Psychometric Validation of the Growth Hormone Deficiency-Child Treatment Burden Measure (GHD-CTB) and the Growth Hormone Deficiency-Parent Treatment Burden Measure (GHD-PTB)

Meryl Brod, Michael Højby Rasmussen, Suzanne Alolga, Jane F Beck, Donald M Bushnell, Kai Wai Lee, Aristides Maniatis, Meryl Brod, Michael Højby Rasmussen, Suzanne Alolga, Jane F Beck, Donald M Bushnell, Kai Wai Lee, Aristides Maniatis

Abstract

Purpose: The aim was to evaluate the measurement properties of the Growth Hormone Deficiency-Child Treatment Burden Measure-Child (GHD-CTB-Child), a patient-reported outcome (PRO) for children aged 9 to < 13 years; the Growth Hormone Deficiency-Child Treatment Burden Measure-Observer (GHD-CTB-Observer), an observer-reported outcome (ObsRO) version completed by parents/guardians of children with growth hormone deficiency (GHD) aged 4 to < 9 years; and the Growth Hormone Deficiency-Parent Treatment Burden Measure (GHD-PTB), a PRO that assesses the treatment burden of parents/guardians living with children with GHD aged 4 to < 13 years.

Methods: A non-interventional, multi-center, clinic-based study across 30 private practice and large institutional sites in the United States and the United Kingdom was conducted. The sample consisted of 145 pre-pubertal children aged 9 to < 13 years at enrollment with a physician confirmed GHD diagnosis as well as 98 parents/guardians of pre-pubertal younger children aged 4 to < 9 years at enrollment with a physician confirmed GHD diagnosis. The child sample consisted of 59 treatment-naïve children (no prior exposure to growth hormone [GH] therapy; were starting GH treatment at study start per standard of care) and 184 children already maintained on treatment for at least 6 months. At baseline, all study participants completed a paper validation battery including all measures needed to conduct the validation analyses. Follow-up assessments with children in the maintenance group and their caregiver/parent were conducted approximately 2 weeks post-baseline to evaluate test-retest reproducibility. To evaluate sensitivity to change and meaningful change thresholds, treatment-naïve participants in both child and parent/guardian populations were assessed within 1 week of report of minimal improvement between week 3 and week 11 and at week 12. Psychometric analyses were implemented following an a priori statistical analysis plan.

Results: Factor analyses confirmed the a priori conceptual domains and Overall score for each measure (GHD-CTB-Child and GHD-CTB-Observer domains: Physical, Emotional Well-being, and Interference; GHD-PTB domains: Emotional Well-being and Interference). Internal consistency was acceptable for all measures (Cronbach's alpha > 0.70). Test-retest reliability was acceptable for the Physical, Emotional, and Overall domains of the GHD-CTB versions, and the Emotional and Overall domains of the GHD-PTB (intraclass correlation coefficient above 0.70). All but one of the convergent validity hypotheses for the GHD-CTB versions and all hypotheses for the GHD-PTB were proven (r > 0.40). Known-groups validity hypotheses were significant for length of time to administer the injections in the GHD-CTB versions (p < 0.001 for Physical, Emotional, and Overall, and p < 0.01 for Interference) and whether parents/guardians versus child gave the injections more often for the Emotional domain of the GHD-PTB (p < 0.05). Associated effect sizes ranged from -0.27 to -0.57 for GHD-CTB versions and from -0.74 to -0.69 for the GHD-PTB, indicating that the measures are sensitive to change. Anchor-based patient and parent/guardian ratings of severity suggest preliminary meaningful change thresholds (GHD-CTB: 6 points for Physical score, 9 for Emotional, and 6 for Interference; GHD-PTB: 10 points for Emotional and 6 for Interference scores).

Conclusions: The psychometric properties of the GHD-CTB-Child, GHD-CTB-Observer, and GHD-PTB support the validity of their use as PRO and ObsRO measures to capture the experiences associated with treatment burden for children with GHD and their parents/guardians in both clinical and research settings. The Clinicaltrials.gov registration number NCT02580032 was first posted October 20, 2015.

Conflict of interest statement

M. Brod, S. Alolga, J.F. Beck, and D.M. Bushnell are paid consultants to the pharmaceutical industry, including Novo Nordisk. M. Højby Rasmussen is an employee of Novo Nordisk A/S and owns stock in the company. K.W. Lee was an employee of Novo Nordisk A/S when the research was conducted. A. Maniatis is a principal investigator for Novo Nordisk, Ascendis, Pfizer/OPKO, Genentech, and Sandoz.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Final theoretical model of GHD treatment burden (child and parent). GHD growth hormone deficiency
Fig. 2
Fig. 2
Conceptual frameworks of the GHD-CTB and GHD-PTB. GHD-CTB Growth Hormone Deficiency–Child Treatment Burden Measure, GHD-CTB–Child Growth Hormone Deficiency–Child Treatment Burden Measure–Child, GHD-CTB–Observer Growth Hormone Deficiency–Child Treatment Burden Measure–Observer, GHD-PTB Growth Hormone Deficiency–Parent Treatment Burden Measure

References

    1. Donaldson MDC, Gregory JW, Van Vliet G, Wolfsdorf JI, Deladoey J. Short stature. In: Practical endocrinology and diabetes in children. 2019. 10.1002/9781119386230. Accessed 22 Jan 2020.
    1. Brod M, Alolga SL, Beck JF, Wilkinson L, Hojbjerre L, Rasmussen MH. Understanding burden of illness for child growth hormone deficiency. Qual Life Res. 2017;26(7):1673–1686. doi: 10.1007/s11136-017-1529-1.
    1. Stabler B, Clopper RR, Siegel PT, Stoppani C, Compton PG, Underwood LE. Academic achievement and psychological adjustment in short children. The National Cooperative Growth Study. J Dev Behav Pediatr. 1994;15(1):1–6. doi: 10.1097/00004703-199402000-00001.
    1. Butler G, Turlejski T, Wales G, Bailey L, Wright N. Growth hormone treatment and health-related quality of life in children and adolescents: a national, prospective, one-year controlled study. Clin Endocrinol. 2019;91(2):304–313. doi: 10.1111/cen.14011.
    1. Geisler A, Lass N, Reinsch N, Uysal Y, Singer V, Ravens-Sieberer U, et al. Quality of life in children and adolescents with growth hormone deficiency: association with growth hormone treatment. Horm Res Paediatr. 2012;78(2):94–99. doi: 10.1159/000341151.
    1. Sommer R, Bullinger M, Chaplin J, Do JK, Power M, Pleil A, et al. Experiencing health-related quality of life in paediatric short stature - a cross-cultural analysis of statements from patients and parents. Clin Psychol Psychother. 2017;24(6):1370–1376. doi: 10.1002/cpp.2105.
    1. Stagi S, Scalini P, Farello G, Verrotti A. Possible effects of an early diagnosis and treatment in patients with growth hormone deficiency: the state of art. Ital J Pediatr. 2017;43(1):81. doi: 10.1186/s13052-017-0402-8.
    1. Ciresi A, Amato MC, Criscimanna A, Mattina A, Vetro C, Galluzzo A, et al. Metabolic parameters and adipokine profile during GH replacement therapy in children with GH deficiency. Eur J Endocrinol. 2007;156(3):353–360. doi: 10.1530/eje.1.02343.
    1. Thomas M, Massa G, Craen M, de Zegher F, Bourguignon JP, Heinrichs C, et al. Prevalence and demographic features of childhood growth hormone deficiency in Belgium during the period 1986–2001. Eur J Endocrinol. 2004;151(1):67–72. doi: 10.1530/eje.0.1510067.
    1. Vimpani GV, Vimpani AF, Lidgard GP, Cameron EH, Farquhar JW. Prevalence of severe growth hormone deficiency. Br Med J. 1977;2(6084):427–430. doi: 10.1136/bmj.2.6084.427.
    1. Lindsay R, Feldkamp M, Harris D, Robertson J, Rallison M. Utah Growth Study: growth standards and the prevalence of growth hormone deficiency. J Pediatr. 1994;125(1):29–35. doi: 10.1016/s0022-3476(94)70117-2.
    1. Ranke MB, Lindberg A, Tanaka T, Camacho-Hubner C, Dunger DB, Geffner ME. Baseline characteristics and gender differences in prepubertal children treated with growth hormone in Europe, USA, and Japan: 25 Years' KIGS(R) experience (1987–2012) and review. Horm Res Paediatr. 2017;87(1):30–41. doi: 10.1159/000452887.
    1. Grimberg A, Stewart E, Wajnrajch MP. Gender of pediatric recombinant human growth hormone recipients in the United States and globally. J Clin Endocrinol Metab. 2008;93(6):2050–2056. doi: 10.1210/jc.2007-2617.
    1. Savendahl L, Polak M, Backeljauw P, Blair JC, Miller BS, Rohrer TR, et al. Long-term safety of growth hormone treatment in childhood: two large observational studies: NordiNet IOS and ANSWER. J Clin Endocrinol Metab. 2021;106(6):1728–1741. doi: 10.1210/clinem/dgab080.
    1. Laron Z. Growth hormone therapy: emerging dilemmas. Pediatric Endocrinol Rev. 2011;8(4):364–373.
    1. Collett-Solberg PF, Ambler G, Backeljauw PF, Bidlingmaier M, Biller BMK, Boguszewski MCS, et al. Diagnosis, genetics, and therapy of short stature in children: a growth hormone research society international perspective. Horm Res Paediatr. 2019;92(1):1–14. doi: 10.1159/000502231.
    1. Grimberg A, DiVall SA, Polychronakos C, Allen DB, Cohen LE, Quintos JB, et al. Guidelines for growth hormone and insulin-like growth factor-I treatment in children and adolescents: growth hormone deficiency, idiopathic short stature, and primary insulin-like growth factor-I deficiency. Horm Res Paediatr. 2016;86(6):361–397. doi: 10.1159/000452150.
    1. Stochholm K, Kiess W. Long-term safety of growth hormone-A combined registry analysis. Clin Endocrinol. 2018;88(4):515–528. doi: 10.1111/cen.13502.
    1. Child CJ, Zimmermann AG, Chrousos GP, Cummings E, Deal CL, Hasegawa T, et al. Safety outcomes during pediatric GH therapy: final results from the prospective GeNeSIS observational program. J Clin Endocrinol Metab. 2019;104(2):379–389. doi: 10.1210/jc.2018-01189.
    1. Allen DB, Backeljauw P, Bidlingmaier M, Biller BM, Boguszewski M, Burman P, et al. GH safety workshop position paper: a critical appraisal of recombinant human GH therapy in children and adults. Eur J Endocrinol. 2016;174(2):P1–9. doi: 10.1530/eje-15-0873.
    1. Souza FM, Collett-Solberg PF. Adverse effects of growth hormone replacement therapy in children. Arq Bras Endocrinol Metabol. 2011;55(8):559–565. doi: 10.1590/s0004-27302011000800009.
    1. Richmond E, Rogol AD. Treatment of growth hormone deficiency in children, adolescents and at the transitional age. Best Pract Res Clin Endocrinol Metab. 2016;30(6):749–755. doi: 10.1016/j.beem.2016.11.005.
    1. Abe S, Okumura A, Mukae T, Nakazawa T, Niijima S, Yamashiro Y, et al. Depressive tendency in children with growth hormone deficiency. J Paediatr Child Health. 2009;45(11):636–640. doi: 10.1111/j.1440-1754.2009.01586.x.
    1. Chaplin JE, Kriström B, Jonsson B, Hägglöf B, Tuvemo T, Aronson AS, et al. Improvements in behaviour and self-esteem following growth hormone treatment in short prepubertal children. Horm Res Paediatr. 2011;75(4):291–303. doi: 10.1159/000322937.
    1. Hodax JK, DiVall SA. Update on methods to enhance growth. Curr Opin Endocrinol Diabetes Obes. 2020;27(1):82–86. doi: 10.1097/med.0000000000000513.
    1. Kaplowitz P, Manjelievskaia J, Lopez-Gonzalez L, Morrow CD, Pitukcheewanont P, Smith A. Economic burden of growth hormone deficiency in a US pediatric population. J Manag Care Spec Pharm. 2021;27(8):1118–1128. doi: 10.18553/jmcp.2021.21030.
    1. Acerini CL, Segal D, Criseno S, Takasawa K, Nedjatian N, Rohrich S, et al. Shared decision-making in growth hormone therapy-implications for patient care. Front Endocrinol (Lausanne). 2018;9:688. doi: 10.3389/fendo.2018.00688.
    1. Yuen KCJ, Miller BS, Biller BMK. The current state of long-acting growth hormone preparations for growth hormone therapy. Curr Opin Endocrinol Diabetes Obes. 2018;25(4):267–273. doi: 10.1097/MED.0000000000000416.
    1. Aydın BK, Aycan Z, Sıklar Z, Berberoğlu M, Ocal G, Cetinkaya S, et al. Adherence to growth hormone therapy: results of a multicenter study. Endocr Pract. 2014;20(1):46–51. doi: 10.4158/ep13194.or.
    1. Desrosiers P, O'Brien F, Blethen S. Patient outcomes in the GHMonitor: the effect of delivery device on compliance and growth. Pediatric Endocrinol Rev. 2005;2(Suppl 3):327–331.
    1. Blanco-López A, Antillón-Ferreira C, Saavedra-Castillo E, Barrientos-Pérez M, Rivero-Escalante H, Flores-Caloca O, et al. Adherence to treatment in children with growth hormone deficiency, small for gestational age and Turner syndrome in Mexico: results of the Easypod™ connect observational study (ECOS) J Endocrinol Invest. 2020;43(10):1447–1452. doi: 10.1007/s40618-020-01218-4.
    1. Mohseni S, Heydari Z, Qorbani M, Radfar M. Adherence to growth hormone therapy in children and its potential barriers. J Pediatr Endocrinol Metabol. 2018;31(1):13–20. doi: 10.1515/jpem-2017-0157.
    1. Kapoor RR, Burke SA, Sparrow SE, Hughes IA, Dunger DB, Ong KK, et al. Monitoring of concordance in growth hormone therapy. Arch Dis Child. 2008;93(2):147–148. doi: 10.1136/adc.2006.114249.
    1. Rosenfeld RG, Bakker B. Compliance and persistence in pediatric and adult patients receiving growth hormone therapy. Endocr Pract. 2008;14(2):143–154. doi: 10.4158/ep.14.2.143.
    1. Wit JM, Deeb A, Bin-Abbas B, Al Mutair A, Koledova E, Savage MO. Achieving optimal short- and long-term responses to paediatric growth hormone therapy. J Clin Res Pediatr Endocrinol. 2019;11(4):329–340. doi: 10.4274/jcrpe.galenos.2019.2019.0088.
    1. Haverkamp F, Gasteyger C. A review of biopsychosocial strategies to prevent and overcome early-recognized poor adherence in growth hormone therapy of children. J Med Econ. 2011;14(4):448–457. doi: 10.3111/13696998.2011.590829.
    1. Fisher BG, Acerini CL. Understanding the growth hormone therapy adherence paradigm: a systematic review. Horm Res Paediatr. 2013;79(4):189–196. doi: 10.1159/000350251.
    1. Norgren S. Adherence remains a challenge for patients receiving growth hormone therapy. Pediatr Endocrinol Rev. 2009;6(Suppl 4):545–548.
    1. Lal RA, Hoffman AR. Perspectives on long-acting growth hormone therapy in children and adults. Arch Endocrinol Metabol. 2019;63(6):601–607. doi: 10.20945/2359-3997000000190.
    1. Haverkamp F, Johansson L, Dumas H, Langham S, Tauber M, Veimo D, et al. Observations of nonadherence to recombinant human growth hormone therapy in clinical practice. Clin Ther. 2008;30(2):307–316. doi: 10.1016/j.clinthera.2008.02.017.
    1. Gau M, Takasawa K. Initial patient choice of a growth hormone device improves child and adolescent adherence to and therapeutic effects of growth hormone replacement therapy. J Pediatr Endocrinol Metabol. 2017;30(9):989–993. doi: 10.1515/jpem-2017-0146.
    1. Reiter EO, Attie KM, Moshang T, Jr, Silverman BL, Kemp SF, Neuwirth RB, et al. A multicenter study of the efficacy and safety of sustained release GH in the treatment of naive pediatric patients with GH deficiency. J Clin Endocrinol Metab. 2001;86(10):4700–4706. doi: 10.1210/jcem.86.10.7932.
    1. Gonzalez Briceno LG, Viaud M, Beltrand J, Flechtner I, Dassa Y, Samara-Boustani D, et al. Improved general and height-specific quality of life in children with short stature after 1 year on growth hormone. J Clin Endocrinol Metab. 2019;104(6):2103–2111. doi: 10.1210/jc.2018-02523.
    1. Brod M, Højbjerre L, Alolga SL, Beck JF, Wilkinson L, Rasmussen MH. Understanding treatment burden for children treated for growth hormone deficiency. The Patient. 2017;10(5):653–666. doi: 10.1007/s40271-017-0237-9.
    1. Carcone AI, Ellis DA, Naar-King S. Linking caregiver strain to diabetes illness management and health outcomes in a sample of adolescents in chronically poor metabolic control. J Dev Behav Pediatr. 2012;33(4):343–351. doi: 10.1097/DBP.0b013e31824eaac8.
    1. Young MT, Lord JH, Patel NJ, Gruhn MA, Jaser SS. Good cop, bad cop: quality of parental involvement in type 1 diabetes management in youth. Curr Diab Rep. 2014;14(11):546. doi: 10.1007/s11892-014-0546-5.
    1. Wiebe DJ, Chow CM, Palmer DL, Butner J, Butler JM, Osborn P, et al. Developmental processes associated with longitudinal declines in parental responsibility and adherence to type 1 diabetes management across adolescence. J Pediatr Psychol. 2014;39(5):532–541. doi: 10.1093/jpepsy/jsu006.
    1. Brod M, Perwien A, Adler L, Spencer T, Johnston J. Conceptualization and assessment of quality of life for adults with attention-deficit/hyperactivity disorder. Prim Psychiatry. 2005;2:58–64.
    1. Patrick DL, Deyo RA. Generic and disease-specific measures in assessing health status and quality of life. Med Care. 1989;27(3 Suppl):217–232. doi: 10.1097/00005650-198903001-00018.
    1. US Food and Drug Administration. Patient-reported outcome measures: use in medical product development to support labeling claims: guidance for industry. 2009. . Accessed 20 Feb 2019.
    1. Savendahl L, Polak M, Backeljauw P, Blair J, Miller BS, Rohrer TR, et al. Treatment of children with GH in the United States and Europe: long-term follow-up from NordiNet(R) IOS and ANSWER program. J Clin Endocrinol Metab. 2019;104(10):4730–4742. doi: 10.1210/jc.2019-00775.
    1. Matza LS, Patrick DL, Riley AW, Alexander JJ, Rajmil L, Pleil AM, Bullinger M. Pediatric patient-reported outcome instruments for research to support medical product labeling: report of the ISPOR PRO good research practices for the assessment of children and adolescents task force. Value Health. 2013;16(4):461–479. doi: 10.1016/j.jval.2013.04.004.
    1. European Medicines Agency. Reflection paper on the regulatory guidance for the use of health-related quality of life (HRQL) measures in the evaluation of medicinal products. 2005. . Accessed 20 Feb 2019.
    1. International Society for Pharmacoepidemiology Guidelines for good pharmacoepidemiology practices (GPP) Pharmacoepidemiol Drug Saf. 2008;17(2):200–208. doi: 10.1002/pds.1471.
    1. U.S. Office of the Federal Register. Electronic Code of Federal Regulations. Titles 21§50 Protection of human subjects and §56 Institutional review boards. Office of the Federal Register, Washington, D.C. 2018. . Accessed 10 May 2019.
    1. Brod M, Højby Rasmussen M, Vad K, Alolga S, Bushnell DM, Bedoin J, et al. Psychometric validation of the growth hormone deficiency-child impact measure (GHD-CIM) PharmacoEconomics Open. 2021;5(3):505–518. doi: 10.1007/s41669-020-00252-5.
    1. Bentler PM, Chou CP. Practical issues in structural modeling. Sociol Methods Res. 1987;16:78. doi: 10.1177/0049124187016001004.
    1. Linacre JM. Sample size and item calibration stability. Rasch Measurement Trans. 1994;7:4.
    1. Bullinger M, Quitmann J, Power M, Herdman M, Mimoun E, DeBusk K, et al. Assessing the quality of life of health-referred children and adolescents with short stature: development and psychometric testing of the QoLISSY instrument. Health Qual Life Outcomes. 2013;11:76. doi: 10.1186/1477-7525-11-76.
    1. Bullinger M, Schmidt S, Petersen C, Disabkids Group. Assessing quality of life of children with chronic health conditions and disabilities: a European approach. Int J Rehabil Res. 2002;25(3):197–206. 10.1097/00004356-200209000-00005.
    1. Whiteside SP. Adapting the Sheehan disability scale to assess child and parent impairment related to childhood anxiety disorders. J Clin Child Adolesc Psychol. 2009;38(5):721–730. doi: 10.1080/15374410903103551.
    1. Snoek FJ, Mollema ED, Heine RJ, Bouter LM, van der Ploeg HM. Development and validation of the diabetes fear of injecting and self-testing questionnaire (D-FISQ): first findings. Diabet Med. 1997;14(10):871–876. doi: 10.1002/(SICI)1096-9136(199710)14:10<871::AID-DIA457>;2-Y.
    1. SPSS Inc. PASW statistics for windows. 18.0 ed. Chicago: SPSS Inc.; 2009.
    1. Carmines EC, Zeller RA. Reliability and validity assessment. Beverly Hills: Sage Publications; 1979.
    1. Gliem JA, Gliem RR. Calculating, interpreting, and reporting Cronbach’s alpha reliability coefficient for Likert-type scales. In: 2003 midwest research to practice conference in adult, continuing, and community education; 2003. p. 82–8.
    1. Byrne BM. Structural equation modeling with AMOS: basic concepts, applications, and programming. New York: Routledge; 2010.
    1. Arbuckle JL. AMOS 20.0 user’s guide. Armonk, N.Y.: IBM Corporation; 2011.
    1. Cronbach LJ. Coefficient alpha and the internal structure of tests. Psychometrika. 1951;16(2):297–334. doi: 10.1007/BF02310555.
    1. Hays RD, Revicki DA. Reliability and validity (including responsiveness) In: Fayers PM, Hays RD, editors. Assessing quality of life in clinical trials. New York: Oxford; 2005. pp. 25–39.
    1. Mokkink LB, Prinsen CAC, Patrick DL, Alonso J, Bouter LM, de Vet HCW et al. COSMIN methodology for systematic reviews of Patient-reported Outcome Measures (PROMs): user manual. 2018.
    1. Guyatt GH, Osoba D, Wu AW, Wyrwich KW, Norman GR, Clinical Significance Consensus Meeting G. Methods to explain the clinical significance of health status measures. Mayo Clin Proc. 2002;77(4):371–83. 10.4065/77.4.371.
    1. Wyrwich KW, Nienaber NA, Tierney WM, Wolinsky FD. Linking clinical relevance and statistical significance in evaluating intra-individual changes in health-related quality of life. Med Care. 1999;37(5):469–478. doi: 10.1097/00005650-199905000-00006.
    1. Kline RB. Principles and practice of structural equation modeling. 3. New York: Guilford Publications; 2010.
    1. Hu L, Bentler PM. Cutoff criteria for fit indexes in covariance structure analysis: conventional criteria versus new alternatives. Struct Equ Model. 1999;6:1–55. doi: 10.1080/10705519909540118.
    1. Cohen J. Statistical power analysis for the behavioral sciences. Hillsdale: L. Erlbaum Associates; 1988.

Source: PubMed

Sponsoren und Mitarbeiter

Krankheiten

Drogeninterventionen

3
Abonnieren