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Measurement instruments for the core outcome set of congenital melanocytic naevi and an assessment of the measurement properties according to COSMIN: a systematic review

  • Author Footnotes
    ⁎ Shared first author
    A.C. Fledderus
    Correspondence
    Corresponding author contact information: Anne Clarice Fledderus, Department of Plastic, Reconstructive and Hand Surgery, Department of Dermatology, Amsterdam UMC, location AMC, University of Amsterdam, 1100 DD Amsterdam, The Netherlands; Telephone number: 0031 20 5662572
    Footnotes
    ⁎ Shared first author
    Affiliations
    Department of Plastic, Reconstructive and Hand Surgery, Amsterdam University Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands

    Department of Dermatology, Amsterdam Public Health, Amsterdam University Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands
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  • Author Footnotes
    ⁎ Shared first author
    T. Boom
    Footnotes
    ⁎ Shared first author
    Affiliations
    Department of Plastic, Reconstructive and Hand Surgery, Amsterdam University Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands
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  • C.M. Legemate
    Affiliations
    Department of Plastic, Reconstructive and Hand Surgery, Amsterdam University Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands
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  • Professor C.M.A.M. van der Horst
    Affiliations
    Department of Plastic, Reconstructive and Hand Surgery, Amsterdam University Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands
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  • Professor P.I. Spuls
    Affiliations
    Department of Dermatology, Amsterdam Public Health, Amsterdam University Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands
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  • Author Footnotes
    ⁎ Shared first author
Open AccessPublished:November 22, 2022DOI:https://doi.org/10.1016/j.jpra.2022.11.003

      Abstract

      Background

      Congenital melanocytic naevi (CMN) can impact on patients’ lives due to their appearance and the risk they carry of neurological complications or melanoma development. Development of a core outcome set (COS) will allow standardised reporting and enable comparison of outcomes. This will help to improve guidelines. In previous research, relevant stakeholders reached a consensus over which core outcomes should be measured in any future care or research. The next step of the COS development is to select the appropriate measurement instruments.

      Aim

      Step 1: to update a systematic review identifying all core outcomes and measurement instruments available for CMN. Step 2: to evaluate the measurement properties of the instruments for the core outcomes.

      Methods

      This study was registered in PROSPERO and performed according to the PRISMA checklist. Step 1 includes a literature search in EMBASE (Ovid), PubMed and the Cochrane Library to identify core outcomes and instruments previously used in research of CMN. Step 2 yields a systematic search for studies on the measurement properties of instruments that were either developed or validated for CMN, including a methodological quality assessment following the COSMIN methodology.

      Results

      Step 1 included twenty-nine studies. Step 2 yielded two studies, investigating two quality of life measurement instruments.

      Conclusion

      Step 1 provided an overview of outcomes and instruments used for CMN. Step 2 showed that additional research on measurement properties is needed to evaluate which instruments can be used for the COS of CMN. This study informs the instrument selection and/or development of new instruments.

      Keywords

      Introduction

      Congenital melanocytic nevi (CMN) are birthmarks present at birth or soon after birth. CMN are associated with an increased risk of melanoma, neurological complications and/or psychological burden due to their appearance
      • Koot HM
      • de Waard-van der Spek F
      • Peer CD
      • Mulder PG
      • Oranje AP.
      Psychosocial sequelae in 29 children with giant congenital melanocytic naevi.
      • Krengel S
      • Hauschild A
      • Schafer T.
      Melanoma risk in congenital melanocytic naevi: a systematic review.
      • Bittencourt FV
      • Marghoob AA
      • Kopf AW
      • Koenig KL
      • Bart RS.
      Large congenital melanocytic nevi and the risk for development of malignant melanoma and neurocutaneous melanocytosis.
      . Treatment of CMN is either conservative (watchful waiting including histology) or interventional (full thickness: excision, partial thickness: laser, curettage, or dermabrasion). Outcomes measured to evaluate treatment of CMN are heterogeneous in care and research, which impedes the comparison and pooling of these outcomes
      • Fledderus A
      • Franke C
      • Eggen C
      • van Etten-Jamaludin F
      • van der Horst C
      • Brinkmann S
      • et al.
      Outcomes and measurement instruments used in Congenital Melanocytic Naevi research: A systematic review.
      . This complicates guidance of optimal management policy.
      The aim of the Outcomes for Congenital Melanocytic Naevi (OCOMEN) project is to develop a core outcome set (COS) for measuring the outcomes of all treatment options for medium, large and giant CMN for care and research
      • Oei W
      • Fledderus AC
      • Korfage I
      • Eggen CAM
      • van der Horst C
      • Spuls PI
      • et al.
      Protocol for the development of core set of domains of the core outcome set for patients with congenital melanocytic naevi (OCOMEN project).
      ,
      • Oei W
      • Fledderus A
      • Spuls P
      • Eggen C
      • Kottner J
      • van der Horst C
      • et al.
      Development of an international core domain set for medium, large and giant congenital melanocytic nevi as a first step towards a core outcome set for clinical practice and research.
      . A ‘core outcome set’ (COS) is a consensus-derived minimum set of outcomes that should be measured and reported in all care and clinical trials of a certain health condition
      • Williamson PR
      • Altman DG
      • Blazeby JM
      • Clarke M
      • Devane D
      • Gargon E
      • et al.
      Developing core outcome sets for clinical trials: issues to consider.
      ,
      • Schmitt J
      • Deckert S
      • Alam M
      • Apfelbacher C
      • Barbaric J
      • Bauer A
      • et al.
      Report from the kick-off meeting of the Cochrane Skin Group Core Outcome Set Initiative (CSG-COUSIN).
      . The use of a COS may enhance homogeneity in outcome and measurement instrument reporting in future studies and could therefore facilitate evidence synthesis for conservative and interventional treatment recommendation in the future.
      In this study, we define ‘domains and outcomes’ as aspects of a disease that could be measured to evaluate different management strategies. ‘Domains’ are broader aspects of a disease, whereas ‘outcomes’ are defined as more precise aspects of a disease on a lower hierarchical level, like ‘presence of melanoma’ is an outcome of the domain ‘neoplasm’.
      Patients included in the OCOMEN project are those presenting with either M1 (1.5–10 cm projected adult size (PAS)) on the face or M2 (>10–20 cm PAS) elsewhere, either single or multiple. The COS will be developed for international use, to evaluate both interventional treatment and conservative treatment. In a recent consensus procedure, relevant stakeholders reached a consensus on the core domains and outcomes that need to be measured in the COS (Table 1)
      • Oei W
      • Fledderus AC
      • Korfage I
      • Eggen CAM
      • van der Horst C
      • Spuls PI
      • et al.
      Protocol for the development of core set of domains of the core outcome set for patients with congenital melanocytic naevi (OCOMEN project).
      ,
      • Oei W
      • Fledderus A
      • Spuls P
      • Eggen C
      • Kottner J
      • van der Horst C
      • et al.
      Development of an international core domain set for medium, large and giant congenital melanocytic nevi as a first step towards a core outcome set for clinical practice and research.
      ,
      • Fledderus AC
      • Pasmans S
      • Wolkerstorfer A
      • Oei W
      • Etchevers HC
      • van Kessel MS
      • et al.
      Domains and outcomes of the core outcome set of congenital melanocytic naevi for clinical practice and research, part 2 (the OCOMEN project).
      . The next step in the development of the COS is to reach a consensus on how these domains must be measured (the core outcome measurement set (COMS)). The first step of developing the COMS is to identify all instruments previously used to measure core domains and outcomes and to evaluate the quality of the measurement properties of the instruments available for the core outcomes. A previous systematic review was performed summarizing all outcomes and measurement instruments used in research for CMN between 2006 and 2019 including sixty-three individual studies
      • Fledderus A
      • Franke C
      • Eggen C
      • van Etten-Jamaludin F
      • van der Horst C
      • Brinkmann S
      • et al.
      Outcomes and measurement instruments used in Congenital Melanocytic Naevi research: A systematic review.
      . This study, as part of the OCOMEN project, aims to update this previously performed systematic review summarising all outcomes and their measurement instruments available for CMN. The second aim of this study is to critically appraise the measurement properties of all available measurement instruments that are developed and/or used in CMN patients, measuring the core outcomes.
      Table 1core domains and outcomes of the Core Outcome Set (COS) of care and research.
      Domainsoutcomes for the COS of careoutcomes for the COS of research
      1. Anatomy of skinSize of CMNSize of CMN
      Color of the CMNColor of the CMN
      Texture of the CMNTexture of the CMN
      Satellite nevi numberSatellite nevi number
      2. Quality of lifeEmotional distressEmotional distress
      3. NeoplasmsPresence of melanomaPresence of melanoma
      4. Nervous systemNeurological symptoms and signsNeurological symptoms and signs
      5. General adverse eventsWound problems of the CMNWound problems of the CMN
      Scar problemsScar problems
      6. PathologyMolecular characteristics

      Methods

      This study consists of two steps

      Step 1: A systematic review to identify and describe the outcomes and instruments used in previously published studies for CMN, an update from a previously performed systematic review
      • Fledderus A
      • Franke C
      • Eggen C
      • van Etten-Jamaludin F
      • van der Horst C
      • Brinkmann S
      • et al.
      Outcomes and measurement instruments used in Congenital Melanocytic Naevi research: A systematic review.
      . The previously systematic review included all outcomes and instruments used, the update only focusses on the outcomes of the COS and their instruments.
      Step 2: A systematic review to evaluate the quality of the measurement instruments developed or validated for domains and outcomes of the COS of CMN.
      Both these steps were registered in PROSPERO, registry number CRD42021238242, and reported according to the PRISMA checklist. The design of the systematic review was based on the guidelines of the Core Outcome Measures in Effectiveness Trials (COMET) initiative and the Cochrane Skin Group Core Outcomes Set Initiative (CS-COUSIN). The Consensus-based Standards for the Selection of Health Status Measurement Instruments (COSMIN) methodology and guidelines were used to critically appraise the measurement properties of instruments. The OCOMEN project was registered in the COMET initiative database.
      • Step 1: Identification and description of instruments used in previously published studies

      Search strategy, quality assessment and data extraction

      This first step is an update of a previously performed systematic review in which a list of domains, outcomes and measurement instruments used in CMN research published between 2006 and 2019 were identified
      • Fledderus A
      • Franke C
      • Eggen C
      • van Etten-Jamaludin F
      • van der Horst C
      • Brinkmann S
      • et al.
      Outcomes and measurement instruments used in Congenital Melanocytic Naevi research: A systematic review.
      . The search strategy used the current and previously performed systematic review was developed with the help of an information specialist (FE) and was performed in EMBASE (Ovid), PubMed, and the Cochrane Library. The complete search strategy can be found in Appendix 1. The research for the current systematic review was performed between January 2019, which marked the end date of the previously performed systematic review
      • Fledderus A
      • Franke C
      • Eggen C
      • van Etten-Jamaludin F
      • van der Horst C
      • Brinkmann S
      • et al.
      Outcomes and measurement instruments used in Congenital Melanocytic Naevi research: A systematic review.
      , and February 2021.
      The same inclusion criteria from the previous systematic review were adopted for this study. We included all studies with ten or more patients that were written in English or Dutch. We excluded case reports, conference reports, and books. Study selection was performed by two independent reviewers (ACF and TB) and disagreements were discussed with a third reviewer. Quality assessment of the included studies was performed independently by two researchers (ACF and TB) according to the level of evidence guidelines set by the Oxford Centre for Evidence-based Medicine
      • Howick J
      • Chalmers I
      • Glasziou P
      • Greenhalgh T
      • Heneghan C
      • Liberati A
      • et al.
      The 2011 Oxford CEBM evidence levels of evidence (introductory document).
      . Any disagreement regarding a study's level of evidence was resolved by discussion.
      We extracted the following data: study characteristics (author, year, country, study design, intervention, number of subjects with CMN, classification system used for CMN), core domain, core outcomes, and their measurement instruments. Unlike the previously performed review, we only extracted the core outcomes and the measurement instruments for the core outcomes. When diagnoses other than CMN were included in the studies, only data from CMN subjects was extracted. Data extraction was conducted independently by two reviewers (ACF and TB). Disagreements were resolved by discussion, or a third reviewer was consulted.

      Data synthesis

      Data on domains, outcomes and measurement instruments was extracted. Descriptive statistics were used to calculate the frequency of outcomes. Measurement instruments were labelled as clinician reported or patient reported outcome measurement instruments (PROMs).
      • Step 2: Evaluation of the quality of measurement instruments developed or validated for CMN

      Search and study selection

      A search was performed in MEDLINE and EMBASE to identify development and validation studies of instruments for CMN, measuring the core outcomes. It used the same controlled terms and words for the concepts of CMN that were used for the search strategy of Step 1 (Appendix 1) including a validated search filter for finding studies on measurement properties, developed by Terwee et al. (sensitive version, Appendix 2)
      • Terwee CB
      • Jansma EP
      • Riphagen II
      • de Vet HC.
      Development of a methodological PubMed search filter for finding studies on measurement properties of measurement instruments.
      .
      Only studies reporting on the evaluation of at least one measurement property of an instrument used or developed for CMN, were included. The COSMIN-taxonomy was used to select which of the following measurement properties of an instrument were evaluated: structural validity, internal consistency, reliability, hypotheses testing, cross-cultural validity and/or responsiveness
      • Mokkink LB
      • Terwee CB
      • Patrick DL
      • Alonso J
      • Stratford PW
      • Knol DL
      • et al.
      The COSMIN checklist for assessing the methodological quality of studies on measurement properties of health status measurement instruments: an international Delphi study.
      ,
      • Mokkink LB
      • Terwee CB
      • Knol DL
      • Stratford PW
      • Alonso J
      • Patrick DL
      • et al.
      The COSMIN checklist for evaluating the methodological quality of studies on measurement properties: a clarification of its content.
      . We included both clinician reported and PROMs instruments including rating systems, questionnaires, medical devices, or other instruments.
      The following data was extracted independently by two reviewers (ACF and TB): study characteristics, patient characteristics, evaluated instruments, aspects of the measurement properties investigated and feasibility aspect of the instruments. Discrepancies were discussed with a third reviewer until a consensus had been reached.

      Evaluation of the methodological quality of the included studies

      The COSMIN Risk of Bias checklist was used to evaluate methodological quality of the included studies
      • Mokkink LB
      • Terwee CB
      • Patrick DL
      • Alonso J
      • Stratford PW
      • Knol DL
      • et al.
      The COSMIN checklist for assessing the methodological quality of studies on measurement properties of health status measurement instruments: an international Delphi study.
      ,
      • Mokkink LB
      • Terwee CB
      • Knol DL
      • Stratford PW
      • Alonso J
      • Patrick DL
      • et al.
      The COSMIN checklist for evaluating the methodological quality of studies on measurement properties: a clarification of its content.
      . Studies were stratified as having very good, adequate, doubtful, or inadequate methodological quality.

      Assessment of measurement property results, best evidence synthesis and generating recommendations

      Two authors (ACF and CML) independently rated the results of each study on a measurement property against the criteria for good measurement properties as either sufficient (+), insufficient (-), or indeterminate (?) as recommended by COSMIN
      • Prinsen CA
      • Vohra S
      • Rose MR
      • Boers M
      • Tugwell P
      • Clarke M
      • et al.
      How to select outcome measurement instruments for outcomes included in a “Core Outcome Set”–a practical guideline.
      ,
      • Terwee CB
      • Bot SD
      • de Boer MR
      • van der Windt DA
      • Knol DL
      • Dekker J
      • et al.
      Quality criteria were proposed for measurement properties of health status questionnaires.
      .
      Results were summarized to produce an overall rating for each individual measurement property of every instrument. Next, the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach was used to grade the quality of the evidence and thereby the trustworthiness of the results. A risk of bias (as determined using the COSMIN Risk of Bias checklist), the consistency of the study results on measurement properties across studies and the sample size could all downgrade the evidence quality rating
      • Prinsen CA
      • Vohra S
      • Rose MR
      • Boers M
      • Tugwell P
      • Clarke M
      • et al.
      How to select outcome measurement instruments for outcomes included in a “Core Outcome Set”–a practical guideline.
      .
      Methods for generating recommendations for the measurement instruments of outcomes used for CMN were based on the methodological quality of the included studies and on the adequacy of an instrument. Four degrees of recommendation were assigned to the instruments included in this review (A-D) and adopted from previously performed studies
      • Gerbens L
      • Prinsen C
      • Chalmers J
      • Drucker A
      • Von Kobyletzki L
      • Limpens J
      • et al.
      Evaluation of the measurement properties of symptom measurement instruments for atopic eczema: a systematic review.
      ,
      • Horbach SE
      • Rongen AP
      • Elbers RG
      • van der Horst CM
      • Prinsen CA
      • Spuls PI.
      Outcome measurement instruments for peripheral vascular malformations and an assessment of the measurement properties: a systematic review.
      : category A, meets all requirements (positive rating for all boxes/measurement properties in the best evidence synthesis) and is recommended for use; B, meets two or more required quality items, but performance in all other required quality items is unclear, so the instrument has the potential to be recommended, depending on the results of further validation studies; C, exhibits low quality in at least one required quality criterion (≥1 rating of ‘minus’) and therefore is not recommended for further use; D, almost not validated, its performance in all or most relevant quality items is unclear, so further validation studies are needed.

      Results

      Results Step 1: Identification and description of instruments used in previously published studies

      Search strategy, quality assessment and data extraction

      The update from the previously performed systematic review yielded a total of 450 unique references after deduplication. A total of 29 studies met the inclusion criteria including 27 original studies with a total of 1938 patients and two systematic reviews. The selection procedure is illustrated in the flow-chart of Figure 1.
      Patient and CMN characteristics of the included studies are listed in Appendix 3. Most studies were conducted in Asia (45%), followed by Europe (35%) and the USA/Canada (10%). Two studies were conducted in the Middle East and one in Egypt. Thirteen studies had a prospective study design (45%). A total of 12 studies were retrospective (41%). Two studies were cross-sectional (7%). Two systematic reviews (7%) were detected with a total of 35 studies.
      Similar to the previously performed systematic review, the quality of the studies included in the update was generally low. Most studies (55%) were rated as level 3 evidence (low evidence). All other studies, 13 in total (44%), were rated as level 4 (very low evidence). The level of evidence was mainly low because of small patient groups, the absence of control groups and retrospective study designs.
      The number of included patients ranged from 15 to 293 CMN patients in the update, and the female to male ratio was 1.35:1. The mean patient age was 15.2 years (range 0–73 years) mentioned in 16 out of 29 studies.
      We found different classification systems used for CMN, equally to the previous systematic review. For location, most studies reported a particular part of the body, but body parts were sometimes classified together. Size was defined in the following ways: the diameter in centimetres in PAS (11 studies) and the percentage of the total body surface area (TBSA) (four studies). The classification of Krengel et al. was used in five studies. Two studies used the ‘6B rule’ to classify the location of giant CMN. Twelve studies did not define size according to a certain classification system.

      Data synthesis

      Table 2 shows the frequency of the core outcomes reported in the 29 studies of the update and their frequency in the sixty-three studies performed in the previous systematic review
      • Fledderus A
      • Franke C
      • Eggen C
      • van Etten-Jamaludin F
      • van der Horst C
      • Brinkmann S
      • et al.
      Outcomes and measurement instruments used in Congenital Melanocytic Naevi research: A systematic review.
      . Table 3 shows the measurement instruments used to measure the core outcomes found in the previously performed systematic review and the update, including information on the instrument, the target population and whether it was a PROM or clinician reported.
      Table 2Frequency of outcomes
      Core DomainCore outcome used in researchReported previous SRn %Reported update SRn %
      Anatomy of skinSize of CMN1/63 23/29 10
      Colour of the CMN31/63 495/29 17
      Texture of the CMN21/63 333/29 10
      Satellite nevi number10/63 160/29 0
      Quality of lifeEmotional distress6/63 107/29 24
      NeoplasmPresence of melanoma21/63 3314/29 48
      Nervous systemNeurological symptoms and signs11/63 175/29 17
      General adverse eventsWound problems of the CMN32/63 5111/29 38
      Scar problems10/63 1612/29 41
      PathologyMolecular characteristics2/63 37/29 26
      n: number of studies reporting the outcome; SR: systematic review
      Table 3measurement instruments
      Measurement instrumentOutcome measured
      The specific core outcome of the core domain in underlined CR: clinician reported, PROM: patient reported outcome measure, S: small, M: medium, L: large, G: giant, NR: not reported, y: years, m: months, QoL: quality of life
      Description of instrumentTarget populationCR/PROM
      Anatomy of the skin (domain)
      Digital assessment of length in cm
      • Han JW
      • Sun H
      • Kim JW
      • Yun JY
      • Chung EH
      • Oh MJ.
      A novel subdermal anchoring technique for the effective treatment of congenital melanocytic nevus using de-epithelialized dermal flaps.
      CMN lesion size and postoperative scar sizeDigital measurement of the size of the lesion in two dimensionsS, M, L CMN

      Age NR
      CR
      Length in cm measured by a ruler
      • Kim JS
      • Lee HS
      • Park DH
      • Seok S
      • Kim TK
      • Lee HS
      • et al.
      Effect of Size and Location of Nevi on Postoperative Pain and Emergence Agitation in Children Undergoing Nevi Excision.
      Long diameter of neviTo measure the long diameter in centimetres by using a ruler.Size NR

      Age range: 10-103 m
      CR
      Rating system, self or proxy reported
      • Neuhaus K
      • Landolt M
      • Vojvodic M
      • Bottcher-Haberzeth S
      • Schiestl C
      • Meuli M
      • et al.
      Surgical treatment of children and youth with congenital melanocytic nevi: self- and proxy-reported opinions.
      Percentage of nevus removalPatients or caregivers were asked to rate removal percentages (<10%, 10–25%, >25–50%, >50–75%, >75%)S, M, L, G CMN

      Mean age: 17.5 y [self] and 6.3 y [proxy]
      PROM
      Tracing on transparent film (area of resection in cm2)
      • Kim JS
      • Lee HS
      • Park DH
      • Seok S
      • Kim TK
      • Lee HS
      • et al.
      Effect of Size and Location of Nevi on Postoperative Pain and Emergence Agitation in Children Undergoing Nevi Excision.
      Area of nevi before resection in cm2To measure the area by tracing the total nevus area onto a transparent film, being transposed onto paper divided into millimetresSize NR

      Age range: 10-103 m
      CR
      L*a*b-colour space model (CIE-LAB) on clinical photos
      • Polubothu S
      • Kinsler VA.
      Final congenital melanocytic naevi colour is determined by normal skin colour and unaltered by superficial removal techniques: a longitudinal study.
      Lightening/ colour changeof CMNA program using mathematical descriptions of all perceivable colours in three dimensionsS, M, L, G CMN

      Age range: 0-17.4 y
      CR
      Kilmer & Lee 5 point lightening scale
      • Funayama E
      • Yamamoto Y
      • Oyama A
      • Murao N
      • Hayashi T
      • Maeda T
      • et al.
      Combination laser therapy as a non-surgical method for treating congenital melanocytic nevi from cosmetically sensitive locations on the body.
      ,
      • Lee MS
      • Jun HJ
      • Cho SH
      • Lee JD
      • Kim HS.
      Intense pulsed light alone and in combination with erbium yttrium-aluminum-garnet laser on small-to-medium sized congenital melanocytic nevi: single center experience based on retrospective chart review.
      Lighteningof CMNA 5-step scale to measure lightening of CMN colour after laser treatment: poor, fair, good, excellent, clearS, M CMN

      Median age: 9 m

      Age range: 0-28 y
      CR
      Zaal & van der Horst 7-point repigmentaion scale
      • Zaal LH
      • van der Horst CM.
      Results of the early use of tissue expansion for giant congenital melanocytic naevi on the scalp and face.
      Repigmentation໿A 10-step scale to measure repigmentation after treatment: 1-4 mild, 5-7 moderate, 8-10 severe.G CMN

      Age range:

      0.4-36 y
      Self-made questionnaire by Kinsler et al.
      • Kinsler V
      • Birley J
      • Atherton D.
      Great Ormond street hospital for children registry for congenital melanocytic naevi: prospective study 1988–2007. Part 2—evaluation of treatments.
      Colour lightening or darkening, hairiness, lumpiness, new CMN in unaffected skin at the edge of the treated area and development and number of new satellite lesions.A questionnaire ໿to measure changes in CMN appearance and development of new satellitesS, M, L, G CMN

      Mean ag: 2.9 y
      PROM
      Estimation by specialist
      • Lim JY
      • Jeong Y
      • Whang KK.
      A combination of dual-mode 2,940 nm Er: YAG laser ablation with surgical excision for treating medium-sized congenital melanocytic nevus.
      Hypopigmentation, hyperpigmentation, repigmentation, infection, erythema, scarring,Reviewing of clinical photographs by clinicianSize NR

      Age range: 7-25 y
      CR
      Evaluation by specialist blinded to study
      • Al-Hadithy N
      • Al-Nakib K
      • Quaba A
      Outcomes of 52 patients with congenital melanocytic naevi treated with UltraPulse Carbon Dioxide and Frequency Doubled Q-Switched Nd-Yag laser.
      Reduction pigmentation after treatmentIndepended third party reviewed clinical photographsSize NR

      Mean age: 12 y
      CR
      Investigator's Global Assessment (IGA) score for skin appearance
      • Oh Y
      • Lee SH
      • Lim JM
      • Chung KY
      • Roh MR.
      Long-term outcomes of laser treatment for congenital melanocytic nevi.
      Pigment clearance, erythema, hypopigmentation, hypertrophic scaring and texture irregularityA 7-point scale to assess improvement of clinical outcomes before and after intervention: 1 worsened - 7 total improvementSize NR

      Mean age 13.4 y
      CR
      Quality of life
      Paediatric Outcomes Data Collection Instrument (PODCI)
      • Alkureishi LWT
      • Purnell CA
      • Park P
      • Bauer BS
      • Fine NA
      • Sisco M.
      Long-term Outcomes After Pediatric Free Flap Reconstruction.
      Physical functioning, mobility, sports, pain/comfort, and happinessTo estimate functional health outcomes, musculoskeletal health, and QoL. It has been extensively reported in the orthopaedic surgery literature.

      Number of items: 86

      Scoring method: Likert-scale, scores range from 0–3 for some items and 0–6 for others

      Total score range: 0 worse -100 best
      Size/age NRPROM
      Children's Dermatology Life Quality Index (CDLQI)
      • Neuhaus K
      • Landolt MA
      • Theiler M
      • Schiestl C
      • Masnari O.
      Skin-related quality of life in children and adolescents with congenital melanocytic naevi - an analysis of self- and parent reports.
      ,
      • Carmen Ceballos-Rodriguez M
      • Redondo P
      • Tomas-Velazquez A
      • Cieza-Diaz D
      • Carlos Lopez-Gutierrez J.
      Surgical outcomes and psychosocial impact of giant congenital melanocytic nevus surgery: A single-center case series of 136 patients.
      ,
      • Wramp ME
      • Langenbruch A
      • Augustin M
      • Zillikens D
      • Krengel S.
      Clinical course, treatment modalities, and quality of life in patients with congenital melanocytic nevi–data from the German CMN registry.
      Skin discomfort, emotional, social and physical functioning, teasing/ bullying/ asking questions, sleep, effect of treatment on QoLTo assess proxy- and self-reported skin-related QoL

      No of items: 10 questions

      Scoring methods: 4-Point Likert scale

      Total score range: sum score, range, 30 best - 0 worst
      S, M, L, G CMN

      Age range: 4-18 y
      PROM

      Pediatric Quality of Life Inventory 4.0 (PedsQol)
      • Masnari O
      • Neuhaus K
      • Aegerter T
      • Reynolds S
      • Schiestl CM
      • Landolt MA.
      Predictors of Health-related Quality of Life and Psychological Adjustment in Children and Adolescents With Congenital Melanocytic Nevi: Analysis of Parent Reports.
      Health relatedQoL, Emotional functioning, Social functioningTo assess self- and proxy reported Health related QoL

      Number of items: 21

      Scoring method: 5-point Likert scale

      Total score range: 0 never - 4 almost always
      S, M, L, G CMN

      Mean age: 6.3 y
      PROM
      Strengths and Difficulties Questionnaire (SDQ)
      • Masnari O
      • Neuhaus K
      • Aegerter T
      • Reynolds S
      • Schiestl CM
      • Landolt MA.
      Predictors of Health-related Quality of Life and Psychological Adjustment in Children and Adolescents With Congenital Melanocytic Nevi: Analysis of Parent Reports.
      Psychological adjustment, emotional conduct, hyperactivity, inattentionTo assess self- and proxy-reported emotional and behavioural problems

      Number of items: 25

      Scoring method: 3-options, not true – somewhat true – certainly true

      Total score range: sum score 0 - 40
      S, M, L, G

      Mean age: 6.3 y
      PROM
      Post-Traumatic Stress Disorder Semi structured Interview (PTSDSSI)
      • Ben-Ari A
      • Margalit D
      • Nachshoni L
      • Benarroch F
      Traumatic Stress Among Children After Surgical Intervention for Congenital Melanocytic Nevi: A Pilot Study.
      Anxiety, depression, withdrawal, somatic complaints, attention problems, thought problems, social problems, rule-breaking behaviour, and aggressive behaviourTo assess the frequency of PTSS

      Number of items: 29

      Scoring method: mixed response no 0, sometimes 1, yes 2
      Size NR

      Mean age: 4.2 y
      PROM
      Teacher Report Form
      • Vourc'h-Jourdain M
      • Martin L
      • Barbarot S.
      Large congenital melanocytic nevi: therapeutic management and melanoma risk: a systematic review.
      Academic competence, adaptive functioning, inattention, hyperactivity, impulsivity, social problems, thought problems, anxious, and

      Depressed
      To rate the child's behavioral competence and behavioral/emotional problems

      Number of items: 113

      Scoring method: 3-point Likert scale 0 Not True, 1 Somewhat or Sometimes True, and 2 Very True or Often True and fill-in blanks questions
      L CMN

      Mean age: 12.6 y
      PROM
      Estimation by parents
      • Margileth AM.
      Spontaneous regression of large congenital melanocytic nevi, with a halo rim in 17 children with large scalp and trunk nevi during 45 years: a review of the literature.
      Estimation by parents of globalQoLGlobal QoLS, M, L, G CMN

      Age NR
      Neoplasms (Cancer)
      Questionnaire for presence of malignancy (proxy report)
      • Masnari O
      • Neuhaus K
      • Aegerter T
      • Reynolds S
      • Schiestl CM
      • Landolt MA.
      Predictors of Health-related Quality of Life and Psychological Adjustment in Children and Adolescents With Congenital Melanocytic Nevi: Analysis of Parent Reports.
      ,
      • Neuhaus K
      • Landolt MA
      • Theiler M
      • Schiestl C
      • Masnari O.
      Skin-related quality of life in children and adolescents with congenital melanocytic naevi - an analysis of self- and parent reports.
      ,
      • Neuhaus K
      • Landolt M
      • Vojvodic M
      • Bottcher-Haberzeth S
      • Schiestl C
      • Meuli M
      • et al.
      Surgical treatment of children and youth with congenital melanocytic nevi: self- and proxy-reported opinions.
      Presence of MelanomaTo indicate the patients’ health status concerning chronic diseases such as the presence of melanoma.S, M, L, G CMN

      Various ages
      PROM
      Histopathological biopsy (unspecified assessor)
      • Fahradyan A
      • Wolfswinkel EM
      • Tsuha M
      • Reinisch JF
      • Magee W
      • Hammoudeh JA
      • et al.
      Cosmetically Challenging Congenital Melanocytic Nevi.
      ,
      • Wu M
      • Yu Q
      • Gao B
      • Sheng L
      • Li Q
      • Xie F.
      A large-scale collection of giant congenital melanocytic nevi: Clinical and histopathological characteristics.
      Presence of MelanomaTo assess histologically for melanoma presence in biopsied CMN lesionsS, M, L, G CMN

      Various ages

      CR
      Clinical photos and Dermascopy
      • Zalaudek I
      • Conforti C
      • Guarneri F
      • Vezzoni R
      • Deinlein T
      • Hofmann-Wellenhof R
      • et al.
      Clinical and dermoscopic characteristics of congenital and noncongenital nevus-associated melanomas.
      Presence of MelanomaA noninvasive and in vivo diagnostic tool to visualize subtle clinical patterns of skin structures invisible to the unaided eye.Size NR

      Mean age: 39.2 y
      CR
      Nervous system
      Questionnaire (proxy report), presence of neurological problems
      • Masnari O
      • Neuhaus K
      • Aegerter T
      • Reynolds S
      • Schiestl CM
      • Landolt MA.
      Predictors of Health-related Quality of Life and Psychological Adjustment in Children and Adolescents With Congenital Melanocytic Nevi: Analysis of Parent Reports.
      ,
      • Neuhaus K
      • Landolt MA
      • Theiler M
      • Schiestl C
      • Masnari O.
      Skin-related quality of life in children and adolescents with congenital melanocytic naevi - an analysis of self- and parent reports.
      ,
      • Neuhaus K
      • Landolt M
      • Vojvodic M
      • Bottcher-Haberzeth S
      • Schiestl C
      • Meuli M
      • et al.
      Surgical treatment of children and youth with congenital melanocytic nevi: self- and proxy-reported opinions.
      Neurological symptoms and signsTo indicate the patients’ health status concerning chronic diseases such as the presence of neurological problems.S, M, L, G CMN

      Various ages
      PROM
      EEG, and classification criteria of ILAE
      • Pellino G
      • Gencarelli J
      • Bertelli S
      • Russo A
      • Fiumana E
      • Faggioli R.
      Epilepsy in isolated parenchymal neurocutaneous melanosis: A systematic review.
      FocalepilepsyTo assess diagnosis of focal epilepsy an EEG was performed and was classified according to the ILAE criteria.G CMN,

      Median age: 5 m
      CR
      Developmental milestones assessment
      • Pellino G
      • Gencarelli J
      • Bertelli S
      • Russo A
      • Fiumana E
      • Faggioli R.
      Epilepsy in isolated parenchymal neurocutaneous melanosis: A systematic review.
      Cognitive developmental delayTo distinguish cognitive development as normal or delayed the developmental milestones in children were used.G CMN,

      Median age: 5 m
      CR
      Physical evaluation by physician
      • August P
      • Ferguson J
      • Madan V
      A study of the efficacy of carbon dioxide and pigment-specific lasers in the treatment of medium-sized congenital melanocytic naevi.
      Neurological symptoms and signsAssessment of neurological symptoms and signs by a clinicianM CMN

      Age range: 9-43 y
      CR
      Adverse events
      Clinical photographs and visual assessment (surgeons)
      • Han JW
      • Sun H
      • Kim JW
      • Yun JY
      • Chung EH
      • Oh MJ.
      A novel subdermal anchoring technique for the effective treatment of congenital melanocytic nevus using de-epithelialized dermal flaps.
      ,
      • Lim JY
      • Jeong Y
      • Whang KK.
      A combination of dual-mode 2,940 nm Er: YAG laser ablation with surgical excision for treating medium-sized congenital melanocytic nevus.
      ,
      • Cho HJ
      • Lee W
      • Jeon MK
      • Park JO
      • Yang EJ.
      Staged Mosaic Punching Excision of a Kissing Nevus on the Eyelid.
      Wound problems of the CMN

      Scar problems
      Based on photographs, the scars and wound problems were visually assessed by cliniciansS, M, L CMN and ‘kissing naevus’

      Various ages
      CR
      Vancouver Scar Scale (VSS) (3 independent evaluators)
      • Qiao C
      • Zou Y
      • Qiu Y
      • Lin X.
      A Simple Approach for the Repair of Intermediate-to-Large Cheek Defects.
      Skar appearance,skarpigmentation,skarheight/thickness,skarpliability, andskarvascularityA tool for scar assessment, with the highest score indicating the worst scar formation and 0 suggesting the best outcome 0 best outcome – 4 worst outcome)M CMN

      Mean age: 20.4 y
      CR
      Investigator's Global Assessment (IGA) score for skin appearance
      • Oh Y
      • Lee SH
      • Lim JM
      • Chung KY
      • Roh MR.
      Long-term outcomes of laser treatment for congenital melanocytic nevi.
      Pigment clearance,erythema,hypopigmentation,hypertrophic scaring andtexture irregularityA 7-point scale to assess improvement of clinical outcomes before and after intervention: 1 worsened - 7 total improvementSize NR

      Mean age: 13.4 y
      CR

      Own assessment (self/proxy report)
      • Masnari O
      • Neuhaus K
      • Aegerter T
      • Reynolds S
      • Schiestl CM
      • Landolt MA.
      Predictors of Health-related Quality of Life and Psychological Adjustment in Children and Adolescents With Congenital Melanocytic Nevi: Analysis of Parent Reports.
      ,
      • Neuhaus K
      • Landolt M
      • Vojvodic M
      • Bottcher-Haberzeth S
      • Schiestl C
      • Meuli M
      • et al.
      Surgical treatment of children and youth with congenital melanocytic nevi: self- and proxy-reported opinions.
      Healing issues or infectionsPatients or parents could indicate if they had wound healing problems through a questionnaireS, M, L, G CMN

      Various ages
      PROM
      Patient and Observer Scar Assessment Scale (POSAS-score)
      • Han JW
      • Sun H
      • Kim JW
      • Yun JY
      • Chung EH
      • Oh MJ.
      A novel subdermal anchoring technique for the effective treatment of congenital melanocytic nevus using de-epithelialized dermal flaps.
      ,
      • Neuhaus K
      • Landolt M
      • Vojvodic M
      • Bottcher-Haberzeth S
      • Schiestl C
      • Meuli M
      • et al.
      Surgical treatment of children and youth with congenital melanocytic nevi: self- and proxy-reported opinions.
      ,
      • Zaal LH
      • van der Horst CM.
      Results of the early use of tissue expansion for giant congenital melanocytic naevi on the scalp and face.
      ,
      • Oh SI
      • Lee YH.
      Multidirectional vector excision leads to better outcomes than traditional elliptical excision of facial congenital melanocytic nevus.
      Scarappearance໿Observer and patient scale

      Number of items: 6

      Scoring method: 10-step score, 10 worst imaginable scar

      Total score range: 6 reflects normal skin – 60 the worst imaginable scar
      S, M, L, G CMN Various agesCR/

      PROM
      Physical examination
      • Elmelegy N
      • Elghamry S.
      Carbon Dioxide Cryotherapy for Treatment of Nasal and Perinasal Congenital Melanocytic Nevi.
      Infection, hypertrophic oratrophic scarringTo assess occurrence of adverse events a physical examination was performed during follow up.CR
      Self-made questionnaire by August et al.
      • August P
      • Ferguson J
      • Madan V
      A study of the efficacy of carbon dioxide and pigment-specific lasers in the treatment of medium-sized congenital melanocytic naevi.
      General adverse events໿Participants could indicate if they had any side-effects from the treatment?

      Rating: 1-10 (10 being worst)
      M CMN

      Age range: 9-43 y
      CR
      Pathology
      Electrochemiluminescence immunoassay
      • Tomás-Velázquez A
      • López-Gutiérrez JC
      • Ceballos C
      • Núñez-Córdoba JM
      • Redondo P.
      S-100B serum protein is elevated in children with medium-to-giant congenital melanocytic nevi: An exploratory case-control study.
      Molecular characteristicTo determine S-100B protein concentrations in peripheral blood in a blinded mannerM, L, G CMN

      Mean age: 5.7 y
      CR
      Phosphokinase-array
      • Rouille T
      • Aractingi S
      • Kadlub N
      • Fraitag S
      • How-Kit A
      • Daunay A
      • et al.
      Local Inhibition of MEK/Akt Prevents Cellular Growth in Human Congenital Melanocytic Nevi.
      Molecular characteristicTo analyse expression of effector proteins of the MAPK/Akt-signalling pathwaysL, G CMN

      Median age 8 m
      CR
      PCR - MC1R screening blood/saliva samples
      • Calbet-Llopart N
      • Pascini-Garrigos M
      • Tell-Martí G
      • Potrony M
      • Martins da Silva V
      • Barreiro A
      • et al.
      Melanocortin-1 receptor (MC1R) genotypes do not correlate with size in two cohorts of medium-to-giant congenital melanocytic nevi.
      Molecular characteristicTo amplify two overlapping fragments of the MC1R-coding region in blood and saliva samplesM, L, G CMN

      Mean age: 16.8 y
      CR
      Sanger sequencing
      • Polubothu S
      • Kinsler VA.
      Final congenital melanocytic naevi colour is determined by normal skin colour and unaltered by superficial removal techniques: a longitudinal study.
      Molecular characteristicGermline MC1R-genotyping was undertaken on leucocyte DNAS, M, L, G CMN

      Age range: 0.0-17.2 y
      CR
      Immunohistochemistry
      • Wu M
      • Yu Q
      • Gao B
      • Sheng L
      • Li Q
      • Xie F.
      A large-scale collection of giant congenital melanocytic nevi: Clinical and histopathological characteristics.
      Molecular characteristicTo assess the proliferative indices in Giant CMN lesions by using proliferation markers (Ki67, Melan-Am S-100, HMHB-45, SOX-10)G CMN

      Median age: 6 y
      CR
      Single-base extension SNaPshot assay

      PCR
      • Phadke PA
      • Rakheja D
      • Le LP
      • Selim MA
      • Kapur P
      • Davis A
      • et al.
      Proliferative nodules arising within congenital melanocytic nevi: a histologic, immunohistochemical, and molecular analyses of 43 cases.
      Molecular characteristic໿To analyse recurrent point mutation in KRAS codons G12, G13, and Q61; NRAS codons G12,

      G13, and Q61; HRAS codons G12, G13, and Q61; GNAQ exon 5; and BRAF codon V600 in proliferative noduli tissue
      S, M, L, G CMN

      Age range: 0-84 y
      CR
      low asterisk The specific core outcome of the core domain in underlinedCR: clinician reported, PROM: patient reported outcome measure, S: small, M: medium, L: large, G: giant, NR: not reported, y: years, m: months, QoL: quality of life
      Results Step 2: Evaluation of the quality of measurement instruments developed or validated for CMN

      Search and study selection

      The search provided 677 unique studies; Figure 2 shows the flow diagram of the study selection. Two studies met our inclusion criteria, with both evaluating one measurement property, internal consistency, of an instrument measuring the domain ‘quality of life’
      • Masnari O
      • Neuhaus K
      • Aegerter T
      • Reynolds S
      • Schiestl CM
      • Landolt MA.
      Predictors of Health-related Quality of Life and Psychological Adjustment in Children and Adolescents With Congenital Melanocytic Nevi: Analysis of Parent Reports.
      ,
      • Neuhaus K
      • Landolt MA
      • Theiler M
      • Schiestl C
      • Masnari O.
      Skin-related quality of life in children and adolescents with congenital melanocytic naevi - an analysis of self- and parent reports.
      .
      We did not find any development studies. Besides ‘quality of life’, there were no studies available for instruments measuring the other core domains and outcomes developed or validated for the CMN population. Moreover, no clinician reported instruments nor rating systems, medical devices, or other instruments were developed or validated for CMN.

      Evaluation of the methodological quality of the included studies

      Both studies had scored a ‘very good’ for their methodological quality regarding the measurement property they assessed (Appendix 4).

      Evaluation of the quality of the measurement properties, evidence synthesis and generating recommendations

      The included studies evaluated the measurement property ‘internal consistency’ of the Paediatric Quality of Life Inventory (PedsQol) and the Children's Dermatology Life Quality Index (CDLQI) to measure the domain ‘quality of life’ including the outcome ‘emotional distress’
      • Masnari O
      • Neuhaus K
      • Aegerter T
      • Reynolds S
      • Schiestl CM
      • Landolt MA.
      Predictors of Health-related Quality of Life and Psychological Adjustment in Children and Adolescents With Congenital Melanocytic Nevi: Analysis of Parent Reports.
      ,
      • Neuhaus K
      • Landolt MA
      • Theiler M
      • Schiestl C
      • Masnari O.
      Skin-related quality of life in children and adolescents with congenital melanocytic naevi - an analysis of self- and parent reports.
      . The following measurement properties were not evaluated: structural validity, reliability, hypotheses testing, cross-cultural validity and/or responsiveness. We did not find any study evaluating these measurement properties in other instruments used for the CMN population.
      Masnari et al studied internal consistency of the PedsQol. They recruited their patients worldwide and included 235 children with a mean age of 6.3 years and a mean TBSA score of 13.14 percent. About half of the included children did not have any surgery to remove the CMN.
      Neuhaus et al. studied internal consistency of the CDLQI and recruited their patients worldwide as well. They included 163 patients. The mean age of children in their proxy report group (4-18 years) was 9.3 years and in the self-report group (14-18 years) was 16.3 years. They had a mean TBSA score of 13.6 and 16,1, respectively. More than half of the patients underwent partial removal of their CMN.
      Table 4 shows the rating of the results and level of evidence.
      Table 4Study characteristics and rating of internal consistency
      Measurement instrumentSample sizeResults(Cronbach's α)COSMINRisk of Bias score
      : Based on the COSMIN risk of bias tool (Appendix 4).
      Level of evidence
      : After application of the GRADE approach.
      Rating of results
      : Rating of results was either sufficient (+), insufficient (−), or indeterminate (?).
      PedsQol
      • Masnari O
      • Neuhaus K
      • Aegerter T
      • Reynolds S
      • Schiestl CM
      • Landolt MA.
      Predictors of Health-related Quality of Life and Psychological Adjustment in Children and Adolescents With Congenital Melanocytic Nevi: Analysis of Parent Reports.
      1-12m310.76 - 0.94
      : Range of cronbachs's α: for each item, cronbach's α was measured separately.
      Very goodLow
      : Downgraded because of the sample size.
      ?
      : Rated as indeterminate due to the absence of evidence for sufficient structural validity.
      13-24m320.72 - 0.91
      : Range of cronbachs's α: for each item, cronbach's α was measured separately.
      Very goodLow
      : Downgraded because of the sample size.
      ?
      : Rated as indeterminate due to the absence of evidence for sufficient structural validity.
      2-18y1700.53 - 0.94
      : Range of cronbachs's α: for each item, cronbach's α was measured separately.
      Very goodModerate
      : Downgraded because of the indirectness, as the exact sample size of the size of the 5–18 years and < 5 years group is not reported.
      ?
      : Rated as indeterminate due to the absence of evidence for sufficient structural validity.
      CDLQI
      • Neuhaus K
      • Landolt MA
      • Theiler M
      • Schiestl C
      • Masnari O.
      Skin-related quality of life in children and adolescents with congenital melanocytic naevi - an analysis of self- and parent reports.
      Proxy1350.83Very goodHigh?
      : Rated as indeterminate due to the absence of evidence for sufficient structural validity.
      Self- report280.87Very goodLow
      : Downgraded because of the sample size.
      ?
      : Rated as indeterminate due to the absence of evidence for sufficient structural validity.
      1 : Range of cronbachs's α: for each item, cronbach's α was measured separately.
      2 : Based on the COSMIN risk of bias tool (Appendix 4).
      3 : After application of the GRADE approach.
      4 : Downgraded because of the sample size.
      5 : Downgraded because of the indirectness, as the exact sample size of the size of the 5–18 years and < 5 years group is not reported.
      6 : Rating of results was either sufficient (+), insufficient (−), or indeterminate (?).
      7 : Rated as indeterminate due to the absence of evidence for sufficient structural validity.
      Despite most Cronbach alpha item scores being >0.7, all ratings were scored as indeterminate due to the absence of “at least low evidence for sufficient structural validity”, which is a requirement for a sufficient rating for internal consistency. Table 5 shows the feasibility aspects of these instruments. The best evidence synthesis is shown in Table 6. As only the internal constancy of these questionnaires had been evaluated, they receive recommendation D, almost not validated. Its performance in all or most relevant quality items is unclear, further validation studies are needed.
      Table 5aspects of feasibility
      InstrumentAvailable for agesAvailable translationsCompletion timeLicensing/costs
      CDLQI

      Self- and proxy reported
      4-12 years

      proxy and self-reported

      Adult version available (DLQI)
      115 Languages2 minutesFree for clinicians, free for nonacademic research (not

      funded externally);

      external funded trial fees dependent on sample size
      Self- and proxy PedsQoL2-18 years

      proxy and self-reported
      176 translations4 minutesThe costs are determined based on, the type of research, the source of funding for the research and the sample size.
      Table 6Best evidence synthesis and recommendations
      Evaluated measurement properties according to the COSMIN taxonomy
      • Mokkink LB
      • Terwee CB
      • Patrick DL
      • Alonso J
      • Stratford PW
      • Knol DL
      • et al.
      The COSMIN checklist for assessing the methodological quality of studies on measurement properties of health status measurement instruments: an international Delphi study.
      PedsQolCDLQI
      Masnari et al. (2019)
      • Masnari O
      • Neuhaus K
      • Aegerter T
      • Reynolds S
      • Schiestl CM
      • Landolt MA.
      Predictors of Health-related Quality of Life and Psychological Adjustment in Children and Adolescents With Congenital Melanocytic Nevi: Analysis of Parent Reports.
      Neuhaus et al. (2020)
      • Neuhaus K
      • Landolt MA
      • Theiler M
      • Schiestl C
      • Masnari O.
      Skin-related quality of life in children and adolescents with congenital melanocytic naevi - an analysis of self- and parent reports.
      Internal consistency??
      ReliabilityNANA
      Measurement errorNANA
      Content validityNANA
      Structural validityNANA
      Hypotheses testingNANA
      Cross-cultural validityNANA
      ResponsivenessNANA
      RecommendationCategory DCategory D
      For each measurement property, the methodological quality of the study is reported as sufficient (+), insufficient (−), or indeterminate (?), NA not available (analysis was not performed for this measurement property).
      Recommendations: category A, meets all requirements (positive rating for all boxes in the best evidence synthesis) and is recommended for use; B, meets two or more required quality items, but performance in all other required quality items is unclear, so that the instrument has the potential to be recommended, depending on the results of further validation studies; C, low quality in at least one required quality criteria (≥1 rating of ‘minus’) and therefore is not recommended to be used anymore; D, almost not validated. Its performance in all or most relevant quality items is unclear, further validation studies are needed.

      Discussion

      This study is the first step of selecting the core measurement instruments for the COS of CMN. We showed a systematic overview of the instruments used to measure core outcomes for CMN published in addition to a previously performed study
      • Fledderus A
      • Franke C
      • Eggen C
      • van Etten-Jamaludin F
      • van der Horst C
      • Brinkmann S
      • et al.
      Outcomes and measurement instruments used in Congenital Melanocytic Naevi research: A systematic review.
      . In addition, studies on measurement properties of instruments used for the CMN population were evaluated. We found a wide heterogeneity in outcomes and measurement instruments in the included studies and there were no studies reporting all core outcomes. We showed that research on measurement properties of these instruments is limited. Therefore, none of the instruments could be recommended based on the quality of their measurement properties and further validation studies are needed.
      Research on CMN is growing; this current update included twenty-nine studies published in a period of two years, while the previously performed systematic review includes sixty-three studies in a period of twelve years
      • Fledderus A
      • Franke C
      • Eggen C
      • van Etten-Jamaludin F
      • van der Horst C
      • Brinkmann S
      • et al.
      Outcomes and measurement instruments used in Congenital Melanocytic Naevi research: A systematic review.
      . Uniformity is therefore of upmost importance to enable combination and comparison of studies. However, heterogeneity in outcomes still exist, highlighting the importance of a COS. Besides heterogeneity in outcomes, we found heterogeneity in CMN classifications as well. To enhance uniformity in CMN care and research, we recommend using the consensus derived, internationally used classification developed by Krengel et al
      • Krengel S
      • Scope A
      • Dusza SW
      • Vonthein R
      • Marghoob AA.
      New recommendations for the categorization of cutaneous features of congenital melanocytic nevi.
      and qualified (the “6B”
      • da Silva VPM
      • Marghoob A
      • Pigem R
      • Carrera C
      • Aguilera P
      • Puig-Butillé JA
      • et al.
      Patterns of distribution of giant congenital melanocytic nevi (GCMN): the 6B rule.
      and “biker glove” distributions
      • Kittler NW
      • Mathes EF
      • Kinsler V
      • Frieden IJ.
      The biker-glove pattern of congenital melanocytic nevi.
      ) for the CMN location.
      Relevant stakeholders should reach consensus over which instruments should be validated for CMN. In this process, the feasibility of instruments should also be considered as well; instruments should be easy and quick to use and should be low-cost or free of charges. Similar systematic reviews investigating the measurement properties according to the COSMIN checklist are available for diseases similar to CMN such as vitiligo, vascular malformations, capillary malformation and burn scars
      • Horbach SE
      • Rongen AP
      • Elbers RG
      • van der Horst CM
      • Prinsen CA
      • Spuls PI.
      Outcome measurement instruments for peripheral vascular malformations and an assessment of the measurement properties: a systematic review.
      ,
      • Vrijman C
      • Homan MWL
      • Limpens J
      • van der Veen W
      • Wolkerstorfer A
      • Terwee CB
      • et al.
      Measurement properties of outcome measures for vitiligo: a systematic review.
      • Legemate CM
      • Spronk I
      • Mokkink LB
      • Middelkoop E
      • Polinder S
      • van Baar ME
      • et al.
      Evaluation of measurement properties of health-related quality of life instruments for burns: A systematic review.
      • van Raath MI
      • Chohan S
      • Wolkerstorfer A
      • van der Horst CM
      • Limpens J
      • Huang X
      • et al.
      Treatment Outcome Measurement Instruments for Port Wine Stains: A Systematic Review of Their Measurement Properties.
      . Although these studies also revealed a low quality of measurement instruments validated for their particular patient population, some of their recommendations may inform which instruments should be validated for CMN.
      The domain ‘anatomy of the skin’ or ‘skin appearance’ is often measured by disease specific measurement instruments, a probable result of the unique manifestations of every skin disease. For CMN, we found both objective instruments, such as L*a*b* colour-space model (CIE-LAB) measurements, as well as subjective rating systems (Table 3). The systematic reviews of similar anomalies revealed that ‘skin appearance’ is generally measured by questionnaires or rating systems completed by both clinicians and patients. These types of instruments are often low-cost and quick and easy to use. For vitiligo, the most effective instrument that measures the size of a lesion was the disease specific (Self-Assessment) Vitiligo Extent Score ((SA)-VES)
      • Peralta-Pedrero ML
      • Morales-Sánchez MA
      • Jurado-Santa Cruz F
      • De la Torre-García ME
      • Cruz-Peralta ES
      • Olguín-García MG
      Systematic Review of Clinimetric Instruments to determine the severity of Non-segmental Vitiligo.
      . For capillary malformation there were only low-quality clinician reported rating systems available
      • van Raath MI
      • Chohan S
      • Wolkerstorfer A
      • van der Horst CM
      • Limpens J
      • Huang X
      • et al.
      Treatment Outcome Measurement Instruments for Port Wine Stains: A Systematic Review of Their Measurement Properties.
      . None of these rating systems were developed by asking patients (or their parents) which outcomes are important to them
      • van Raath MI
      • Chohan S
      • Wolkerstorfer A
      • van der Horst CM
      • Limpens J
      • Huang X
      • et al.
      Treatment Outcome Measurement Instruments for Port Wine Stains: A Systematic Review of Their Measurement Properties.
      . The systematic review for vascular malformations also showed low-quality rating systems
      • Horbach SE
      • Rongen AP
      • Elbers RG
      • van der Horst CM
      • Prinsen CA
      • Spuls PI.
      Outcome measurement instruments for peripheral vascular malformations and an assessment of the measurement properties: a systematic review.
      . Therefore, a new PROM questionnaire is now in development; the Outcome Measures for Vascular Malformations (OVAMA) questionnaire
      • Lokhorst MM
      • Horbach SER
      • DA Young-Afat
      • Stor MLE
      • Haverman L
      • Spuls PI
      • et al.
      Development of a condition-specific patient-reported outcome measure for measuring symptoms and appearance in vascular malformations: the OVAMA questionnaire.
      . For burn scars, both PROMs, clinician reported rating systems and objective measurement instruments are available
      • Tyack Z
      • Simons M
      • Spinks A
      • Wasiak J.
      A systematic review of the quality of burn scar rating scales for clinical and research use.
      . For instance, objective instruments to measure color of burn scars include: reflectance spectroscopy (colorimetry/spectrophotometry), laser imaging or computerized analysis of digital photographs
      • Lee KC
      • Dretzke J
      • Grover L
      • Logan A
      • Moiemen N.
      A systematic review of objective burn scar measurements.
      .
      Various questionnaires are available to measure the domain ‘quality of life’, including the outcome ‘emotional distress’, in patients with a skin disease. To measure health related ‘quality of life’, disease specific and generic instruments are available. In addition, for skin conditions, dermatology specific questionnaires are available
      • Lewis-Jones M
      • Finlay A.
      The Children's Dermatology Life Quality Index (CDLQI): initial validation and practical use.
      . Disease specific instruments measure the impact of a specific condition on the different aspects of ‘quality of life’, while generic instruments measure the overall ‘quality of life’ of a subject allowing comparison between a group of patients with a certain disease and their peers of the general populations. The systematic review evaluating ‘quality of life’ instruments for burn scars showed that burn scar specific instruments have the best measurement properties
      • Legemate CM
      • Spronk I
      • Mokkink LB
      • Middelkoop E
      • Polinder S
      • van Baar ME
      • et al.
      Evaluation of measurement properties of health-related quality of life instruments for burns: A systematic review.
      .
      No disease specific questionnaires are available for CMN. Rare diseases may be best measured with a generic ‘quality of life’ measurement instrument, as the development of a high-quality disease specific instrument is hindered by the limited number of subjects to validate the instrument. An existing generic instrument may be the best option for CMN, as there are various generic quality of life PROMs available. The systematic review for capillary malformations provisionally recommends the PROMs Perceived Stress Questionnaire (PSQ) or the DLQI. The DLQI was proposed by the vitiligo group as well
      • Vrijman C
      • Homan MWL
      • Limpens J
      • van der Veen W
      • Wolkerstorfer A
      • Terwee CB
      • et al.
      Measurement properties of outcome measures for vitiligo: a systematic review.
      . The systematic review for vascularity malformations states that the Short Form-36 (for adults) and PedsQol (for children) seem to be the most appropriate generic instrument
      • Horbach SE
      • Rongen AP
      • Elbers RG
      • van der Horst CM
      • Prinsen CA
      • Spuls PI.
      Outcome measurement instruments for peripheral vascular malformations and an assessment of the measurement properties: a systematic review.
      . However, this same research group showed in a subsequent study that these questionnaires do not sufficiently measure effectiveness i.e., change in the ‘quality of life’ before and after treatment. They therefore advise using Patient-Reported Outcomes Measurement Information System (PROMIS)
      • Lokhorst MM
      • Horbach SER
      • DA Young-Afat
      • Stor MLE
      • Haverman L
      • Spuls PI
      • et al.
      Development of a condition-specific patient-reported outcome measure for measuring symptoms and appearance in vascular malformations: the OVAMA questionnaire.
      ,
      • Lokhorst M
      • Horbach S
      • Waner M
      • O T
      • Van der Vleuten C
      • Mokkink L
      • et al.
      Responsiveness of quality-of-life measures in patients with peripheral vascular malformations: the OVAMA project.
      . The use of PROMIS is advised for rare diseases and may be suitable to use for CMN
      • Sabino G
      • Mills A
      • Jonker A
      • Lau L
      • Ayme S.
      Patient-centered outcome measures in the field of rare diseases.
      • Benjamin K
      • Vernon MK
      • Patrick DL
      • Perfetto E
      • Nestler-Parr S
      • Burke L.
      Patient-Reported Outcome and Observer-Reported Outcome Assessment in Rare Disease Clinical Trials: An ISPOR COA Emerging Good Practices Task Force Report.
      • Slade A
      • Isa F
      • Kyte D
      • Pankhurst T
      • Kerecuk L
      • Ferguson J
      • et al.
      Patient reported outcome measures in rare diseases: a narrative review.
      . PROMIS consists of item banks for every subdomain of ‘quality of life’ which have been extensively validated in large populations. An item bank is a large set of questions for multiple ‘quality of life’ outcomes. These item banks are available in short form and with computer adaptive testing. With computer adaptive testing, the most relevant questions for an individual will be asked based on their previous answers. This decreases the number of questions and causes accurate and person-centred outcomes. In contrast to other generic instruments, PROMIS facilitates the measurement of the outcome ‘emotional distress’ without measuring the outcomes ‘social and physical functioning'.
      For measuring the domain ‘neoplasm’ a panel of stakeholders agreed that the core outcome ‘presence of melanoma’ should always be measured in care and research. In this study, we found ‘presence of melanoma’ to be measured by self/proxy report of patients or their parents through online questionnaires or by pathological confirmations. In future research, a consensus should be reached regarding whether melanoma should be confirmed by pathology for all research or if an anamnesis of patients or parents is sufficient for survey studies.
      The domain ‘neurology’ is defined by the outcome ‘neurological symptoms and signs’. A consensus procedure with international stakeholders should be held to decide how neurological symptoms and signs should be measured. For instance, a questionnaire screening for the most common symptoms or signs could be used and/or stakeholders could decide that neurological examinations should as a standard be performed by, for example, a neurologist or paediatrician. None of the studies included in this study or the previously performed systematic review used a questionnaire for specific symptoms and signs of CMN patients
      • Fledderus A
      • Franke C
      • Eggen C
      • van Etten-Jamaludin F
      • van der Horst C
      • Brinkmann S
      • et al.
      Outcomes and measurement instruments used in Congenital Melanocytic Naevi research: A systematic review.
      . Questionnaires to measure developmental delay or epilepsy are available for clinicians and for patients
      • Melbourne-Chambers R
      • Clarke D
      • Gordon-Strachan G
      • Tapper J
      • Tulloch-Reid MK
      The UWIMONA Pediatric Epileptic Seizure Screening Questionnaire was equivalent to clinical assessment in identifying children with epilepsy.
      • Ottman R
      • Barker-Cummings C
      • Leibson CL
      • Vasoli VM
      • Hauser WA
      • Buchhalter JR.
      Validation of a brief screening instrument for the ascertainment of epilepsy.
      • Bayley N.
      Manual for the Bayley scales of infant development.
      • Palisano R
      • Rosenbaum P
      • Walter S
      • Russell D
      • Wood E
      • Galuppi B.
      Development and reliability of a system to classify gross motor function in children with cerebral palsy.
      . Questionnaires to measure general neurology disorders are available and are frequently developed for patients in low- and mid-income countries
      • Bower JH
      • Howlett W
      • Maro VP
      • Wangai H
      • Sirima N
      • Reyburn H.
      A screening instrument to measure the prevalence of neurological disability in resource-poor settings.
      • Zaman SS
      • Khan NZ
      • Islam S
      • Banu S
      • Dixit S
      • Shrout P
      • et al.
      Validity of the ‘Ten Questions’ for screening serious childhood disability: results from urban Bangladesh.

      Organization WH. WHO International Classification of Functioning, Disability and Health (ICF) [Internet]26-10-2019 [cited 26-10-2019]. Podcast. Available from: http://apps.who.int/classifications/icfbrowser/

      . If relevant stakeholders decide that a neurological questionnaire should be used for the core outcome set, future research should assess the accuracy and feasibility of the questionnaires for neurological involvement in CMN patients or decide to develop a CMN specific instrument.
      The domain ‘general adverse event’ includes the core outcomes ‘wound problems of the CMN’ and ‘scar problems’. Classifications such as The Common Terminology Criteria for Adverse Events (CTCAE), the Medical Dictionary for Regulatory Activities (MedDRA) or the Clavien-Dindo Classification can be consulted to classify the severity or define the adverse events. A consensus should be reached over which classification should be used to report adverse events. For the outcome ‘scar problems’ the Patient and Observer Scar Assessment Scale (POSAS) is used in four CMN studies. A new version of the POSAS is now in development, in which the patients’ opinion on scar appearance is implemented. A consensus with international stakeholders should be reached over which standard instrument and classification system should be used to report adverse events.
      The importance of the outcome ‘molecular characteristics’ of the domain ‘pathology’ is growing in the research of CMN. A quarter of the studies included in this systematic review measured this outcome. Increasing knowledge regarding molecular characteristics of CMN could help in the future to estimate the risk of melanoma or neurological complications
      • Kinsler VA
      • Reyes-Mugica M
      • Marghoob A.
      Congenital Melanocytic Naevi.
      . Moreover, new pharmacological therapies may be developed that could be offered to patients with a certain DNA mutation
      • Mir A
      • Agim NG
      • Kane AA
      • Josephs SC
      • Park JY
      • Ludwig K.
      Giant congenital melanocytic nevus treated with trametinib.
      ,
      • Kinsler VA
      • O'Hare P
      • Jacques T
      • Hargrave D
      • Slater O
      MEK inhibition appears to improve symptom control in primary NRAS-driven CNS melanoma in children.
      . We showed that various molecular characteristics are reported in literature. For now, alongside all relevant stakeholders, we have decided that all molecular characteristics that are already measured for care purpose should be standard documented in research of CMN in a standardised manner.

      Strengths and limitations

      We systemically reviewed the availability and quality of measurement instruments of CMN according to the COMET, CS-COUSIN and COSMIN guidelines. We included a broad range of studies on CMN including both outcomes and instruments for studies of intervention treatment and watchful waiting. A limitation could be that we only included studies written in English or Dutch, however, there is a wide geographical spread in the included publications. Because of the heterogeneity in the classification of CMN, we could not describe differences between measurement instruments used for different CMN size or location (visible/non-visible) categories.

      Future perspectives

      This systematic review was the first step of developing the COMS of the COS of medium-to-giant CMN care and research. Relevant stakeholders should reach a consensus over which measurement instruments should be used for the domains and outcomes of CMN. Firstly, relevant stakeholders should decide whether every domain and outcome should be clinician and/or patient reported and if questionnaires, rating systems, clinical devices or other instruments are needed. In addition, they should consider the feasibility of an instrument. Secondly, relevant stakeholders should decide which measurement instruments should be developed or validated for the CMN patient population. This study informs the instrument selection and/or the development of new instruments.

      Uncited References

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      Declaration of Competing Interest

      The authors have no other financial or personal relationships relevant to this study to disclose.

      Acknowledgements

      The authors would like to thank Farid van Etten for helping with the search strategy and Ingmar van Raath for methodological advice.

      Funding

      This study was partly funded by foundation ‘De Merel’.

      Ethical Approval

      Not required

      Appendix. Supplementary materials

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