The Pharmacogenomics Global Research Network Implementation Working Group: global collaboration to advance pharmacogenetic implementation.

Pharmacogenetics promises to optimize treatment-related outcomes by informing optimal drug selection and dosing based on an individual's genotype in conjunction with other important clinical factors. Despite significant evidence of genetic associations with drug response, pharmacogenetic testing has not been widely implemented into clinical practice. Among the barriers to broad implementation are limited guidance for how to successfully integrate testing into clinical workflows and limited data on outcomes with pharmacogenetic implementation in clinical practice. The Pharmacogenomics Global Research Network Implementation Working Group seeks to engage institutions globally that have implemented pharmacogenetic testing into clinical practice or are in the process or planning stages of implementing testing to collectively disseminate data on implementation strategies, metrics, and health-related outcomes with the use of genotype-guided drug therapy to ultimately help advance pharmacogenetic implementation. This paper describes the goals, structure, and initial projects of the group in addition to implementation priorities across sites and future collaborative opportunities.

CYP3A5 pharmacogenetic testing for tacrolimus in pediatric heart transplant patients: a budget impact analysis.

BACKGROUND: Pharmacogenomic testing can optimize drug efficacy and minimize adverse effects. CYP3A5 polymorphisms affect the metabolism of tacrolimus. We sought to estimate the budget impact of preemptive pharmacogenomic testing for CYP3A5 in pediatric heart transplantation patients from an institutional perspective. METHODS: A decision tree was constructed to estimate the budget impact of pediatric heart transplant patients (age ≤18 years) initiated on tacrolimus with and without CYP3A5 pharmacogenomic testing. The budget impact of preemptive pharmacogenomic testing versus no pharmacogenomic testing was calculated. One-way sensitivity analysis and alternative analyses were conducted to assess the robustness of results to changes in model parameters. RESULTS: CYP3A5 genotype-guided dosing provided savings of up to $17 225 per patient compared to standard dosing. These savings decreased to $11 759 when using another institution's data for the standard-dosing group. The time to achieve therapeutic concentration in the poor metabolizer genotype-guided dosing group had the largest impact on cost savings while the cost of the pharmacogenetic test had the smallest impact on cost savings. CONCLUSION: Implementing CYP3A5 testing could save $17 225 per pediatric heart transplant patient receiving tacrolimus. As pharmacogenomic testing becomes more widespread, institutions should track resource requirements and outcomes to determine the best implementation policies going forward.

Long-term natural history in type II and III spinal muscular atrophy: a 4-year international study on the Hammersmith Functional Motor Scale Expanded.

BACKGROUND AND PURPOSE: Spinal muscular atrophy (SMA) is a genetic disorder caused by SMN1 gene mutations. Although studies on available disease-modifying treatments have reported their efficacy and safety, long-term natural history data are lacking for comparison. The aim of this prospective study was to report 4-year changes on the Hammersmith Functional Motor Scale Expanded (HFMSE) in type II and III SMA in relation to several variables such as age, functional status and SMN2 copy number. METHODS: The study involves retrospective analysis of prospectively collected data from international datasets (Belgium, Italy, Spain, USA, UK). HFMSE longitudinal changes were analyzed using linear mixed effect models, examining annualized HFMSE change and its association with variables such as age at baseline, sex, motor function, SMN2 copy number. RESULTS: In SMA type II (n = 226), the 4-year mean change was -2.20 points. The largest mean changes were observed in sitters aged 5-14 years and the lowest in those who lost the ability to sit unsupported. In SMA type III (n = 162), the 4-year mean change was -2.75 points. The largest mean changes were in those aged 7-15 years, whilst the lowest were in those below 7 and in the SMA type IIIa subgroup over 15. Age and score at baseline were predictive of 4-year changes. CONCLUSIONS: Our findings provide natural history reference data for comparison with long-term follow-up of clinical trials or real-world data, highlighting the need to define patterns of changes in smaller SMA subgroups instead of reporting mean changes across an entire SMA cohort.

Upper limb function changes over 12 months in untreated SMA II and III individuals: an item-level analysis using the Revised Upper Limb Module.

The Revised upper limb module (RULM) has been increasingly used in clinical trials and in clinical settings. The aim of this study was to use the 'shift analysis' to assess the patterns of lost or gained abilities for each item on the RULM in an untreated cohort, stratified by SMA type, age, SMN2 copy number, and motor functional status. The analysis was performed on 222 12-month paired assessments from 129 individuals (115 assessment from type II and 107 from type III) who had at least two assessments at yearly intervals. There was a loss of one or more activities in 54% in type II and in 29% type III. A gain of one or more activities was found in 42% type II and in 22% type III. There were concomitant gains and losses in 27% in SMA II and in 9% in SMA III. Our results, measuring the number of abilities that are lost or gained, provide an additional method of detecting changes that can be used for the interpretation of the longitudinal data collected in treated SMA individuals.

Long-term efficacy, safety, and patient-reported outcomes of apitegromab in patients with spinal muscular atrophy: results from the 36-month TOPAZ study.

Background and purpose: At 12 months in the phase 2 TOPAZ study, treatment with apitegromab was associated with both an improved motor function in patients with Type 2 or 3 spinal muscular atrophy (SMA) and with a favorable safety profile. This manuscript reports the extended efficacy and safety in the nonambulatory group of the TOPAZ study at 36 months. Methods: Patients who completed the primary study (NCT03921528) could enroll in an open-label extension, during which patients received apitegromab 20 mg/kg by intravenous infusion every 4 weeks. Patients were assessed periodically via the Hammersmith Functional Motor Scale-Expanded (HFMSE), Revised Upper Limb Module (RULM), World Health Organization (WHO) motor development milestones, Pediatric Evaluation of Disability Inventory Computer Adaptive Test (PEDI-CAT) Daily Activities and Mobility domains, and Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue questionnaire. Results: Of the 58 patients enrolled in TOPAZ, 35 were nonambulatory (mean age 7.3 years). The mean change at 36 months in HFMSE score from baseline was +4.0 (standard deviation [SD]: 7.54), and + 2.4 (3.24) for RULM score (excluding n = 7 after scoliosis surgery). Caregiver-reported outcomes (PEDI-CAT and PROMIS Fatigue) showed improvements from baseline over 36 months. In addition, most patients (28/32) improved or maintained WHO motor milestones achieved at baseline. The most frequently reported treatment-emergent adverse events were pyrexia (48.6%), nasopharyngitis (45.7%), COVID-19 infection (40.0%), vomiting (40.0%), and upper respiratory tract infection (31.4%). Conclusion: The benefit of apitegromab treatment observed at 12 months was sustained at 36 months with no new safety findings.

Changes in abilities over the initial 12 months of nusinersen treatment for type II SMA.

Several studies have shown the efficacy of new disease-modifying therapies in slowing down type II SMA progression using the Hammersmith Functional Motor Scale Expanded (HFMSE). This research aims to enhance understanding of activity changes across age groups post-nusinersen treatment using shift analysis, compared with untreated individuals. Retrospective data from the, international SMA consortium (iSMAc) dataset were analyzed, assessing individual item changes over 12 months. Shift analysis was used to determine the gain or loss of abilities, defining "gain" as a positive change between scores from 0 to either 1 or 2 and "loss" as a negative change from either 2 or 1 to 0. The cohort included 130 SMA II patients who underwent 12-month assessments from their first nusinersen dose, with age range between 0.6 and 49.6 years. One-third of the entire cohort experienced at least a loss in one activity, while 60% experienced a gain, particularly notable in children aged 2.5 to 5 years and 5 to 13 years. Overall, the study demonstrates a positive impact of nusinersen treatment on SMA II patients, showing a trend of increased activity gains and decreased probability of ability loss across different age groups.

Beyond Contractures in Spinal Muscular Atrophy: Identifying Lower-Limb Joint Hypermobility.

Background: The natural history of spinal muscular atrophy (SMA) is well understood, with progressive muscle weakness resulting in declines in function. The development of contractures is common and negatively impacts function. Clinically, joint hypermobility (JH) is observed but is poorly described, and its relationship with function is unknown. Methods: Lower-limb ROM (range of motion) assessments of extension and flexion at the hip, knee, and ankle were performed. ROMs exceeding the published norms were included in the analysis. The functional assessments performed included the six-minute walk test (6 MWT) and the Hammersmith Functional Motor Scale-Expanded (HFMSE). Results: Of the 143 participants, 86% (n = 123) had at least one ROM measure that was hypermobile, and 22% (n = 32) had three or more. The HFMSE scores were inversely correlated with hip extension JH (r = -0.60, p = 0.21; n = 6) and positively correlated with knee flexion JH (r = 0.24, p = 0.02, n = 89). There was a moderate, inverse relationship between the 6 MWT distance and ankle plantar flexion JH (r = -0.73, p = 0.002; n = 15). Conclusions: JH was identified in nearly all participants in at least one joint in this study. Hip extension, knee flexion and ankle plantar flexion JH was associated with function. A further understanding of the trajectory of lower-limb joint ROM is needed to improve future rehabilitation strategies.

Determining minimal clinically important differences in the Hammersmith Functional Motor Scale Expanded for untreated spinal muscular atrophy patients: An international study.

BACKGROUND AND PURPOSE: Spinal muscular atrophy (SMA) is a rare and progressive neuromuscular disorder with varying severity levels. The aim of the study was to calculate minimal clinically important difference (MCID), minimal detectable change (MDC), and values for the Hammersmith Functional Motor Scale Expanded (HFMSE) in an untreated international SMA cohort. METHODS: The study employed two distinct methods. MDC was calculated using distribution-based approaches to consider standard error of measurement and effect size change in a population of 321 patients (176 SMA II and 145 SMA III), allowing for stratification based on age and function. MCID was assessed using anchor-based methods (receiver operating characteristic [ROC] curve analysis and standard error) on 76 patients (52 SMA II and 24 SMA III) for whom the 12-month HFMSE could be anchored to a caregiver-reported clinical perception questionnaire. RESULTS: With both approaches, SMA type II and type III patients had different profiles. The MCID, using ROC analysis, identified optimal cutoff points of -2 for type II and -4 for type III patients, whereas using the standard error we found the optimal cutoff points to be 1.5 for improvement and -3.2 for deterioration. Furthermore, distribution-based methods uncovered varying values across age and functional status subgroups within each SMA type. CONCLUSIONS: These results emphasize that the interpretation of a single MCID or MDC value obtained in large cohorts with different functional status needs to be made with caution, especially when these may be used to assess possible responses to new therapies.

Disease Trajectories in the Revised Hammersmith Scale in a Cohort of Untreated Patients with Spinal Muscular Atrophy types 2 and 3.

Background: Spinal muscular atrophy (SMA) is a neuromuscular disorder characterised by progressive motor function decline. Motor function is assessed using several functional outcome measures including the Revised Hammersmith Scale (RHS). Objective: In this study, we present longitudinal trajectories for the RHS in an international cohort of 149 untreated paediatric SMA 2 and 3 patients (across 531 assessments collected between March 2015 and July 2019). Methods: We contextualise these trajectories using both the Hammersmith Functional Motor Scale Expanded (HFMSE) and Revised Upper Limb Module (RULM). At baseline, this cohort included 50% females and 15% of patients had undergone spinal fusion surgery. Patient trajectories were modelled using a natural cubic spline with age, sex, and random effects for each patient. Results: RHS and HFMSE scores show similar trends over time in this cohort not receiving disease modifying therapies. The results confirm the strong correlation between the RHS and RULM previously observed in SMA types 2 and 3a. Scoliosis surgery is associated with a reduction of 3 points in the RHS, 4.5 points in the HFMSE for the SMA 2 population, and a reduction of 11.8 points in the RHS, and 13.4 points in the HFMSE for the SMA 3a populations. When comparing the RHS and RULM, there is a lower correlation in the type 3a's than the type 2 patients. In the SMA 2 population, there is no significant difference between the sexes in either the RHS or HFMSE trajectories. There is no significant difference in the RULM trajectory in the SMA 2 or 3a participants by sex. Conclusions: This study demonstrates that the RHS could be used in conjunction with other functional measures such as the RULM to holistically detect SMA disease progression. This will assist with fully understanding changes that occur with treatments, further defining trajectories and therapy outcomes.

Risk of Toxicity From Topical 5-Fluorouracil Treatment in Patients Carrying DPYD Variant Alleles.

Patients carrying DPYD variant alleles have increased risk of severe toxicity from systemic fluoropyrimidine chemotherapy. There is a paucity of data regarding risk of toxicity from topical 5-fluorouracil (5-FU) treatment in these patients, leading to inconsistent guideline recommendations for pretreatment testing and topical 5-FU dosing. The objective of this retrospective cohort study was to investigate whether DPYD variant allele carriers have increased risk of toxicity from topical 5-FU. Treatment and toxicity data were retrospectively abstracted from the electronic medical records. Genotypes for the five DPYD variants that are associated with increased toxicity from systemic fluoropyrimidine chemotherapy (DPYD*2A, DPYD*13, DPYD p.D949V, DPYD HapB3, and DPYD p.Y186C) were collected from a genetic data repository. Incidence of grade 3+ (primary end point) and 1+ (secondary end point) toxicity was compared between DPYD variant carriers vs. wild-type patients using Fisher's exact tests. The analysis included 201 patients, 7% (14/201) of whom carried a single DPYD variant allele. No patients carried two variant alleles or experienced grade 3+ toxicity. DPYD variant allele carriers did not have a significantly higher risk of grade 1+ toxicity (21.4% vs. 10.2%, odds ratio = 2.40, 95% confidence interval: 0.10-2.53, P = 0.19). Given the low toxicity risk in patients carrying a single DPYD variant allele, there is limited potential clinical benefit of DPYD genetic testing prior to topical 5-FU. However, the risk of severe toxicity in patients with complete DPD deficiency remains unknown and topical 5-FU treatment should be avoided in these patients.

Accurate COP Trajectory Estimation in Healthy and Pathological Gait Using Multimodal Instrumented Insoles and Deep Learning Models.

Measuring center-of-pressure (COP) trajectories in out-of-the-lab environments may provide valuable information about changes in gait and balance function related to natural disease progression or treatment in neurological disorders. Traditional equipment to acquire COP trajectories includes stationary force plates, instrumented treadmills, electronic walkways, and insoles featuring high-density force sensing arrays, all of which are expensive and not widely accessible. This study introduces novel deep recurrent neural networks that can accurately estimate dynamic COP trajectories by fusing data from affordable and heterogeneous insole-embedded sensors (namely, an eight-cell array of force sensitive resistors (FSRs) and an inertial measurement unit (IMU)). The method was validated against gold-standard equipment during out-of-the-lab ambulatory tasks that simulated real-world walking. Root-mean-square errors (RMSE) in the mediolateral (ML) and anteroposterior (AP) directions obtained from healthy individuals (ML: 0.51 cm, AP: 1.44 cm) and individuals with neuromuscular conditions (ML: 0.59 cm, AP: 1.53 cm) indicated technical validity. In individuals with neuromuscular conditions, COP-derived metrics showed significant correlations with validated clinical measures of ambulatory function and lower-extremity muscle strength, providing proof-of-concept evidence of the convergent validity of the proposed method for clinical applications.

Confirmatory DPYD Testing in Patients Receiving Fluoropyrimidines Who are Suspected DPYD Variant Carriers Based on a Genetic Data Repository.

Using pharmacogenetics (PGx) to inform clinical decision making can benefit patients but clinical use of PGx testing has been limited. Existing genetics data obtained in the course of research could be used to identify patients who are suspected, but have not yet been confirmed, to carry clinically actionable genotypes, in whom confirmatory genetic testing could be conducted for highly efficient PGx implementation. Herein, we demonstrate that it is regulatorily and technically feasible to implement PGx by identifying suspected carriers of actionable genotypes within an institutional genetics data repository and conduct confirmatory PGx testing immediately prior to that patient receiving the PGx-relevant drug, using a case study of DPYD testing prior to fluoropyrimidine chemotherapy. In 2 years since launching this program, ~ 3,000 suspected DPYD carriers have been passively monitored and one confirmed DPYD carrier was prevented from receiving unacceptably toxic fluoropyrimidine treatment, for minimal cost and effort. Now that we have demonstrated the feasibility of this strategy, we plan to transition to PGx panel testing and expand implementation to other genes and drugs for which the evidence of clinical benefit of PGx-informed treatment is high but PGx testing is not generally conducted. This highly efficient implementation process will maximize the clinical benefits of testing and could be explored at other institutions that have research-only genetic data repositories to expand the number of patients who benefit from PGx-informed treatment while we continue to work toward wide-scale adoption of PGx testing and implementation.

Development of an International SMA Bulbar Assessment for Inter-professional Administration.

BACKGROUND: Progressive weakness can affect bulbar muscles in individuals with moderate to severe forms of spinal muscular atrophy (SMA). The paucity of standardized, valid bulbar assessments capturing clinically significant deficits in SMA impedes the ability to monitor function, facilitate intervention, or detect treatment response. OBJECTIVE: To fill this void, an international multidisciplinary team gathered to develop an agreed upon consensus-derived assessment of bulbar function in SMA for inter-professional administration to enhance our ability to monitor disease progression, support clinical management, and evaluate treatment effects. METHODS: Fifty-six international clinicians experienced in SMA were invited and engaged using the Delphi method over multiple rounds of web-based surveys to establish consensus. RESULTS: Serial virtual meetings occurred with 42 clinicians (21 speech and language therapists, 11 physical therapists, 5 neurologists, 4 occupational therapists, and 1 dentist). Seventy-two validated assessments of bulbar function were identified for potential relevance to individuals with SMA (32 accessible objective, 11 inaccessible objective, 29 patient-reported outcomes). Delphi survey rounds (n = 11, 15, 15) achieved consensus on individual items with relevance and wording discussed. Key aspects of bulbar function identified included: oral intake status, oral facial structure and motor strength, swallowing physiology, voice & speech, and fatigability. CONCLUSIONS: Multidisciplinary clinicians with expertise in bulbar function and SMA used Delphi methodology to reach consensus on assessments/items considered relevant for SMA across all age groups. Future steps include piloting the new scale moving towards validation/reliability. This work supports the advancement of assessing bulbar function in children and adults with SMA by a variety of professionals.

2-Year Change in Revised Hammersmith Scale Scores in a Large Cohort of Untreated Paediatric Type 2 and 3 SMA Participants.

The Revised Hammersmith Scale (RHS) is a 36-item ordinal scale developed using clinical expertise and sound psychometrics to investigate motor function in participants with Spinal Muscular Atrophy (SMA). In this study, we investigate median change in the RHS score up to two years in paediatric SMA 2 and 3 participants and contextualise it to the Hammersmith Functional Motor Scale-Expanded (HFMSE). These change scores were considered by SMA type, motor function, and baseline RHS score. We consider a new transitional group, spanning crawlers, standers, and walkers-with-assistance, and analyse that alongside non-sitters, sitters, and walkers. The transitional group exhibit the most definitive change score trend, with an average 1-year decline of 3 points. In the weakest patients, we are most able to detect positive change in the RHS in the under-5 age group, whereas in the stronger patients, we are most able to detect decline in the RHS in the 8-13 age group. The RHS has a reduced floor effect compared to the HFMSE, although we show that the RHS should be used in conjunction with the RULM for participants scoring less than 20 points on the RHS. The timed items in the RHS have high between-participant variability, so participants with the same RHS total can be differentiated by their timed test items.

Assessing Bulbar Function in Spinal Muscular Atrophy Using Patient-Reported Outcomes.

BACKGROUND: Novel Spinal Muscular Atrophy (SMA) treatments have demonstrated improvements on motor measures that are clearly distinct from the natural history of progressive decline. Comparable measures are needed to monitor bulbar function, which is affected in severe SMA. OBJECTIVE: To assess bulbar function with patient-reported outcome measures (PROs) and determine their relationships with clinical characteristics. METHODS: We recruited 47 non-ambulatory participants (mean (SD) age = 29.8 (13.7) years, range = 10.3-73.2) with SMA. PROs including Voice Handicap Index (VHI) and Eating Assessment Tool-10 (EAT-10) were collected alongside clinical characteristics and standardized motor assessments. Associations were assessed using Spearman correlation coefficients and group comparisons were performed using Wilcoxon rank sum tests. RESULTS: A majority of the 47 participants were SMA type 2 (70.2%), non-sitters (78.7%), 3 copies of SMN2 (77.5%), and using respiratory support (66.0%). A majority (94%) reported voice issues primarily in 8/30 VHI questions. Problems included: difficulty understanding me in a noisy room (87.2%); difficult for people to hear me (74.5%); and people ask me to repeat when speaking face-to-face (72.3%). A majority (85.1%) reported swallowing issues primarily in 3/10 EAT-10 questions: swallowing pills (68.1%); food sticks to my throat (66.0%); and swallowing solids (61.7%). The two PROs were moderately associated (rs = 0.66). CONCLUSIONS: Weaker individuals with SMA experience bulbar problems including difficulties with voice and swallowing. Further refinement and assessment of functional bulbar scales will help determine their relevance and responsiveness to changes in SMA. Additional study is needed to quantify bulbar changes caused by SMA and their response to disease-modifying treatments.

Predictive Capacity of Population Pharmacokinetic Models for the Tacrolimus Dose Requirements of Pediatric Solid Organ Transplant Recipients.

BACKGROUND: Transplant recipients require individualized tacrolimus doses to maximize graft survival. Multiple pediatric tacrolimus population pharmacokinetic (PopPK) models incorporating CYP3A5 genotype and other covariates have been developed. Identifying the optimal popPK model is necessary for clinical implementation in pediatric solid organ transplant. The primary objective was to compare the dose prediction capabilities of the developed models in pediatric kidney and heart transplant recipients. METHODS: Pediatric kidney or heart transplant recipients treated with tacrolimus and available CYP3A5 genotype data were identified. The initial weight-based tacrolimus dose and first therapeutic tacrolimus dose were collected retrospectively. Three published popPK models were used to predict the tacrolimus dose required to achieve a tacrolimus trough concentration of 10 ng/mL. Model dose predictions were compared with the initial and first therapeutic doses using Friedman test. The first therapeutic dose was plotted against the model-predicted dose. RESULTS: The median initial dose approximately 2-fold lower than the first therapeutic dose for CYP3A5 expressers. The Chen et al model provided the closest estimates to the first therapeutic dose for kidney transplant recipients; however, all 3 models tended to underpredict the observed therapeutic dose. For heart transplant recipients, Andrews et al model predicted doses that were higher than the initial dose but similar to the actual therapeutic dose. CONCLUSIONS: Weight-based tacrolimus dosing appears to underestimate the tacrolimus dose requirements. The development of a separate popPK model is necessary for heart transplant recipients. A genotype-guided strategy based on the Chen et al model provided the best estimates for doses in kidney transplant recipients and should be prospectively evaluated.

Identifying the prevalence of clinically actionable drug-gene interactions in a health system biorepository to guide pharmacogenetics implementation services.

Understanding patterns of drug-gene interactions (DGIs) is important for advancing the clinical implementation of pharmacogenetics (PGx) into routine practice. Prior studies have estimated the prevalence of DGIs, but few have confirmed DGIs in patients with known genotypes and prescriptions, nor have they evaluated clinician characteristics associated with DGI-prescribing. This retrospective chart review assessed prevalence of DGI, defined as a medication prescription in a patient with a PGx phenotype that has a clinical practice guideline recommendation to adjust therapy or monitor drug response, for patients enrolled in a research genetic biorepository linked to electronic health records (EHRs). The prevalence of prescriptions for medications with pharmacogenetic (PGx) guidelines, proportion of prescriptions with DGI, location of DGI prescription, and clinical service of the prescriber were evaluated descriptively. Seventy-five percent (57,058/75,337) of patients had a prescription for a medication with a PGx guideline. Up to 60% (n = 26,067/43,647) of patients had at least one DGI when considering recommendations to adjust or monitor therapy based on genotype. The majority (61%) of DGIs occurred in outpatient prescriptions. Proton pump inhibitors were the most common DGI medication for 11 of 12 clinical services. Almost 25% of patients (n = 10,706/43,647) had more than one unique DGI, and, among this group of patients, 61% had a DGI with more than one gene. These findings can inform future clinical implementation by identifying key stakeholders for initial DGI prescriptions, helping to inform workflows. The high prevalence of multigene interactions identified also support the use of panel PGx testing as an implementation strategy.

Functional outcome measures in young, steroid-naïve boys with Duchenne muscular dystrophy.

The purpose of this study was to quantitate motor performance in 196 genetically confirmed steroid-naïve boys with Duchenne muscular dystrophy (DMD), to evaluate the test-retest reliability of measures of motor performance in young DMD boys, and to assess correlations among the different functional outcomes including timed tests. Boys aged 4-7 years were recruited in the FOR-DMD study, a comparative effectiveness study of different steroid regimens in DMD. Eligible boys had to be able to rise from the floor independently and to perform pulmonary function testing consistently. The boys were evaluated with standardized assessments at the screening and baseline visits at 32 sites in 5 countries (US, UK, Canada, Italy, Germany). Assessments included timed rise from floor, timed 10 m walk/run, six-minute walk distance, North Star Ambulatory Assessment (NSAA) and forced vital capacity (FVC). Mean age at baseline was 5.9 years (range 4.1-8.1 years). Test-retest reliability was high for functional assessments, regardless of time lag between assessments (up to 90 days) and for the majority of age groups. Correlations were strong among the functional measures and timed tests, less so with FVC. Physiotherapy measures are reliable in a young, steroid-naïve population and rise from floor velocity appears to be a sensitive measure of strength in this population.

Best-worst scaling methodology to evaluate constructs of the Consolidated Framework for Implementation Research: application to the implementation of pharmacogenetic testing for antidepressant therapy.

BACKGROUND: Despite the increased demand for pharmacogenetic (PGx) testing to guide antidepressant use, little is known about how to implement testing in clinical practice. Best-worst scaling (BWS) is a stated preferences technique for determining the relative importance of alternative scenarios and is increasingly being used as a healthcare assessment tool, with potential applications in implementation research. We conducted a BWS experiment to evaluate the relative importance of implementation factors for PGx testing to guide antidepressant use. METHODS: We surveyed 17 healthcare organizations that either had implemented or were in the process of implementing PGx testing for antidepressants. The survey included a BWS experiment to evaluate the relative importance of Consolidated Framework for Implementation Research (CFIR) constructs from the perspective of implementing sites. RESULTS: Participating sites varied on their PGx testing platform and methods for returning recommendations to providers and patients, but they were consistent in ranking several CFIR constructs as most important for implementation: patient needs/resources, leadership engagement, intervention knowledge/beliefs, evidence strength and quality, and identification of champions. CONCLUSIONS: This study demonstrates the feasibility of using choice experiments to systematically evaluate the relative importance of implementation determinants from the perspective of implementing organizations. BWS findings can inform other organizations interested in implementing PGx testing for mental health. Further, this study demonstrates the application of BWS to PGx, the findings of which may be used by other organizations to inform implementation of PGx testing for mental health disorders.

Survey of US Medical Oncologists' Practices and Beliefs Regarding DPYD Testing Before Fluoropyrimidine Chemotherapy.

PURPOSE: Patients who carry reduced-activity DPYD polymorphisms have increased fluoropyrimidine (FP) toxicity risk. Although pretreatment DPYD testing is recommended throughout most of Europe, it is not recommended in the United States, and adoption has been limited. The objective of this survey was to describe the current practice in the United States regarding pretreatment DPYD testing and understand the factors deterring oncologists from ordering testing. METHODS: Survey invitations were e-mailed to 325 medical oncologists practicing in the United States who are members of the SWOG Cancer Research Network Gastrointestinal Cancer, Breast Cancer, or Early Therapeutics Committees. Descriptive statistics were used to evaluate survey responses. RESULTS: Responses were collected from 59 (18.2%) US medical oncologists, of whom 98% strongly or somewhat agree that patients with dihydropyrimidine dehydrogenase (DPD) deficiency have increased toxicity risk and 96% would modify FP dosing for a patient with known DPD deficiency. However, only 32% strongly or somewhat agree that pretreatment DPYD testing is useful to inform FP treatment, 20% have ever ordered pretreatment testing, and 3% order testing for at least 10% of their FP-treated patients. The most important factors that deter oncologists from ordering testing were low prevalence of DPD deficiency (54%) and lack of clinical practice guideline recommendations (48%). CONCLUSION: Clinical adoption of pretreatment DPYD testing is extremely limited in the United States. Utilization may be substantially increased by inclusion in the oncology clinical practice guideline recommendations, coverage through health insurance, and potentially education of medical oncologists regarding available treatment modification guidelines.