Measurement of respiratory function decline in patients with Duchenne muscular dystrophy: a conjoint analysis

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1 For reprint orders, please contact: Measurement of respiratory function decline in patients with Duchenne muscular dystrophy: a conjoint analysis Elena Ripamonti*,1 & Grazia D Angelo 2 1 Elma Research s.r.l., Via Felice Casati 32, Milano, Italy 2 Unità Operativa Semplice Patologie Neuromuscolari, Riabilitazione Funzionale, IRCCS E. Medea, Via Don Luigi Monza, 20, Bosisio Parini LC, Italy * Author for correspondence: eripamonti@elmaresearch.com Aim: In Duchenne muscular dystrophy (DMD), little attention has been paid to severity of respiratory function decline (RFD) based on disease progression. We performed a conjoint analysis among 123 Italian clinicians to generate a scale for RFD in DMD patients. Methods: Before the interview, 11 attributes were selected by discussion among experts. Thirty-two patient profiles were generated. Each physician assessed the severity of RFD for each profile. Each level/attribute was assigned an estimated usefulness to understand its impact on RFD. Results: The identified attributes were forced vital capacity, forced vital capacity decline, dysphagia, type of ventilation and peak cough flow. These results allowed the development of a scale for RFD severity. Conclusion: This scale can stratify DMD patients according to the severity of their RFD. First draft submitted: 11 vember 2017; Accepted for publication: 15 January 2018; Published online: 07 February 2018 Keywords: conjoint analysis Duchenne muscular dystrophy pulmonary function respiratory function Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy, which causes progressive weakness of all the striated muscles [1,2]. The consequences of this progressive weakness are progressive impairment of motor skills, loss of ambulation, cardiac complications and breathing difficulties. If left untreated, DMD ultimately leads to death around the age of 20 due to cardiac and respiratory failure [2]. However, the natural history of the disease may be modified thanks to a more comprehensive therapeutic approach, which also comprises adequate respiratory care [2 4]. In particular, respiratory care includes proper monitoring of respiratory function to deal with respiratory complications timely, lung volume recruitment techniques, the use of a cough-assisted device to improve airway clearance, pharmacological management and noninvasive ventilation [2 4]. When DMD is properly managed, the life expectancy of the affected patient can extend up to the fourth decade [2 5]. However, in clinical practice, loss of respiratory function continues to be a predominant cause of early morbidity and mortality in DMD patients [6]. Therefore, prevention of these complications and institution of early treatment as necessary now represent major goals [7]. To this end, tools able to stratify patients on the basis of their risk to develop respiratory complications would be a landmark improvement in the management of DMD. Conjoint analysis is a survey-based statistical approach, which helps determine how people value different attributes such as features, functions and benefits that ultimately make up an individual entity. teworthy, this approach has been recently used in the rheumatology field to stratify clinical response to treatment in patients with juvenile dermatomyositis [8]. Given its characteristics, conjoint analysis can be a valuable tool for the stratification of risk of pulmonary decline and respiratory complications in DMD patients. We have therefore conducted a conjoint analysis among Italian clinicians involved in the treatment of neuromuscular disorders, with the aim to generate a scale measuring the severity of the respiratory function decline (RFD) in DMD patients based on commonly agreed predictive and prognostic factors /nmt C 2018 Elena Ripamonti Neurodegener. Dis. Manag. (Epub ahead of print) ISSN

2 Ripamonti & D Angelo Table 1. Details of the participants (n = 123). Characteristic Percentage Speciality (%) Neurologists 76% Neuropsychiatrists 12% Pediatricians 4% Geneticists 3% Pulmonologists 2% Other 3% Number of patients with neuromuscular disorders seen per month, mean 36 ± 28 Number of patients with neuromuscular disorders seen per month (%) Up to 15 23% % % % % Over 55 16% Years of experience on neuromuscular disorders, mean 12 ± 10 Years of experience on neuromuscular disorders (%) Less than 2 5% % % % % Over 21 19% Methods Setting During the 17th National Congress of the Italian Myology Society (AIM), which took place in Siracusa on 31 May 3 June 2017, two interviewers from Elma Research (Milan, Italy), a well-recognized market research group specialized in the medicine and pharmaceutical fields, interviewed 123 physicians involved in the management of neuromuscular disorders, who freely decided to participate in the analysis. Information on the participants is provided in Table 1. The wide majority of participants (76%) were neurologists, with a mean of 12 years of experience in the treatment of neuromuscular disorders. On average, each physician treated 6.5 different neuromuscular disorders. Design & analysis Conjoint analysis Before the interview, a group of experts of DMD was asked to list attributes and their correlates able to describe severity of RFD in DMD patients, on the basis of their clinical experience and available literature [1 6,9 10]. Withthis approach, 11 attributes distributed on a total of 30 levels have been identified to provide an exhaustive picture of the clinical situation and symptoms associated with RFD in patients with DMD (Table 2). Then, 32 patient profiles were generated through an orthogonal fractional design to represent a complete pool of 41,472 combinations of attributes and levels. These profiles were then randomized and tested with the sample of interviewed physicians. Each physician assessed the severity of the decline in pulmonary function according to the showed symptoms for each of the 32 profiles using a continuous visual analog scale (0 10 cm). Through the conjoint analysis, each level tested was assigned an estimated usefulness and each attribute was assigned an importance to understand their impact on the perceived severity of the RFD and on the definition of the different levels of severity. Data were then transformed on a 0 1 scale in order to estimate the usefulness of each level in evaluating the severity of RFD. Utilities close to 0 do not play a role in the definition of severity. The further from 0, the more levels contribute (positively or negatively) to defining severity /nmt Neurodegener. Dis. Manag. (Epub ahead of print) future science group

3 Measurement of respiratory function decline in patients with Duchenne muscular dystrophy: a conjoint analysis Research Article Table 2. Attributes and levels considered in the conjoint analysis. Attribute Levels FVC predicted absolute FVC predicted absolute: 71 80% FVC predicted absolute: 61 70% FVC predicted absolute: 50 60% FVC predicted absolute: 50% FVC predicted absolute decline decline in FVC predicted absolute in the last year -2% in the last year -5% in the last year -8% in the last year PCF PCF: 270 l/min PCF: l/min PCF: 160 l/min Dysphagia dysphagia Dysphagia without PEG Dysphagia and PEG feeding Airways infections Less than 2 infections which required hospitalization in the last year 2 or more infections which required hospitalization in the last year Ventilation ventilation ninvasive night ventilation ninvasive night and day ventilation Cough assist machine With cough assist machine Without cough assist machine Sleep disorders (morning headaches) sleep disorders (does not have morning headaches) Sleep disorders (has morning headaches) Echocardiogram rmal ejection fraction Pathological ejection fraction Obesity/weight gain signs of obesity/weight gain (BMI 25) Signs of obesity/weight gain (BMI 25) Ambulation Assisted ambulation Wheelchair dependent Wheelchair dependent with reduced upper limb mobility FVC: Forced vital capacity; PCF: Peak cough flow. Complementary analysis In a complementary analysis, each physician interviewed was asked to choose from the list of 11 identified attributes, those which they considered important for the assessment of the severity of the RFD, and rank them in order of importance. The results were then compared with those of the conjoint analysis. Statistical analysis Data were then analyzed by descriptive statistics: percentage, means and standard deviations. For complementary analysis, the ranking declared by physicians was assessed based on their mean weighted rating scores per attribute. The relative importance of each of the attributes was determined by means of a linear model. The effect size of each attribute was expressed as a β-coefficient above or below 0 (the reference value) that indicates that the attribute contributes to a higher or lower severity score, respectively. A p-value <0.05 was considered statistically significant. The descriptive analyses were performed using Quantum software, while all analyses related to conjoint analysis were performed using the SPSS software. Results Conjoint analysis Overall, no specific attribute or level played a predominant role, and therefore multiple factors were identified to contribute to the assessment of the RFD (Figure 1). future science group /nmt

4 Ripamonti & D Angelo With assistance Walking ability Echocardiography Sleep disturbances (morning cephalea) Respiratory tract infections Obesity/weight gain Cough machine On wheelchair On wheelchair and poor function of upper limbs rmal LVEF Abnormal LVEF Yes < 2 episodes requiring hospitalization in the last year 2 episodes requiring hospitalization in the last year (BMI <25) Yes (BMI 25) Yes FVC predicted absolute: 71 80% FVC Predicted absolute Decline FVC Predicted absolute in the last year Dysphagia Ventilation PCF FVC predicted absolute: 61 70% FVC predicted absolute: 50 60% FVC predicted absolute: <50% -2% -5% -8% Yes, without PEG Yes, with PEG n invasive, at nights n invasive, at nights and days PCF: >270 l/min PCF: 270 l/min l/min PCF: <160 l/min Figure 1. Conjoint analysis: estimated usefulness of levels. The relative importance of each of the attributes was determined by means of a linear model. The effect size of each attribute was expressed as a β-coefficient above or below 0 (the reference value) that indicates that the attribute contributes to a higher or lower severity score, respectively /nmt Neurodegener. Dis. Manag. (Epub ahead of print) future science group

5 Measurement of respiratory function decline in patients with Duchenne muscular dystrophy: a conjoint analysis Research Article Table 3. Concordance between the ranking of attributes identified of the conjoint analysis and the ranking declared by physicians. Ranking identified in the conjoint analysis Ranking Ranking declared FVC predicted absolute 1# FVC predicted absolute decline FVC predicted absolute decline 2# FVC predicted absolute decline Dysphagia and PEG 3# Airways infections Type of ventilation 4# PCF levels PCF levels 5# Sleep disorders (morning headaches) Type of ambulation 6# Dysphagia and PEG Echocardiogram and ejection fraction 7# Cough assist machine Sleep disorders (morning headaches) 8# Type of ventilation Airways infections 9# Echocardiogram and ejection fraction Obesity & weight gain (BMI) 10# Obesity & weight gain (BMI) Cough assist machine 11# Type of ambulation FVC: Forced vital capacity; PCF: Peak cough flow; PEG: Percutaneous endoscopic gastrostomy. Then, the first five attributes in terms of importance were forced vital capacity (FVC), FVC decline, dysphagia and type of ventilation and peak cough flow (PCF). Together, they accounted for 63% of the perceived severity, with no differences between physicians specifically involved in the treatment of DMD (n = 63 51%) and those who were not (n = 60 49%). Complementary analysis Results of the complementary analysis are shown in Table 3. Overall, concordance between the ranking of attributes identified of the conjoint analysis and the ranking declared by physicians was good, with 3/5 attributes (FVC, FVC decline and PCF) ranked as the most important five in each group. However, some discrepancies were identified, for example, a perceived higher importance of airways infections and sleep disorders compared with the actual results of the conjoint analysis. Development of a scale These results represented the basis for the development of a scale for RFD (Figure 2). In more details, patients with minimum and maximum severity were identified by adding up the minimum usefulness scores for all the levels for the former, and maximum usefulness scores for the latter. Severity ratings were normalized on a scale from 0 to 10; the scale was divided into four parts with equidistant scores: mild (scores 0 2.5); mild moderate (scores 2.6 5); moderate severe (scores ); and severe (7.6 10). By entering patients clinical levels and symptoms into the tool, the developed algorithm positions patients in this severity scale for RFD. With this tool, all possible patients may be assessed on this severity scale. The scale can be presented either in an extensive version (all 11 attributes considered) or in a short version (only five most significant attributes considered). Discussion Proper management of the decline of respiratory function has a major role in prolonging survival of DMD patients [2,5]. To this end, a number of measures are used, including lung volume recruitment, cough-assisted devices, ventilation techniques and pharmacological therapy [11 13]. This latter was based, until some years ago, on glucocorticoids [5,6]; however, not all patients respond to these medications, which are also associated with relevant side effects [14]. Side effects are more relevant at time of loss of ambulation (i.e., alteration of bone metabolism and risk of spontaneous fractures) [15]. This gap has been fixed by the introduction of a different molecule: idebenone, a short-chain benzoquinone characterized by potent antioxidant activity and with the ability to stimulate mitochondrial electron flux and cellular energy production [16,17]. It has been shown in multicenter clinical trials that idebenone is able to slow the decline of pulmonary function of DMD patients, with a consequent reduced risk of bronchopulmonary complications and a reduced need for systemic antibiotics [6 7,18 19]. Since now effective and safe therapies are able to slow down respiratory symptoms which appear available, the key issue is to institute a dedicated management and treatment early in the natural course of the disease, when the future science group /nmt

6 Ripamonti & D Angelo Please select from drop down menu FVC predicted absoluted FVC predicted absolute decline Dysphagia Ventilation PCF Ambulation Echocardiogram Sleep disorders (morning headaches) Airways infections Obesity/weight gain Cough assist machine FVC predicted absolute: < 50% 8% in the last year dysphagia n-invasive night and day ventilation PCF: 270 I/min 160 I/min Wheelchair dependent Pathological ejection fraction Sleep disorders (has morning headaches) Less than 2 infections which required hospitalisation in the last year Signs of obesity/weight gain (BMI 25) Without cough assist machine Level of severity Moderate severe 7.09 Min Figure 2. Severity scale for respiratory function decline. decline of pulmonary function is still mild. To this end, our analysis led to the definition of a simple scale, with potential large-scale availability (e.g., with a web-based tool), able to stratify patients according to the severity of their decline of pulmonary function as assessed by a number of well-recognized parameters. By this scale, patients may be given adequate monitoring and treatment according to the actual level of pulmonary function decline. Conclusion Our conjoint analysis, conducted in Italy, was developed according to a statistical method with mounting importance in medicine [8], and therefore it can be considered robust although it was conducted on the evaluation of computer generated patient profiles and not on actual patients. Similarly, attributes were identified ab initio by experts and we cannot rule out that other attributes (e.g., symptoms of chronic alveolar hypoventilation, probnp, use of steroids, cough assist machine or noninvasive overnight monitoring of carbon dioxide, overnight SpO 2 and maximum inspiration capacity could have been evaluated) could contribute to a closer definition of severity of respiratory symptoms. Therefore, further validation in a larger, international sample of physicians, including expert pneumologists, by another robust approach such as a multidisciplinary Delphi panel and/or web-based collection of consensus appears necessary. Moreover, the score must be correlated with clinical findings and compared with standard testing based on guidelines, in order to correlate the perceived decline and its quantitative evaluation by pneumologists. This will help define clinical approach in line with the severity of pulmonary function evaluated by our score and allow early management of DMD patients /nmt Neurodegener. Dis. Manag. (Epub ahead of print) future science group

7 Measurement of respiratory function decline in patients with Duchenne muscular dystrophy: a conjoint analysis Research Article Summary points In Duchenne muscular dystrophy (DMD), little attention has been paid to severity of respiratory function decline (RFD) based on disease progression. We performed a conjoint analysis among 123 Italian clinicians to generate a scale for RFD in DMD patients. Before the interview, 11 attributes were selected by discussion among experts. Thirty-two patient profiles were generated. Each physician assessed the severity of RFD for each profile. Each level/attribute was assigned an estimated usefulness to understand its impact on RFD. The identified attributes were forced vital capacity, forced vital capacity decline, dysphagia, type of ventilation and peak cough flow. These results allowed the development of a scale for RFD severity. This scale can stratify DMD patients according to the severity of their RFD. Further validation in a larger, international sample of physicians, including expert pneumologists, by another robust approach such as a multidisciplinary Delphi panel and/or web-based collection of consensus appears necessary. This score must be correlated with clinical findings and compared with standard testing based on guidelines, in order to correlate the perceived decline and its quantitative evaluation. This will help define clinical approach in line with the severity of pulmonary function evaluated by our score and allow early management of DMD patients. Acknowledgements The research was conducted at the Santhera stand at 17th National Congress of the Italian Myology Society (AIM), Siracusa on 31 May 3 June Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Editorial assistance for the preparation of this manuscript was provided by L Giacomelli on behalf of Elma Research; this assistance was supported by Santhera. Open access This work is licensed under the Attribution-nCommercial-Derivatives 4.0 Unported License. To view a copy of this license, visit References Papers of special note have been highlighted as: of interest; of considerable interest 1. Mendell JR, Lloyd-Puryear M. Report of MDA muscle disease symposium on newborn screening for Duchenne muscular dystrophy. Muscle Nerve. 48, (2013). 2. LoMauro A, D Angelo MG, Aliverti A. Assessment and management of respiratory function in patients with Duchenne muscular dystrophy: current and emerging options. Ther. Clin. Risk Manag. 11, (2015). 3. Birnkrant DJ, Bushby KM, Amin RS et al. The respiratory management of patients with Duchenne muscular dystrophy: a DMD care considerations working group specialty article. Pediatr. Pulmonol. 45, (2010). 4. Bushby K, Finkel R, Birnkrant DJ et al. Diagnosis and management of Duchenne muscular dystrophy, part 2: implementation of multidisciplinary care. Lancet Neurol. 9, (2010). These recommendations allow diagnosis and management to occur in a coordinated multidisciplinary fashion. 5. Bushby K, Finkel R, Birnkrant DJ et al. Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and pharmacological and psychosocial management. Lancet Neurol. 9, (2010). Describes the overall perspective on care, pharmacological treatment and psychosocial management of Duchenne muscular dystrophy patients. 6. Buyse GM, Voit T, Schara U et al. Efficacy of idebenone on respiratory function in patients with Duchenne muscular dystrophy not using glucocorticoids (DELOS): a double-blind randomised placebo-controlled Phase 3 trial. Lancet 385, (2015). This pivotal trial shows that idebenone reduces the loss of respiratory function for patients with Duchenne muscular dystrophy. future science group /nmt

8 Ripamonti & D Angelo 7. McDonald CM, Meier T, Voit T et al. Idebenone reduces respiratory complications in patients with Duchenne muscular dystrophy. Neuromuscul. Disord. 26, (2016). This post hoc analysis of DELOS indicates that the protective effect of idebenone on respiratory function is associated with a reduced risk of bronchopulmonary complications and a reduced need for systemic antibiotics. 8. Rider LG, Aggarwal R, Pistorio A et al American College of Rheumatology/European League Against Rheumatism criteria for minimal, moderate, and major clinical response in juvenile dermatomyositis: an International Myositis Assessment and Clinical Studies Group/Paediatric Rheumatology International Trials Organisation collaborative initiative. Arthritis Rheumatol. 69, (2017). 9. Mayer OH, Finkel RS, Rummey C et al. Characterization of pulmonary function in Duchenne muscular dystrophy. Pediatr. Pulmonol. 50, (2015). 10. Phillips MF, Quinlivan RC, Edwards RH, Calverley PM. Changes in spirometry over time as a prognostic marker in patients with Duchenne muscular dystrophy. Am.J.Respir.Crit.CareMed.164, (2001). 11. Khirani S, Ramirez A, Aubertin G et al. Respiratory muscle decline in Duchenne muscular dystrophy. Pediatr. Pulmonol. 49(5), (2014). 12. LoMauro A, Romei M, D Angelo MG, Aliverti A. Determinants of cough efficiency in Duchenne muscular dystrophy. Pediatr. Pulmonol. 49(4), (2014). 13. Meier T, Rummey C, Leinonen M et al. DELOS Study Group. Characterization of pulmonary function in year old patients with Duchenne muscular dystrophy. Neuromuscul. Disord. 27(4), (2017). 14. Henricson EK, Abresch RT, Cnaan A et al. The cooperative international neuromuscular research group Duchenne natural history study: glucocorticoid treatment preserves clinically meaningful functional milestones and reduces rate of disease progression as measured by manual muscle testing and other commonly used clinical trial outcome measures. Muscle Nerve. 48, (2013). 15. Wong BL, Rybalsky I, Shellenbarger KC et al. Long-term outcome of interdisciplinary management of patients with Duchenne muscular dystrophy receiving daily glucocorticoid treatment. J. Pediatr. 182, 296.e1 303.e1 (2017). 16. Haefeli RH, Erb M, Gemperli AC et al. NQO1-dependent redox cycling of idebenone: effects on cellular redox potential and energy levels. PLoS ONE 6(3), e17963 (2011). 17. Jaber S, Polster BM. Idebenone and neuroprotection: antioxidant, pro-oxidant, or electron carrier? J. Bioenerg. Biomembr. 47, (2015). 18. Buyse GM, Voit T, Schara U et al. Treatment effect of idebenone on inspiratory function in patients with Duchenne muscular dystrophy. Pediatr. Pulmonol. 52, (2017). 19. Buyse GM, Goemans N, van den Hauwe M et al. Idebenone as a novel, therapeutic approach for Duchenne muscular dystrophy: results from a 12 month, double-blind, randomized placebo-controlled trial. Neuromuscul. Disord. 21, (2011) /nmt Neurodegener. Dis. Manag. (Epub ahead of print) future science group