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Children with FXS exhibit a variety of challenging behaviors such as irritability, anxiety, and preference for solitary activities. The Aberrant Behavior Checklist-Community (ABC-C) is an observer-reported outcome (ObsRO) measure that captures many of the behavioral concerns (e.g., outbursts, social anxiety, difficulty connecting with others) salient to caregivers of individuals with FXS. An FXS-specific scoring algorithm of the ABC-C, considered more representative of the FXS phenotype (ABC-C\n                      <jats:sub>FXS<\/jats:sub>\n                      ), has been included in numerous clinical studies of treatments for FXS. The goal of this qualitative research was to establish the content validity of the ABC-C\n                      <jats:sub>FXS<\/jats:sub>\n                      domain structure in parents\/caregivers of children with FXS and determine whether it is fit-for-purpose for measuring treatment benefit in clinical studies of FXS.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      The qualitative data came from 3 sources: (1) Concept elicitation (CE) interviews with caregivers of children with FXS (\n                      <jats:italic>N<\/jats:italic>\n                      \u2009=\u200910); (2) Caregiver survey (CS) (\n                      <jats:italic>N<\/jats:italic>\n                      \u2009=\u2009212) completed at entry to CONNECT-FX (NCT03614663); and (3) Cognitive interviews of the ABC-C\n                      <jats:sub>FXS<\/jats:sub>\n                      with caregivers of children with FXS (\n                      <jats:italic>N<\/jats:italic>\n                      \u2009=\u200925). Qualitative coding and analysis were consistent with best practices and followed principles in applied thematic (content) analysis. Item comprehension and relevancy of the ABC-C\n                      <jats:sub>FXS<\/jats:sub>\n                      were also examined based on data from cognitive interviews.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The mean age of individuals with FXS was 10 (range 3\u201317) years and was consistent across the 3 data sources. The most frequently reported behavioral challenges described by caregivers were generally consistent across the CE interviews and the CS. Socially avoidant behaviors were most prevalent (70% and 49%, respectively) followed by socially unresponsive\/lack of interaction (60% and 51%, respectively) and aggression (60% and 43%, respectively). Saturation of behavioral challenges related to FXS was reached in both the CE interviews and CS and was consistent with the content of the ABC-C\n                      <jats:sub>FXS<\/jats:sub>\n                      . Cognitive interviews showed that caregivers could understand and interpret the content and response options of the ABC-C\n                      <jats:sub>FXS<\/jats:sub>\n                      and deemed its content relevant to their experience.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      The content validity evidence from this qualitative research supports the use of ABC-C\n                      <jats:sub>FXS<\/jats:sub>\n                      as an efficacy measure in FXS clinical research studies.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Clinical trial registration<\/jats:title>\n                    <jats:p>Not applicable.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s41687-026-01054-9","type":"journal-article","created":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T14:46:28Z","timestamp":1775054788000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Caregiver-perceived behavioral challenges in fragile X syndrome and implications for measuring treatment benefit in clinical trials"],"prefix":"10.1186","volume":"10","author":[{"given":"Elizabeth","family":"Merikle","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nancy","family":"Tich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Terri","family":"Sebree","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Randi","family":"Hagerman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"O\u2019Quinn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George","family":"Nomikos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristen","family":"Bzdek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,1]]},"reference":[{"issue":"4","key":"1054_CR1","doi-asserted-by":"publisher","first-page":"503","DOI":"10.1016\/j.ajhg.2009.09.007","volume":"85","author":"B Coffee","year":"2009","unstructured":"Coffee B, Keith K, Albizua I, Malone T, Mowrey J, Sherman SL et al (2009) Incidence of fragile X syndrome by newborn screening for methylated FMR1 DNA. 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Institutional Review Board (IRB; Approval Number: Pro00037386). Concept Elicitation Interviews: Caregivers provided written informed consent for the interviews to be recorded for data collection purposes. Caregiver Survey: The protocol for the study (CONNECT-FX) was approved by the individual institution Investigational Review Boards (IRBs) and Ethics Committees or by the central IRB, WCG IRB. Cognitive Interviews: The protocol for the cognitive interview study was approved by the central IRB, Advarra.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"All authors have reviewed the manuscript and approved it for publication.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"EM was an employee of Fortrea, Inc. at the time of the study, which received funding from Harmony Biosciences for this research. EM, NT, KB and GN are employees of Harmony Biosciences. RH has received funding from Zynerba Pharmaceuticals\/Harmony Biosciences and Tetra\/Shionogi Pharma to carry out clinical trials in Fragile X syndrome. TS and SOQ are paid consultants for Harmony Biosciences.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"77"}}