. We describe the protocol for evaluating a 2-year pilot project, Genome-wide Sequencing Ontario, to offer high-quality clinical genome-wide sequencing in Ontario, Canada. METHODS: The Genome-wide Sequencing Ontario protocol was codesigned by the Ontario Ministry of Health, the Hospital for Sick Children in Toronto and the Children's Hospital of Eastern Ontario in Ottawa. Enrolment of a prospective cohort of patients began on Apr. 1, 2021. Eligible cases with blood samples available for the index case and both parents (i.e., trios) are randomized to receive exome sequencing or genome sequencing. We will collect patient-level data and ascertain costs associated with the laboratory workflow for exome sequencing and genome sequencing. We will compare point estimates for the diagnostic utility and timeliness of exome sequencing and genome sequencing, and we will determine an incremental cost-effectiveness ratio (expressed as the incremental cost of genome sequencing versus exome sequencing per additional patient with a causal variant detected). INTERPRETATION: Findings from this work will provide robust evidence for the diagnostic utility, cost-effectiveness and timeliness of exome sequencing and genome sequencing, and will be disseminated via academic publications and policy briefs. Findings will inform provincial and cross-provincial policy related to the long-term organization, delivery and reimbursement of clinical-grade genome diagnostics for rare disease.

Does the person's context influence engagement in life activities following primary knee replacement? Results from a Canadian prospective cohort study.

OBJECTIVE: The impact of the context of a person's life on recovery from surgical interventions is not well understood. This study evaluated if people's social, environmental and biomedical context was associated with change in frequency in engagement in life activities after total knee replacement (TKR). METHODS: 418 people aged 30+ years who had TKR were followed presurgery to 1 year postsurgery. The outcome was change in frequency in engagement in life activities measured by the Late Life Disability Index (LLDI). Predictor variables of interest evaluated in multivariable linear regression analysis were positive and negative life events (Life Experiences Survey), development of a new comorbidity, another joint replacement and complications after TKR surgery. RESULTS: Mean age was 65 years, 36% were male; 22% and 21% had no comorbidity presurgery and postsurgery. Presurgery LLDI frequency was 69.6 (±11.4) and the mean change was 6.1 (±10.2). Thirty-four per cent and 65% reported at least one positive or negative life event. Seven per cent developed hypertension, 6% cardiovascular disease, 2% lung disease and 2% diabetes. Eleven per cent had a complication and 9% another hip or knee replaced. Smaller changes in LLDI frequency were associated with more negative life events (beta=-0.56; 95% CI -0.92 to-0.18) and complications (beta=-4.01; 95% CI -6.63 to -1.38) after adjusting for age, sex, education, body mass index, comorbidities presurgery, number of symptomatic joints and knee-specific pain and function, LLDI limitations and depression. A new comorbidity or another joint replacement was not associated with outcome in unadjusted or adjusted analysis. CONCLUSIONS: Multifaceted life experiences shape the context of peoples' lives impacting their engagement in activities important for healthy living post-TKR.

The influence of patient factors on patient-reported outcomes of orthopedic surgery involving implantable devices: a systematic review.

OBJECTIVES: Recent evidence suggests that patient factors can influence response to medical and surgical treatment and may play an under-recognized role in predicting treatment outcomes. However, the current state of knowledge concerning potential associations following orthopedic surgery in particular is unclear. The purpose of the present study was to systematically review current literature to investigate the currently known associations between pre-operative patient factors and patient-reported outcomes following orthopedic surgery. METHODS: A systematic review was performed of the PubMed database to identify original studies that investigated the relationships between one or more patient factors and patient-reported outcomes of primary orthopedic surgical procedures involving implantation of a medical device. A total of 10,174 records were identified, with 83 studies included in the final review. RESULTS: The most commonly assessed patient factors included age, sex, and body mass index (BMI), reported in 63%, 55%, and 48% of studies, respectively. The only other patient factors identified were socioeconomic status and race, both of which were assessed in a single study. Considerable heterogeneity was observed in the methods used to stratify subjects by patient factors, patient-reported outcome constructs assessed, and follow-up intervals. Only 10% of studies performed appropriate sample size or power calculations, only 51% used methodologies to control for potentially confounding factors, and 6% assessed responder status. Overall, variable and conflicting findings were seen. While female sex and increasing BMI did appear to be associated with worse absolute outcomes, these differences did not appear to be maintained when differences in baseline status were considered. No clear associations between age and outcomes were identified. CONCLUSIONS: The present understanding of these relationships between patient factors and patient-reported outcomes following orthopedic surgery is limited. There is a need for further studies using high-quality methodology, consistent stratification of participants based on patient factors, accepted patient-reported outcome constructs, and appropriate assessment of responder status.

Expectations of recovery from revision knee replacement.

OBJECTIVE: To evaluate outcome expectations of patients undergoing revision total knee replacement (TKR) and to examine personal factors, patient functioning, previous experiences with knee replacement surgery, concerns about surgery, and general health as predictors of expectations. METHODS: Revision TKR patients (n = 184, 54% women; mean age 69 years) completed a questionnaire up to 2 weeks before surgery. This included demographics, experience with previous knee surgery, concerns about surgery, the Life Orientation Test (LOT), the Arthritis Helplessness Scale, the Western Ontario and McMaster Universities Osteoarthritis Index, and a rating of overall health. Outcome expectations were evaluated as 5 questions assessing global benefit; relief of pain; ease of disability; expectations of having complications; and whether the person expected to be fully recovered from surgery in <6 months, 6-12 months, >12 months, or did not expect to recover. Predictors of each of the 5 outcome expectations were evaluated using univariable and multivariable regression analyses. RESULTS: Expectations are a multidimensional construct (Cronbach's alpha = 0.63). Expectation of global benefit of surgery was high, but was lower for benefits related to ease of pain and improved function. Concerns about surgery were a consistent predictor of all expectation outcomes in multivariable modeling. When concerns about surgery and general health were entered into the model as an interaction with expectation of recovery time as the outcome, past experience (P = 0.05), pain (P = 0.03), LOT (P = 0.03), and interaction between concerns about surgery and general health were significant predictors. CONCLUSION: Clinicians need to understand and help patients shape appropriate expectations for recovery from revision TKR.