Table 1.

Items of the Delphi working group.

Definition	Consensus		References
	Percentuage of sum 4 + 5	Mean score
DEFINITION OF PRIMARY MITOCHONDRIAL MYOPATHIES
PMM are genetically defined disorders leading to defects of oxidative phosphorylation affecting predominantly, but not exclusively, skeletal muscle. Secondary involvement of mitochondria, frequently observed in multiple neuromuscular diseases (i.e. inclusion body myositis, Duchenne muscular dystrophy, Kennedy disease) are not considered PMM.	100%	4.88
MITOCHONDRIAL REGISTRIES HARMONIZATION
The clinical phenotype should be recorded in a “computer readable” format, which enables automatic comparisons between patients, e.g. through an ontology	92%	4.52
To assess changes in natural history studied and therapeutic clinical trials, the manifestations should be “graded” using consensus and user-friendly outcome measures	100%	4.72
Should protocols for mitochondrial disease trials be harmonized?	88%	4.28
Should data elements collected in different registries and natural history studies be harmonized between groups internationally?	96%	4.52
The interrater-reliability of clinical manifestation quality and quantity should be established during the study by the independent rating of the patients’ manifestations by two raters who are blind to the rating of their counterpart	80%	4.12
Should outcome measures be harmonized between different studies?	80%	4.24
Clinician-reported outcome measures: Clinical scales to be used in adulthoods
Newcastle Mitochondrial Disease Adult Scale	76%	4.24	Schaefer, 2006 [9]
Hammersmith Functional Motor Scale, Expanded	84%	4.2	O’Hagen, 2007 [10] Glanzman, 2011 [11] Ramsey,2017 [12]
Short Form 36 Health Survey (SF-36) score	76%	3.8	Pfeffer, 2012 [3] Lins, 2016 [13]
Myasthenia gravis tests	72%	3.96	Sharshar, 2000 [14] Bedlack, 2005 [15]
EOM/ptosis	88%	4.4	Richardson, 2005 [16] Fahnehjelm, 2012 [17]
Clinician-reported outcome measures: Clinical scales to be used in childhood
Newcastle Pediatric Mitochondrial Disease Scale (3 age range)	80%	4.16	Phoenix, 2006 [18]
International Pediatric Mitochondrial Disease Scale	84%	4.14	Koene, 2016 [19]
PedsQL Neuromuscular Module (PedsQL)	92%	4.5	Varni, 2009 [20] Varni, 2011 [21] Davis, 2010 [22]
Gross Motor Function Measure (GMFM)	92%	4.4	Russell, 1989 [23] Alotaibi, 2014 [24]
Pediatric Evaluation of Disability Inventory (PEDI-CAT)	96%	4.44	Haley, 1992 [25] Haley, 2010 [26] Dumas, 2016 [27] Pasternak, 2016 [28]
The Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND)	92%	4.36	Glanzman, 2010 [29] Glanzman, 2011 [30]
Hammersmith Functional Motor Scale, Expanded	96%	4.52	O’Hagen, 2007 [10] Glanzman, 2011 [11] Ramsey, 2017 [12]
Childhood Myositis Assessment Scale	76%	3.96	Huber, 2004 [31]
Myasthenia gravis tests	72%	3.96	Sharshar, 2000 [14] Bedlack, 2005 [15]
Serious Adverse Events	88%	4.48	Pfeffer, 2012 [3]
Number of Hospitalization	44%	3.32	Pfeffer, 2012 [3]
IDENTIFICATION OF ELEMENTS TO BE MONITORED DURING A CLINICAL TRIAL
Functional Tests: ADULTHOOD
6-Minute Walk Test	84%	4.24	Guyatt, 1985 [32] McDonald, 2013a and b [33,34] Tveter, 2014 [35] Dunaway Young, 2016 [36]
Timed Up-and-Go test (x3)	76%	4	Dunaway, 2014 [37] Newman, 2015 [38]
Five times Sit-To-Stand test	96%	4.52	Newman, 2015 [38]
Timed water swallow	72%	3.8	Hughes and Wiles, 1996 [39] Nathadwarawala,1992 [40] Patterson, 2011 [41]
Test of masticating and swallowing solids (TOMASS)	80%	4.16	Hughes and Wiles, 1996 [39]
IDENTIFICATION OF ELEMENTS TO BE MONITORED DURING A CLINICAL TRIAL
Functional Tests: CHILDHOOD
6-Minute Walk Test	84%	4.2	McDonald, 2013 [33,34] Tveter, 2014 [35] Dunaway Young, 2016 [36]
Timed Up-and-Go test (x3)	92%	4.4	Dunaway, 2014 [37] Newman, 2015 [38]
Five times Sit-To-Stand test	92%	4.4	Newman, 2015 [38]
Test of masticating and swallowing solids (TOMASS)	83%	4.16	Hughes and Wiles, 1996 [39]
IDENTIFICATION OF ELEMENTS TO BE MONITORED DURING A CLINICAL TRIAL
Performance outcome measures
Aerobic exercise testing: Cardiopulmonary cycle ergometry (above 14 years of age)	96%	4.6	Tarnopolsky, 2004 [42] Tarnopolsky, 2012 [43] Taivassalo, 2003 [44] Heinicke, 2011 [45] Puente-Maestu, 2016 [46]
Systemic arteriovenous oxygen difference (calculated from measurement of cardiac output and rate of oxygen utilization during exercise)	100%	4.56	Connes, 2009 [47]
6MWT with mobile telemetric cardiopulmonary monitoring	96%	4.44	Kern, 2014 [48] Van Gestel,2014 [49]
Standardized Lactate pre and post-exercise	88%	4.4	Tarnopolsky, 2003 [50] Taivassalo, 2003 [44]
Quantitative dynamometry for muscle strength and endurance.	88%	4.16	Barden, 2012 [51] Tveter, 2014 [35] Tarnopolsky, 2004 [42] Taivassalo, 2002 [52]
30 Second Sit-To-Stand test	92%	4.36	Tveter, 2014 [35]
Nine hole peg test	84%	4.04	Kellor, 1971 [53] Mathiowetz, 1985 [54]
6 Minutes Mastication Test (PILOT)	84%	3.88	vd Engel-Hoek, 2017 [55]
GAITRite	96%	4.4	McDonough, 2001 [56] Bilney, 2003 [57]
Physical Activity meters (including sleep monitoring)	96%	4.4	Koene S, 2017 [58] McDonald, 2013 [33,34] Stehling, 2016 [59] Georges, 2016 [60]
Spirometry	92%	4.52	Paschoal, 2007 [61] Fauroux, 2014 [62]
SNIP (Sniff nasal pressures)	96%	4.44	Fauroux, 2007 [63] Barnes, 2014 [64] Fauroux, 2014 [62]
IDENTIFICATION OF ELEMENTS TO BE MONITORED DURING A CLINICAL TRIAL
Biomarkers
31P MRS of muscle at baseline	52%	3.08	Chance, 1981 [65] Kemp, 1994 [66] Prompers, 2006 [67]
31P MRS of muscle at baseline - then during exercise (pedal depressing) – and then during recovery	72%	3.56	Kemp, 1994 [66] Taylor, 1994 [68] Argov, 2000 [69] Valkovič, 2016 [70]
Proton MRS of muscle (research only)	40%	3.04
GDF15	88%	4.4	Yatsuga, 2015 [71] Koene, 2015 [72] Fujita, 2015 [73] Fujita, 2016 [74] Montero, 2016 [75]
FGF21	92%	4.24	Suomalainen, 2011 [76] Suomalainen, 2013 [77] Davis, 2013 [78] Lehtonen, 2016 [79]
Basal venous blood lactate and pyruvate	80%	4.2	Debray, 2007 [80] Patel, 2012 [81] Tarnopolsky, 2012 [43] Sperl, 2015 [82] Parikh, 2015 [83]
Resting blood CK	92%	4.36	Marsden, 2001 [84] Chanprasert, 2013 [85] Parikh, 2015 [83]
Metabolomic studies (including AA, urine OA, acyl-carnitine profiles)	96%	4.4	Barshop, 2000 [86] Barshop, 2004 [87] Wortmann, 2009 [88] Sakamoto, 2011 [89] Su, 2014 [90] Parikh, 2015 [83]
Metabolomic studies: creatine (exploratory only)	64%	3.64
ICF-CY and other methods to classify and search for outcome measures
Should we develop outcome measures that are applicable to a large majority of patients?	92%	4.16
Should we focus on one domain of mitochondrial disease (e.g. eye) to prove the effectiveness of a compound in all mitochondrial diseases?	32%	2.72
Should we target the development of outcome measures per syndrome/mutation individually?	64%	3.6
Should we develop outcome measures for subjects who are not able to follow instructions?	92%	4.32
Identification of PMM outcome measures
Patient-reported outcome measures Measurements of patient function or feeling
NMDAS/NPMDS Section IV	96%	4.56	Schaefer, 2006 [9] Phoenix, 2006 [18]
Quality of Life: Patient-Reported Outcomes Measurement Information System (PROMIS)	88%	4.28	Fries, 2005 [91] Cella, 2007 [92]
Quality of Life: The World Health Organization Quality of Life (WHOQOL)	92%	4.36	WHOQOL Group, 1995 [93]
Fatigue scale: Checklist individual strength (CIS)	80%	4.04	Chalder, 1993 [94] Koopman, 2014 [4]
Fatigue scale: Fatigue Severity Scale (FSS)	80%	4.24	Hewlett, 2011 [95]
Fatigue scale: Multidimensional Fatigue Inventory (MFI)	80%	4.2	Smets, 1995 [96]
Patients’ Global Impression of Change (PGIC) scale	64%	4.44	Arnold, 2011 [97]
Mitochondrial disease-specific patient questionnaires? (to be developed)	92%	4.52
PEDS QL (Pediatric quality of life inventory)	88%	4.48	Varni, 2009 [20] Varni, 2011 [21] Davis, 2010 [22]
Pain to be monitored in PMM	100%	4.3
West Haven-Yale Multidimensional Pain Inventory (WHYMPI) in adulthood	82%	4.1	Kerns, 1985 [98]
West Haven-Yale Multidimensional Pain Inventory (WHYMPI) in children	50%	3.4	Kerns, 1985 [98]