Clinical trial; Drug registration; Guidelines; Recommendations; Sarcopenia; Treatment
Abstract :
[en] BACKGROUND: In 2016, an expert working group was convened under the auspices of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) and formulated consensus recommendations for the conduct of clinical trials for drugs to prevent or treat sarcopenia. AIMS: The objective of the current paper is to provide a 2020 update of the previous recommendations in accordance with the evidence that has become available since our original recommendations. METHODS: This paper is based on literature reviews performed by members of the ESCEO working group and followed up with face to face meetings organized for the whole group to make amendments and discuss further recommendations. RESULTS: The randomized placebo-controlled double-blind parallel-arm drug clinical trials should be the design of choice for both phase II and III trials. Treatment and follow-up should run at least 6 months for phase II and 12 months for phase III trials. Overall physical activity, nutrition, co-prescriptions and comorbidity should be recorded. Participants in these trials should be at least 70-years-old and present with a combination of low muscle strength and low physical performance. Severely malnourished individuals, as well as bedridden patients, patients with extremely limited mobility or individuals with physical limitations clearly attributable to the direct effect of a specific disease, should be excluded. Multiple outcomes are proposed for phase II trials, including, as example, physical performance, muscle strength and mass, muscle metabolism and muscle-bone interaction. For phase III trials, we recommend a co-primary endpoint of a measure of functional performance and a Patient Reported Outcome Measure. CONCLUSION: The working group has formulated consensus recommendations on specific aspects of trial design, and in doing so hopes to contribute to an improvement of the methodological robustness and comparability of clinical trials. Standardization of designs and outcomes would advance the field by allowing better comparison across studies, including performing individual patient-data meta-analyses, and different pro-myogenic therapies.
Disciplines :
Rheumatology Public health, health care sciences & services
Author, co-author :
Reginster, Jean-Yves ; Université de Liège - ULiège > Département des sciences de la santé publique > Santé publique, Epidémiologie et Economie de la santé
Beaudart, Charlotte ; Université de Liège - ULiège > Département des sciences de la motricité > Département des sciences de la motricité
Al-Daghri, Nasser
Avouac, Bernard
Bauer, Jürgen
Bere, Nathalie
Bruyère, Olivier ; Université de Liège - ULiège > Département des sciences de la santé publique > Santé publique, Epidémiologie et Economie de la santé
Cerreta, Francesca
Cesari, Matteo
Rosa, Mario Miguel
Cooper, Cyrus
Cruz Jentoft, Alfonso J.
Dennison, Elaine
Geerinck, Anton ; Université de Liège - ULiège > Département des sciences de la santé publique > Santé publique, Epidémiologie et Economie de la santé
Reginster J-Y, Cooper C, Rizzoli R et al (2016) Recommendations for the conduct of clinical trials for drugs to treat or prevent sarcopenia. Aging Clin Exp Res 28:47–58. 10.1007/s40520-015-0517-y DOI: 10.1007/s40520-015-0517-y
Cruz-Jentoft AJ, Bahat G, Bauer J et al (2019) Sarcopenia: revised European consensus on definition and diagnosis. Age Ageing 48:16–31. 10.1093/ageing/afy169 DOI: 10.1093/ageing/afy169
Peña Ordóñez GG, Bustamante Montes LP, Ramírez Duran N et al (2017) Populations and outcome measures used in ongoing research in sarcopenia. Aging Clin Exp Res 29:695–700. 10.1007/s40520-016-0610-x DOI: 10.1007/s40520-016-0610-x
Chen LK, Woo J, Assantachai P et al (2020) Asian working group for sarcopenia: 2019 consensus update on sarcopenia diagnosis and treatment. J Am Med Dir Assoc 21:300–307.e2. 10.1016/j.jamda.2019.12.012 DOI: 10.1016/j.jamda.2019.12.012
Bhasin S, Travison TG, Manini TM et al (2020) Sarcopenia definition: the position statements of the sarcopenia definition and outcomes consortium. J Am Geriatr Soc. 10.1111/jgs.16372 DOI: 10.1111/jgs.16372
Saggini R, Carmignano S, Cosenza L et al (2017) Sarcopenia in chronic illness and rehabilitative approaches. Frailty Sarcopenia Onset, Dev Clin Chall. 10.1016/j.colsurfa.2011.12.014 DOI: 10.1016/j.colsurfa.2011.12.014
Anker SD, Morley JE, von Haehling S (2016) Welcome to the ICD-10 code for sarcopenia. J Cachexia Sarcopenia Muscle 7:512–514. 10.1002/jcsm.12147 DOI: 10.1002/jcsm.12147
Vellas B, Fielding RA, Bens C et al (2018) Implications of ICD-10 for sarcopenia clinical practice and clinical trials: report by the international conference on frailty and sarcopenia research task force. J Frailty Aging 7:2–9. 10.14283/jfa.2017.30 DOI: 10.14283/jfa.2017.30
Hardee JP, Lynch GS (2019) Current pharmacotherapies for sarcopenia. Expert Opin Pharmacother 20:1645–1657. 10.1080/14656566.2019.1622093 DOI: 10.1080/14656566.2019.1622093
Morley JE (2016) Pharmacologic options for the treatment of sarcopenia. Calcif Tissue Int 98:319–333. 10.1007/s00223-015-0022-5 DOI: 10.1007/s00223-015-0022-5
Rooks D, Roubenoff R (2019) Development of pharmacotherapies for the treatment of sarcopenia. J Frailty Aging 8:120–130. 10.14283/jfa.2019.11 DOI: 10.14283/jfa.2019.11
Chumlea WC, Cesari M, Evans WJ et al (2011) Sarcopenia: designing phase IIB trials. J Nutr Health Aging 15:450–455 DOI: 10.1007/s12603-011-0092-7
Cruz-Jentoft AJ, Landi F, Schneider SM et al (2014) Prevalence of and interventions for sarcopenia in ageing adults: a systematic review. Report of the International Sarcopenia Initiative (EWGSOP and IWGS). Age Ageing 43:748–759. 10.1093/ageing/afu115 DOI: 10.1093/ageing/afu115
Abellan Van Kan G, Cameron Chumlea W, Gillette-Guyonet S et al (2011) Clinical trials on sarcopenia: methodological issues regarding phase 3 trials NIH Public Access. Clin Geriatr Med 27:471–482. 10.1016/j.cger.2011.03.010 DOI: 10.1016/j.cger.2011.03.010
Visser M, Goodpaster BH, Kritchevsky SB et al (2005) Muscle mass, muscle strength, and muscle fat infiltration as predictors of incident mobility limitations in well-functioning older persons. J Gerontol A Biol Sci Med Sci 60:324–333 DOI: 10.1093/gerona/60.3.324
Landi F, Cesari M, Calvani R et al (2017) The “sarcopenia and physical fRailty IN older people: multi-componenT Treatment strategies” (SPRINTT) randomized controlled trial: design and methods. Aging Clin Exp Res 29:89–100. 10.1007/s40520-016-0715-2 DOI: 10.1007/s40520-016-0715-2
Pahor M, Guralnik JM, Ambrosius WT et al (2014) Effect of structured physical activity on prevention of major mobility disability in older adults: the LIFE study randomized clinical trial. JAMA 311:2387–2396. 10.1001/jama.2014.5616 DOI: 10.1001/jama.2014.5616
Beaudart C, Rolland Y, Cruz-Jentoft AJ et al (2019) Assessment of muscle function and physical performance in daily clinical practice: a position paper endorsed by the european society for clinical and economic aspects of osteoporosis, osteoarthritis and musculoskeletal diseases (ESCEO). Calcif Tissue Int 105:1–14. 10.1007/s00223-019-00545-w DOI: 10.1007/s00223-019-00545-w
Schaap LA, Fox B, Henwood T et al (2016) Grip strength measurement: towards a standardized approach in sarcopenia research and practice. Eur Geriatr Med. 10.1016/j.eurger.2015.11.012 DOI: 10.1016/j.eurger.2015.11.012
Dodds RM, Syddall HHE, Cooper R et al (2014) Grip strength across the life course: normative data from twelve British studies. PLoS ONE 9:e113637. 10.1371/journal.pone.0113637 DOI: 10.1371/journal.pone.0113637
Cesari M, Kritchevsky SB, Newman AB et al (2009) Added value of physical performance measures in predicting adverse health-related events: results from the health, aging and body composition study. J Am Geriatr Soc 57:251–259. 10.1111/j.1532-5415.2008.02126.x DOI: 10.1111/j.1532-5415.2008.02126.x
Pavasini R, Guralnik J, Brown JC et al (2016) Short physical performance battery and all-cause mortality: systematic review and meta-analysis. BMC Med 14:215. 10.1186/s12916-016-0763-7 DOI: 10.1186/s12916-016-0763-7
Studenski S, Perera S, Patel K et al (2011) Gait speed and survival in older adults. JAMA 305:50–58. 10.1001/jama.2010.1923 DOI: 10.1001/jama.2010.1923
Bischoff HA, Stähelin HB, Monsch AU et al (2003) Identifying a cut-off point for normal mobility: a comparison of the timed “up and go” test in community-dwelling and institutionalised elderly women. Age Ageing 32:315–320. 10.1093/ageing/32.3.315 DOI: 10.1093/ageing/32.3.315
Guigoz Y, Vellas B, Garry PJ (1996) Assessing the nutritional status of the elderly: the mini nutritional assessment as part of the geriatric evaluation. Nutr Rev 54:S59–65 DOI: 10.1111/j.1753-4887.1996.tb03793.x
Cederholm T, Jensen GL (2017) To create a consensus on malnutrition diagnostic criteria: a report from the global leadership initiative on malnutrition (GLIM) meeting at the ESPEN Congress 2016. Clin Nutr 36:7–10. 10.1016/j.clnu.2016.12.001 DOI: 10.1016/j.clnu.2016.12.001
Cederholm T, Jensen GL, Correia MITD et al (2019) GLIM criteria for the diagnosis of malnutrition—a consensus report from the global clinical nutrition community. J Cachexia Sarcopenia Muscle 38:1–9. 10.1016/j.clnu.2018.08.002 DOI: 10.1016/j.clnu.2018.08.002
Sánchez-Rodríguez D, Marco E, Schott A-M et al (2018) Malnutrition according to ESPEN definition predicts long-term mortality in general older population: findings from the EPIDOS study-Toulouse cohort. Clin Nutr. 10.1016/j.clnu.2018.11.016 DOI: 10.1016/j.clnu.2018.11.016
Beaudart C, Sanchez-Rodriguez D, Locquet M et al (2019) Malnutrition as a strong predictor of the onset of sarcopenia. Nutrients 11:2883. 10.3390/nu11122883 DOI: 10.3390/nu11122883
Delanaye P, Bataille S, Quinonez K et al (2019) Myostatin and insulin-like growth factor 1 are biomarkers of muscle strength, muscle mass, and mortality in patients on hemodialysis. J Ren Nutr 29:511–520. 10.1053/j.jrn.2018.11.010 DOI: 10.1053/j.jrn.2018.11.010
Beaudart C, McCloskey E, Bruyère O et al (2016) Sarcopenia in daily practice: assessment and management. BMC Geriatr 16:170. 10.1186/s12877-016-0349-4 DOI: 10.1186/s12877-016-0349-4
Veronese N, Demurtas J, Soysal P et al (2019) Sarcopenia and health-related outcomes: an umbrella review of observational studies. Eur Geriatr Med 10:853–862. 10.1007/s41999-019-00233-w DOI: 10.1007/s41999-019-00233-w
de Wit M, Cooper C, Reginster JY (2019) Practical guidance for patient-centred health research. Lancet 393:1095–1096. 10.1016/S0140-6736(19)30034-0 DOI: 10.1016/S0140-6736(19)30034-0
de Wit M, Cooper C, Tugwell P et al (2019) Practical guidance for engaging patients in health research, treatment guidelines and regulatory processes: results of an expert group meeting organized by the World Health Organization (WHO) and the European society for clinical and economic aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO). Aging Clin Exp Res. 10.1007/s40520-019-01193-8 DOI: 10.1007/s40520-019-01193-8
Mercieca-Bebber R, King MT, Calvert MJ et al (2018) The importance of patient-reported outcomes in clinical trials and strategies for future optimization. Patient Relat Outcome Meas 9:353–367. 10.2147/prom.s156279 DOI: 10.2147/prom.s156279
McLeod C, Norman R, Litton E et al (2019) Choosing primary endpoints for clinical trials of health care interventions. Contemp Clin Trials Commun 16:100486. 10.1016/j.conctc.2019.100486 DOI: 10.1016/j.conctc.2019.100486
Tsekoura M, Billis E, Tsepis E et al (2018) The effects of group and home-based exercise programs in elderly with sarcopenia: a randomized controlled trial. J Clin Med 7:480. 10.3390/jcm7120480 DOI: 10.3390/jcm7120480
Geerinck A, Bruyere O, Locquet M et al (2018) Evaluation of the Responsiveness of the SarQoL((R)) Questionnaire, a patient-reported outcome measure specific to sarcopenia. Adv Ther 35:1842–1858. 10.1007/s12325-018-0820-z DOI: 10.1007/s12325-018-0820-z
Kwon S, Perera S, Pahor M et al (2009) What is a meaningful change in physical performance? Findings from a clinical trial in older adults (The LIFE-P study). J Nutr Heal Aging 13:538–544. 10.1007/s12603-009-0104-z DOI: 10.1007/s12603-009-0104-z
Vestergaard S, Patel KV, Bandinelli S et al (2009) Characteristics of 400-meter walk test performance and subsequent mortality in older adults. Rejuvenation Res 12:177–184. 10.1089/rej.2009.0853 DOI: 10.1089/rej.2009.0853
Newman AB, Simonsick EM, Naydeck BL et al (2006) Association of long-distance corridor walk performance with mortality, cardiovascular disease, mobility limitation, and disability. JAMA 295:2018–2026. 10.1001/jama.295.17.2018 DOI: 10.1001/jama.295.17.2018
Hardy SE, Kang Y, Studenski SA, Degenholtz HB (2011) Ability to walk 1/4 mile predicts subsequent disability, mortality, and health care costs. J Gen Intern Med 26:130–135. 10.1007/s11606-010-1543-2 DOI: 10.1007/s11606-010-1543-2
Vasunilashorn S, Coppin AK, Patel KV et al (2009) Use of the short physical performance battery score to predict loss of ability to walk 400 meters: analysis from the InCHIANTI study. J Gerontol Ser A Biol Sci Med Sci 64A:223–229. 10.1093/gerona/gln022 DOI: 10.1093/gerona/gln022
Cesari M, Onder G, Zamboni V et al (2008) Physical function and self-rated health status as predictors of mortality: results from longitudinal analysis in the ilSIRENTE study. BMC Geriatr 8:34. 10.1186/1471-2318-8-34 DOI: 10.1186/1471-2318-8-34
Hedman S, Nydahl M, Faxén-Irving G (2016) Individually prescribed diet is fundamental to optimize nutritional treatment in geriatric patients. Clin Nutr 35:692–698. 10.1016/j.clnu.2015.04.018 DOI: 10.1016/j.clnu.2015.04.018
Hiligsmann M, Beaudart C, Bruyère O et al (2019) Outcome priorities for older persons with sarcopenia. J Am Med Dir Assoc. 10.1016/j.jamda.2019.08.026 DOI: 10.1016/j.jamda.2019.08.026
Evans CJ, Chiou C-F, Fitzgerald KA et al (2011) Development of a new patient-reported outcome measure in sarcopenia. J Am Med Dir Assoc 12:226–233. 10.1016/j.jamda.2010.09.010 DOI: 10.1016/j.jamda.2010.09.010
Beaudart C, Biver E, Reginster J-Y et al (2015) Development of a self-administrated quality of life questionnaire for sarcopenia in elderly subjects: the SarQoL. Age Ageing 44:960–966. 10.1093/ageing/afv133 DOI: 10.1093/ageing/afv133
Beaudart C, Biver E, Reginster J-Y et al (2017) Validation of the SarQoL®, a specific health-related quality of life questionnaire for Sarcopenia. J Cachexia Sarcopenia Muscle. 10.1002/jcsm.12149 DOI: 10.1002/jcsm.12149
Geerinck A, Alekna V, Beaudart C et al (2019) Standard error of measurement and smallest detectable change of the sarcopenia quality of Life (Sarqol) questionnaire: an analysis of subjects from 9 validation studies. PLoS ONE 14:e0216065. 10.1371/journal.pone.0216065 DOI: 10.1371/journal.pone.0216065
Ader DN (2007) Developing the patient-reported outcomes measurement information system (PROMIS). Med Care 45:1–2. 10.1097/01.mlr.0000260537.45076.74 DOI: 10.1097/01.mlr.0000260537.45076.74
Zeeshan B, David C, Jensen S, Shaunfield S Development of a context of use and PROMIS Physical Function outcome assessment for patients with sarcopenia.
Bodilsen AC, Juul-Larsen HG, Petersen J et al (2015) Feasibility and inter-rater reliability of physical performance measures in acutely admitted older medical patients. PLoS ONE 10:e0118248. 10.1371/journal.pone.0118248 DOI: 10.1371/journal.pone.0118248
Roberts HC, Denison HJ, Martin HJ et al (2011) A review of the measurement of grip strength in clinical and epidemiological studies: towards a standardised approach. Age Ageing 40:423–429. 10.1093/ageing/afr051 DOI: 10.1093/ageing/afr051
Beaudart C, Reginster JY, Slomian J et al (2015) Estimation of sarcopenia prevalence using various assessment tools. Exp Gerontol. 10.1016/j.exger.2014.11.014 DOI: 10.1016/j.exger.2014.11.014
Bohannon RW (2017) Test-Retest reliability of measurements of hand-grip strength obtained by dynamometry from older adults: a systematic review of research in the PubMed Database. J Frailty Aging 6:83–87. 10.14283/jfa.2017.8 DOI: 10.14283/jfa.2017.8
Santanasto AJ, Glynn NW, Lovato LC et al (2017) Effect of Physical activity versus health education on physical function, grip strength and mobility. J Am Geriatr Soc 65:1427–1433. 10.1111/jgs.14804 DOI: 10.1111/jgs.14804
Nitschke JE, McMeeken JM, Burry HC, Matyas TA (1999) When is a change a genuine change?: a clinically meaningful interpretation of grip strength measurements in healthy and disabled women. J Hand Ther 12:25–30. 10.1016/S0894-1130(99)80030-1 DOI: 10.1016/S0894-1130(99)80030-1
Beaudart C, Dawson A, Shaw SC et al (2017) Nutrition and physical activity in the prevention and treatment of sarcopenia: systematic review. Osteoporos Int. 10.1007/s00198-017-3980-9 DOI: 10.1007/s00198-017-3980-9
Buckinx F, Landi F, Cesari M et al (2018) Pitfalls in the measurement of muscle mass: a need for a reference standard. J Cachexia Sarcopenia Muscle 9:269–278. 10.1002/jcsm.12268 DOI: 10.1002/jcsm.12268
Dehghan M, Merchant AT (2008) Is bioelectrical impedance accurate for use in large epidemiological studies? Nutr J 7:26. 10.1186/1475-2891-7-26 DOI: 10.1186/1475-2891-7-26
Jensen SM, Mølgaard C, Ejlerskov KT et al (2015) Validity of anthropometric measurements to assess body composition, including muscle mass, in 3-year-old children from the SKOT cohort. Matern Child Nutr 11:398–408. 10.1111/mcn.12013 DOI: 10.1111/mcn.12013
Evans WJ, Hellerstein M, Orwoll E et al (2019) D 3 -Creatine dilution and the importance of accuracy in the assessment of skeletal muscle mass. J Cachexia Sarcopenia Muscle 10:14–21. 10.1002/jcsm.12390 DOI: 10.1002/jcsm.12390
Perkisas S, Baudry S, Bauer J et al (2018) Application of ultrasound for muscle assessment in sarcopenia: towards standardized measurements. Eur Geriatr Med 9:739–757. 10.1007/s41999-018-0104-9 DOI: 10.1007/s41999-018-0104-9
Auyeung TW, Lee SW, Leung J et al (2014) Age-associated decline of muscle mass, grip strength and gait speed: a 4-year longitudinal study of 3018 Community-Dwelling Older Chinese. Geriatr Gerontol Int. 10.1111/GGI.12213 DOI: 10.1111/GGI.12213
Shaw SC, Dennison EM, Cooper C (2017) Epidemiology of sarcopenia: determinants throughout the lifecourse. Calcif Tissue Int 101:229–247. 10.1007/s00223-017-0277-0 DOI: 10.1007/s00223-017-0277-0
Haran PH, Rivas DA, Fielding RA (2012) Role and potential mechanisms of anabolic resistance in sarcopenia. J Cachexia Sarcopenia Muscle 3:157. 10.1007/S13539-012-0068-4 DOI: 10.1007/S13539-012-0068-4
Verlaan S, Aspray TJ, Bauer JM et al (2017) Nutritional status, body composition, and quality of life in community-dwelling sarcopenic and non-sarcopenic older adults: a case-control study. Clin Nutr 36:267–274. 10.1016/J.CLNU.2015.11.013 DOI: 10.1016/J.CLNU.2015.11.013
Rizzoli R, Stevenson JC, Bauer JM et al (2014) The role of dietary protein and vitamin D in maintaining musculoskeletal health in postmenopausal women: a consensus statement from the European society for clinical and economic aspects of osteoporosis and osteoarthritis (ESCEO). Maturitas 79:122–132. 10.1016/j.maturitas.2014.07.005 DOI: 10.1016/j.maturitas.2014.07.005
Paddon-Jones D, Rasmussen BB (2009) Dietary protein recommendations and the prevention of sarcopenia. Curr Opin Clin Nutr Metab Care 12:86–90. 10.1097/MCO.0b013e32831cef8b DOI: 10.1097/MCO.0b013e32831cef8b
Tieland M, van de Rest O, Dirks ML et al (2012) Protein supplementation improves physical performance in frail elderly people: a randomized, double-blind, placebo-controlled trial. J Am Med Dir Assoc 13:720–726. 10.1016/j.jamda.2012.07.005 DOI: 10.1016/j.jamda.2012.07.005
Bauer JM, Mikušová L, Verlaan S et al (2020) Safety and tolerability of 6-month supplementation with a vitamin D, calcium and leucine-enriched whey protein medical nutrition drink in sarcopenic older adults. Aging Clin Exp Res. 10.1007/s40520-020-01519-x DOI: 10.1007/s40520-020-01519-x
Beaudart C, Locquet M, Touvier M et al (2019) Association between dietary nutrient intake and sarcopenia in the SarcoPhAge study. Aging Clin Exp Res. 10.1007/s40520-019-01186-7 DOI: 10.1007/s40520-019-01186-7
Sanz-París A, Gómez-Candela C, Martín-Palmero Á et al (2016) Application of the new ESPEN definition of malnutrition in geriatric diabetic patients during hospitalization: a multicentric study. Clin Nutr 35:1564–1567. 10.1016/j.clnu.2016.02.018 DOI: 10.1016/j.clnu.2016.02.018
Peterson MD, Rhea MR, Sen A, Gordon PM (2010) Resistance exercise for muscular strength in older adults: a meta-analysis. Ageing Res Rev 9:226–237. 10.1016/j.arr.2010.03.004 DOI: 10.1016/j.arr.2010.03.004
Beckwée D, Delaere A, Aelbrecht S et al (2019) Exercise interventions for the prevention and treatment of sarcopenia. A systematic umbrella review. J Nutr Heal Aging 23:494–502. 10.1007/s12603-019-1196-8 DOI: 10.1007/s12603-019-1196-8
Meier NF, Lee DC (2019) Physical activity and sarcopenia in older adults. Aging Clin Exp Res. 10.1007/s40520-019-01371-8 DOI: 10.1007/s40520-019-01371-8
Xia W, Cooper C, Li M et al (2019) East meets West: current practices and policies in the management of musculoskeletal aging. Aging Clin Exp Res 31:1351–1373. 10.1007/s40520-019-01282-8 DOI: 10.1007/s40520-019-01282-8
Taylor HL, Jacobs DR, Schucker B et al (1978) A questionnaire for the assessment of leisure time physical activities. J Chronic Dis 31:741–755. 10.1016/0021-9681(78)90058-9 DOI: 10.1016/0021-9681(78)90058-9
Logan SL, Gottlieb BH, Maitl SB et al (2013) The physical activity scale for the elderly (PASE) questionnaire; does it predict physical health? Int J Environ Res Public Health 10:3967–3986. 10.3390/ijerph10093967 DOI: 10.3390/ijerph10093967
Beuscart J-B, Knol W, Cullinan S et al (2018) International core outcome set for clinical trials of medication review in multi-morbid older patients with polypharmacy. BMC Med 16:21. 10.1186/s12916-018-1007-9 DOI: 10.1186/s12916-018-1007-9