Reproducibility of cognitive endpoints in clinical trials: lessons from neurofibromatosis type 1

被引：32

作者：

Payne, Jonathan M. ^{[1
,2
]}

Hearps, Stephen J. C. ^{[1
]}

Walsh, Karin S. ^{[3
]}

Paltin, Iris ^{[4
]}

Barton, Belinda ^{[5
,6
,7
]}

Ullrich, Nicole J. ^{[8
]}

Haebich, Kristina M. ^{[1
]}

Coghill, David ^{[1
,2
]}

Gioia, Gerard A. ^{[3
]}

Cantor, Alan ^{[9
]}

Cutter, Gary ^{[10
]}

Tonsgard, James H. ^{[11
]}

Viskochil, David ^{[12
]}

Rey-Casserly, Celiane ^{[13
]}

Schorry, Elizabeth K. ^{[14
]}

Ackerson, Joseph D. ^{[15
]}

Klesse, Laura ^{[16
]}

Fisher, Michael J. ^{[4
]}

Gutmann, David H. ^{[17
]}

Rosser, Tena ^{[18
]}

Packer, Roger J. ^{[3
]}

Korf, Bruce ^{[19
]}

Acosta, Maria T. ^{[3
,20
]}

North, Kathryn N. ^{[1
,2
]}

机构：

[1] Royal Childrens Hosp, Murdoch Childrens Res Inst, Flemington Rd, Parkville, Vic 3052, Australia

[2] Univ Melbourne, Fac Med Dent & Hlth Sci, Dept Paediat, Melbourne, Vic, Australia

[3] Childrens Natl Hlth Syst, Ctr Neurosci & Behav Med, Washington, DC USA

[4] Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA 19104 USA

[5] Childrens Hosp Westmead, Kids Neurosci Ctr, Westmead, NSW, Australia

[6] Childrens Hosp Westmead, Childrens Hosp Educ Res Inst, Westmead, NSW, Australia

[7] Univ Sydney, Univ Sydney Childrens Hosp, Westmead Clin Sch, Westmead, NSW, Australia

[8] Boston Childrens Hosp, Dept Neurol, Boston, MA USA

[9] Univ Alabama Birmingham, Dept Preventat Med, Birmingham, AL USA

[10] Univ Alabama Birmingham, Sch Publ Hlth, Birmingham, AL 35294 USA

[11] Univ Chicago Med, Div Neurol, Comer Childrens Hosp, Chicago, IL USA

[12] Univ Utah, Dept Genet, Salt Lake City, UT USA

[13] Boston Childrens Hosp, Ctr Neuropsychol, Boston, MA USA

[14] Cincinnati Childrens Hosp Med Ctr, Human Genet, Cincinnati, OH 45229 USA

[15] Univ Alabama Birmingham, Dept Psychol, Birmingham, AL 35294 USA

[16] Univ Texas Southwestern Med Ctr Dallas, Dept Pediat, Dallas, TX USA

[17] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA

[18] Childrens Hosp Los Angeles, Dept Neurol, Los Angeles, CA 90027 USA

[19] Univ Alabama Birmingham, Dept Genet, Birmingham, AL USA

[20] NHGRI, NIH, Bethesda, MD 20892 USA

来源：

ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY | 2019年 / 6卷 / 12期

关键词：

CHILDREN; DEFICITS; ATTENTION; SIMVASTATIN; DYSFUNCTION; OUTCOMES; ADHD;

D O I：

10.1002/acn3.50952

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

Objective: Rapid developments in understanding the molecular mechanisms underlying cognitive deficits in neurodevelopmental disorders have increased expectations for targeted, mechanism-based treatments. However, translation from preclinical models to human clinical trials has proven challenging. Poor reproducibility of cognitive endpoints may provide one explanation for this finding. We examined the suitability of cognitive outcomes for clinical trials in children with neurofibromatosis type 1 (NF1) by examining test-retest reliability of the measures and the application of data reduction techniques to improve reproducibility. Methods: Data were analyzed from the STARS clinical trial (n = 146), a multi-center double-blind placebo-controlled phase II trial of lovastatin, conducted by the NF Clinical Trials Consortium. Intra-class correlation coefficients were generated between pre- and post-performances (16-week interval) on neuropsychological endpoints in the placebo group to determine test-retest reliabilities. Confirmatory factor analysis was used to reduce data into cognitive domains and account for measurement error. Results: Test-retest reliabilities were highly variable, with most endpoints demonstrating unacceptably low reproducibility. Data reduction confirmed four distinct neuropsychological domains: executive functioning/attention, visuospatial ability, memory, and behavior. Test-retest reliabilities of latent factors improved to acceptable levels for clinical trials. Applicability and utility of our model was demonstrated by homogeneous effect sizes in the reanalyzed efficacy data. Interpretation: These data demonstrate that single observed endpoints are not appropriate to determine efficacy, partly accounting for the poor test-retest reliability of cognitive outcomes in clinical trials in neurodevelopmental disorders. Recommendations to improve reproducibility are outlined to guide future trial design.

引用

页码：2555 / 2565

页数：11

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