FORWARD: A Registry and Longitudinal Clinical Database to Study Fragile X Syndrome Stephanie L. Sherman, PhD,a Sharon A. Kidd, PhD, MPH,b Catharine Riley, PhD, MPH,c Elizabeth Berry-Kravis, PhD,d, e, f Howard F. Andrews, PhD,g Robert M. Miller, BA, b Sharyn Lincoln, MS, CGC,h Mark Swanson, MD, MPH,c Walter E. Kaufmann, MD,i, j W. Ted Brown, MD, PhDk

BACKGROUND AND OBJECTIVE: Advances in the care of patients with fragile X syndrome (FXS) abstract have been hampered by lack of data. This deficiency has produced fragmentary knowledge regarding the natural history of this condition, healthcare needs, and the effects of the disease on caregivers. To remedy this deficiency, the Fragile X Clinic and Research Consortium was established to facilitate research. Through a collective effort, the Fragile X Clinic and Research Consortium developed the Fragile X Online Registry With Accessible Research Database (FORWARD) to facilitate multisite data collection. This report describes FORWARD and the way it can be used to improve health and quality of life of FXS patients and their relatives and caregivers. METHODS: FORWARD collects demographic information on individuals with FXS and their family members (affected and unaffected) through a 1-time registry form. The longitudinal database collects clinician- and parent-reported data on individuals diagnosed with FXS, focused on those who are 0 to 24 years of age, although individuals of any age can participate. RESULTS: The registry includes >2300 registrants (data collected September 7, 2009 to August 31, 2014). The longitudinal database includes data on 713 individuals diagnosed with FXS (data collected September 7, 2012 to August 31, 2014). Longitudinal data continue to be collected on enrolled patients along with baseline data on new patients. CONCLUSIONS: FORWARD represents the largest resource of clinical and demographic data for the FXS population in the United States. These data can be used to advance our understanding of FXS: the impact of cooccurring conditions, the impact on the day-to- day lives of individuals living with FXS and their families, and short-term and long-term outcomes.

a Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia; bNational Fragile X Foundation, Washington, District of Columbia; cNational Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, Georgia; Departments of dPediatrics, eNeurological Sciences, and fBiochemistry, Rush University Medical Center, Chicago, Illinois; gDepartment of Biostatistics, Mailman School of Public Health, Columbia University, New York, New York; hDivision of Genetics and Genomics, Boston Children’s Hospital, Boston, Massachusetts; iDepartment of Neurology, Boston Children’s Hospital, Boston Massachusetts; jCenter for Translational Research, Greenwood Genetic Center, Greenwood, South Carolina; and kDepartment of Human Genetics, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York

Dr Sherman drafted the original manuscript; Drs Riley and Kidd revised and edited the manuscript for review by all other authors; Dr Andrews conducted analyses for the data presented; Drs Andrews, Brown, Berry-Kravis, Kaufmann, Kidd, and Sherman have been involved in all aspects of design, implementation, and evaluation; Dr Riley has been involved in the implementation and evaluation of FORWARD; Dr Swanson, Mr Miller, and Ms Lincoln were involved in the initial design and implementation; and all authors read, edited, and approved the fi nal version for submission. The fi ndings and conclusions in this report are those of the authors and do not necessarily represent the offi cial position of the Centers for Disease Control and Prevention. DOI: https://doi. org/ 10. 1542/ peds. 2016- 1159E

Downloaded from www.aappublications.org/news by guest on September 27, 2021 PEDIATRICS Volume 139 , Number s3 , June 2017:e 20161159 SUPPLEMENT ARTICLE In 1943, Martin and Bell 1 described to grow. This research shows that understanding of the needs of 11 males with severe intellectual although a classic FXS “phenotype” individuals and families with FXS, disability (ID) in a 2-generation exists, there is considerable and there is only a small literature family. Nearly 50 years later, symptomatic variability. Males on evidence-based practices for researchers discovered the molecular with the full mutation typically treating individuals with FXS. 34, 35 basis of what is now known as experience mild to moderate ID, This limitation could have negative fragile X syndrome (FXS).2, 3 FXS is but others may have more severe consequences for individuals who nearly always due to an expanded disabilities. Although not common, could benefit from intervention CGG repeat sequence (>200 several studies have reported “high- services as early as possible.36 To hypermethylated CGG repeats, full functioning” males with intellectual conduct well-designed clinical mutation) in the 5′ untranslated ability in the normal to borderline trials that capture the entire region of the FMR1 gene located at range.19 – 22 One-third to one-half of spectrum of the disorder, the Xq27.3. FXS is the most common females with the full mutation has natural history of FXS needs to known inherited form of ID4 and has intellectual function in the normal be determined. To address the been reported as the most common range, due to the masking effect of limitations in knowledge, 2 known inherited single-gene disorder the normal X-chromosome FMR1 important resources are needed: associated with autism spectrum allele.23, 24 Numerous associated (1) a sample of individuals with disorder (ASD), accounting for ∼2% conditions and symptoms of variable FXS and their relatives, and (2) a to 3% of all cases of ASD.5, 6 Studies severity can occur, including ASD, collection of longitudinal clinical estimate the prevalence of FXS to attention deficits, hyperactivity/ data from individuals with FXS be ∼1 in 4000 to 1 in 7000 in males impulsivity, hyperarousal, anxiety, to facilitate answers to clinical and ∼1 in 6000 to 1 in 11 000 in self-injurious behavior, sleep care and public health research females.7 –10 disturbance, seizures, and medical questions. problems, such as frequent otitis Premutation carriers (those media, strabismus, and joint The Fragile X Clinical and with 55–200 unmethylated CGG hyperflexibility. However, these Research Consortium (FXCRC) is repeats) typically do not show conditions are not universally a collaborative infrastructure of symptoms of FXS, but are at risk experienced, and their actual clinics that specializes in the care of for transmitting an expanded full prevalence and impact are still individuals and families affected by mutation to their offspring.11, 12 unknown. FXS. Initially conceived by fragile X Approximately 1 in 500 to 1 in clinicians in 2006, with the support 800 males and 1 in 200 to 1 in Small sample sizes and referral of the National Fragile X Foundation 300 females are premutation bias of most studies make the (NFXF), the FXCRC has grown carriers.9, 10,13 – 16 In addition, true prevalence of associated to include 27 fragile X specialty premutation carriers are at high conditions difficult to determine. clinics across the United States risk for fragile X–associated tremor/ For example, the prevalence of ASD (see Acknowledgments for a list of ataxia syndrome, a late-onset among individuals with FXS varies FXCRC clinics). In 2008, the Centers neurodegenerative disorder,17 and, among studies between 15% and for Disease Control and Prevention among women, fragile X–associated 60%.25 –29 Also, studies of cooccurring (CDC) funded the creation of a primary ovarian insufficiency.18 conditions have typically focused on Fragile X Registry and a pilot study Together, these 3 disorders, FXS, single conditions, without examining to test multisite clinical research in fragile X–associated tremor/ataxia associations with other features of FXS. The pilot study (phase I) syndrome, and fragile X–associated FXS. Findings from a survey of >1300 showed that using a consortium primary ovarian insufficiency, are FXS parents (convenience sample) of clinics was an effective way referred to as fragile X–associated indicate that parents report a higher to engage multiple clinics and disorders (FXD). There are reports of frequency of conditions, such as facilitate research.29 In 2011, the other clinical manifestations among seizures, ASD, and anxiety, among CDC funded a second pilot study premutation carriers that may lead individuals with FXS compared with (phase II) to support the collection to expansion of this definition of FXD; general population. 30 – 33 Additional and management of longitudinal however, this remains an area of examination of cooccurring data, incorporating the existing active research. conditions and how they relate to Fragile X Registry. The result was the other FXS features using clinical data Focusing on FXS, research to development and implementation are needed. understand the range of phenotypic of the Fragile X Online Registry expression of the full mutation and In addition to the limitations noted With Accessible Research Database how families adapt to FXS continues above, there is an inadequate (FORWARD).

Downloaded from www.aappublications.org/news by guest on September 27, 2021 S184 SHERMAN et al FIGURE 1 Fragile X specialty clinics participating in FXCRC and contributing data to FORWARD.

METHODS There are 2 main components to the FORWARD project staff, and CDC FORWARD: (1) the registry, which collaborators, taking into account Study Design of FORWARD collects primarily demographic the variables used in national parent FORWARD is a multisite, information from families with surveys, including Our Fragile X observational study that includes FXD, including both affected World (www.ourfragilexworld. data from individuals with FXS and and unaffected family members org) and the Autism Treatment their family members, collected (full mutation, premutation, and Network (www. autismspeaks.org/ thus far by 25 of the 27 established noncarriers); and (2) the longitudinal science/ resources- programs/ autism- fragile X clinics affiliated with database, which collects data from treatment-network/ what- atn). Data the FXCRC (Fig 1). Each clinic individuals with full mutation (FXS), in the longitudinal database are must obtain institutional review currently focusing on those aged 0 to collected by clinicians, primarily board (IRB) approval from their 24 years (although individuals of all during a patient’s scheduled clinic own institutions before enrolling ages may participate). Because this is visit, and by parents/caregivers. A families in FORWARD. The goals of a multisite study, standardization of participant is considered to have a FORWARD are to: (1) enhance the understanding of FXS, its cooccurring clinical data collection is important. complete set of baseline data if both conditions, and associated risk The evaluation of phase I (2008 to a clinician report form and a parent factors; (2) identify service barriers, 2011) data collection forms led to report form have been completed service needs, and services used the development of phase II (2011 and submitted. Parameters of the among people diagnosed with FXS to 2015) data collection forms. To registry and database forms are and the impact of these services on facilitate data sharing across ASD outlined in Table 1. Additionally, health outcomes; and (3) document and FXS data sets when possible, there are 3 standardized parent- medical and behavioral treatments the forms for the longitudinal report instruments requested at used by FXS patients and their effects database were developed and baseline: the Social Responsiveness on outcomes. revised by members of the FXCRC, Scale, Second Edition (SRS-2), 37 the

Downloaded from www.aappublications.org/news by guest on September 27, 2021 PEDIATRICS Volume 139 , number s3 , June 2017 S185 TABLE 1 Overview of the FORWARD Study Design of cognitive function based on Eligibility Registry Longitudinal Study their interactions with the patient Age All ages 0–24 y for compensated enrollment; and available medical/education however, all ages can be enrolled records. As in phase I, data on the Sex Males and females Males and females measure of the full-scale IQ and Race/ethnicity All race/ethnic groups All race/ethnic groups related details (test score, age at FMR1 mutation status Noncarriers, premutation, and full Full mutation carriers, including mutation carriers mosaics testing, etc) and the composite and Data collection source 2-page registry form Clinician report form subscale scores from the Vineland Self or guardian report form Parent report form Adaptive Behavior Scales–II 40 are Standardized self- and parent-report still requested, if available. Second, behavioral assessments (ABC-C, SRS-2, SCQ) we ask the parents to complete 3 Data domains Demographics Clinician report form standardized behavioral assessments FMR1 mutation/diagnostic status Physical exam (eg, height, weight, about their child, as described above. and head circumference) These combined efforts provide Primary spoken language Medical history (eg, seizures, vision problems, musculoskeletal a more robust description of the problems, chronic medical level of impairment observed in this problems) population. Availability of participant for Language, speech, and research projects communication Cognition As noted in Table 2, the longitudinal Behavior component of the FORWARD Psychopharmacology for behaviors database is now coming into fruition.

Hyperarousal or sensory issues Data collection for FORWARD is FMR1 mutation laboratory diagnostics conducted in conjunction with a Parent report form clinic visit, and although most fragile Developmental milestones X specialty clinics recommend

Sleep characteristics patients be seen on at least an Education and transition history and intervention annual basis, this may not Family support always occur. To help encourage Social participation and residential continued participation, newsletters settings describing the status of the project Heath monitoring practices Socioeconomic status are provided to clinics to distribute to Data collection Once Clinician and parent report forms: participants. frequency annually ABC-C: annually Leadership of the FXCRC is provided SRS-2 and SCQ: once through the executive council, an elected body comprised of parents Social Communication Questionnaire and behavioral impairments of children with FXS, patient 38 (SCQ), and the Aberrant Behavior influence almost all other domains advocates, clinicians, and clinical – 39 Checklist Community (ABC-C). in the life of an individual with FXS researchers. A separate steering The SRS-2 and SCQ only need to be and their family. In the first pilot committee was formed to oversee entered once, whereas it is requested study (phase 1), data on this domain the implementation of FORWARD, that the ABC-C be completed annually were often missing, because the as well as 3 other committees: (1) along with the clinician and parent source of the data was not from the membership and infrastructure report forms. the clinic. That is, results from committee, (2) the clinical practices As previously mentioned, the current standardized tests were usually committee, and (3) the research data collection tools are built on part of school records or assessments committee. A national coordinator lessons learned from the initial pilot done at other types of clinical (NC) facilitates communication study. One crucial domain to be centers. By using the lessons learned between these committees, provides captured in FORWARD is the level of in phase I, additional approaches support to the clinics to enhance cognitive and behavioral functioning were used in phase II. First, the ongoing participation in the project, of patients with FXS. These data are clinician is asked in the clinician helps to manage data collection essential to evaluate the primary and report form to provide a clinical and monitor data quality, and secondary features of FXS. Cognitive impression of the patient’s level facilitates analysis. Figure 2 provides

Downloaded from www.aappublications.org/news by guest on September 27, 2021 S186 SHERMAN et al an overview of the administrative TABLE 2 Demographics of Participants Enrolled in the FORWARD Registry Between September 7, 2009 structure. and August 31, 2014 With Known FMR1 Mutation Status (N = 1961) Noncarrier Premutation Carrier Full Mutation Carrier Clinic-based Recruitment Participants, n 65 541 1355 Sex: % male 46.2 8.1 75.6 Recruitment for this study is Median age, y (range) 33 (1–80) 40 (1–84) 10 (0–69) clinic based, and, therefore, only Ethnicity individuals choosing to attend Hispanic/Latino, % 10.8 7.2 9.7 Race specialty clinics are approached White, % 86.2 94.3 87.9 to participate in FORWARD. African American, % 7.7 2.8 7.2 Additionally, sometimes it is not Asian, % 1.5 1.1 2.1 possible to approach all clinic Other, % 4.6 1.8 2.9 patients due to the circumstances of the visit, and, of those who FORWARD, it may enroll a larger data collection and entry, the fragile X are approached, not everyone proportion of the eligible clinic specialty clinics are compensated for participates. To understand some of participants. Demographic data from their efforts. They are compensated the differences in the characteristics the registry, used in combination for obtaining initial IRB approval of individuals who participate in with the nonenrollment log, will help and subsequently for data collection. the database and those who do not determine whether patients in the The latter is based on the number participate, clinics have been asked database are representative of all to implement, with IRB approval, and type of forms submitted to individuals with FXS attending fragile FORWARD for each study participant. nonenrollment logs to gather a X clinics. minimal set of data. Because the To reduce the burden on clinics, the Data Coordinating Center (DCC) registry entails only a simple Clinic Compensation 2-page form completed by a family can enter data for clinics from the member compared with the more To enhance the participation of deidentified clinical forms. These intensive database component of clinics in FORWARD and to support combined efforts have contributed

FIGURE 2 Administrative structure of the FXCRC and the FORWARD longitudinal study.

Downloaded from www.aappublications.org/news by guest on September 27, 2021 PEDIATRICS Volume 139 , number s3 , June 2017 S187 to enhance the clinics’ capacity to forms of each type submitted Because this is a multisite study, participate in this longitudinal study. by each clinic, and provide participants may be seen at >1 clinic compensation to clinics for their over the course of the study time line. Data Management data collection. To facilitate Because the clinics assign unique The registry and longitudinal longitudinal data collection, the identifiers and the DCC does not database were developed under DCC provides regular reports to have access to participant identifiers, secure data transmission and the clinics to identify participants it is difficult to identify data that centralized housing of all data. who are due for an annual ought to be linked but are not. The The DCC at Columbia University is follow-up examination. The steering registry form inquires whether the responsible for the development committee is responsible for the individual has been seen at any and maintenance of the system and oversight of all requests for data other fragile X specialty clinic. If a thoroughly tests each component of analyses and access to FORWARD clinician thinks the participant has the online data entry system before participants for recruitment into contributed data from >1 site based making it available to the users. other studies. on their responses, they contact the User-specific identification and NC. The NC facilitates communication Quality Assurance and Quality passwords are managed centrally between the clinics to confirm the Control by the DCC. Programmed checks linkage. If confirmed, a new (eg, out-of-range checks for The NC conducts site visits, hosts umbrella unique identifier is variables) are incorporated to webinars, and communicates assigned to the participant, linking ensure high data quality. For with participating clinics to help his or her data. Completion of longitudinal data collection, data clinics with IRB submissions, these comprehensive quality checks ensure that individual implementation of research control measures has resulted in patterns of change over time protocols, and identification of the development of FORWARD’s represent reasonable trajectories. methods to improve data collection first fixed data set (FORWARD If anomalies are detected, queries and entry. These efforts are data set version 1.0), representing are generated and sent to the source complemented by a yearly FXCRC baseline data collected for the clinic for verification or possible meeting that brings the clinics longitudinal database from correction. together to discuss successes September 7, 2012 to August 31, and challenges with regard to 2014 and linked data from the The identity of FORWARD participating in FORWARD and registry form for participants in the participants in the online system FXCRC, share ideas for ways to longitudinal database. is known only to clinic staff. The improve, collaboratively think about individual clinics are the gatekeepers appropriate uses for these data, and of their participants’ contact brainstorm about ways to build on RESULTS information and keep the link these efforts. between the participant’s unique All individuals diagnosed with FXS identifier in the online system and In addition to the ongoing quality who attend a fragile X specialty the name and contact information control measures implemented clinic and all family members of the individual patient or family by the DCC and the NC, several (including premutation carriers member. An additional level of strategies have been conducted and those with no FMR1 mutations) security has been created by to improve data quality: a data are eligible to participate in FXCRC policy, the role-based access review workgroup conducted the FORWARD registry. From control. Each site-based coordinator an in-depth assessment of data September 7, 2009 to August 31, can enter, edit, and view data quality, evaluating each variable 2014, 2376 individuals registered, on patients and family members for outliers and potential errors, the majority of whom reported registered from his/her site, but and documenting any identified their FMR1 mutational status (n = cannot see data entered by other limitations; a process evaluation 1961), and the remaining 17% did sites. In phase II of the project, was conducted to assess recruitment not know, had unrelated testing, only the DCC has access to and data collection processes. or chose not to respond. Table 2 deidentified individual-level data This process helped inform the provides the demographic data of for purposes of quality control and consistency of data collection and, those with known mutational analyses. together with the data review status. As expected for this FXS The DCC and the NC monitor results, is being used to improve clinic–based ascertainment, the progress, create monthly reports the data collection process moving majority (69%) of tested individuals enumerating the number of forward. carry the full mutation and most

Downloaded from www.aappublications.org/news by guest on September 27, 2021 S188 SHERMAN et al are male (76%) (Table 2). The TABLE 3 Summary of the FORWARD Longitudinal Database Forms Completed for Participants majority of premutation carriers Diagnosed With FXS Between September 7, 2012 and August 31, 2014 are female (92%), and they are Form Completed Baseline Assessment Follow-up Assessment primarily the mothers of individuals Clinician report form 713 178 diagnosed with FXS. Race and Parent report form 549 127 ethnicity are reported by the ABC-C 557 131 respondent (ie, self-report or SCQ 534 N/A SRS-2 457 N/A parent/caregiver report). Overall, Both clinician and parent report forms, n 503 114 9% of registrants reported their N/A, not applicable. ethnicity as Hispanic and ∼10% reported their racial group as <7 years of age, clinicians reported care of individuals and families nonwhite (Table 2). whether there was evidence of diagnosed with FXD. FORWARD developmental delay. Among is the only such structure of this The participants enrolled in the these younger individuals, all kind in the United States, FORWARD longitudinal database male participants and 70.1% of collecting longitudinal data are a subset of those in the female participants with the full based on both clinician and parent FORWARD registry, because only mutation were reported to have report. The results from FORWARD those who have been diagnosed evident developmental delays, with will provide a forum to better with the full mutation and who frequency differences by sex being understand the natural history attend a fragile X clinic are eligible statistically significant (Pearson χ2; of FXS, identify important gaps in for this component. Table 3 shows P < .0001). Among the patients ≥7 our knowledge about the needs the number of completed forms in years of age, we present a finer of FXS patients and their families, the FORWARD database collected scale of the impression of the level and guide clinical care. The data from September 7, 2009 to August of impairment. Among male collected through FORWARD 31, 2014. As expected for this patients, ∼60% fall into the will provide essential information X-linked disorder, 78% of the moderate ID range, whereas the to assist health care professionals in participants are male (Table 4). majority of female patients fall into their goal of providing excellent care As observed in the FORWARD the borderline to mild ID range with the long-term objective of improving health outcomes. registry, the vast majority of (64%). The differences observed The FORWARD registry also participants in the FORWARD among male and female patients provides centralized data that can database are non-Hispanic (90%) in the level of impairment are be used to facilitate recruitment and white (88%), as reported statistically significant (Pearson χ2; by the parent or caregiver. The P < .0001). current data collection focuses To provide an indicator of the TABLE 4 Demographics of Participants Diag- on individuals with FXS ages 0 presence of behavioral problems, we nosed With FXS Enrolled Between to 24 years, and, as such, ∼94% present one of many parameters in September 7, 2012 and August 31, of participants are ≤24 years of the FORWARD longitudinal database: 2014 in the FORWARD Longitudinal Database age. The age group frequencies of the percent of participants ≥3 years participants attending the clinic of age who have a current diagnosis Male Female at baseline did not differ by sex of ASD, as reported by the clinician. Participants, N 558 155 (21.7%) (Pearson χ2; P > .10), with the The status of ASD was reported for (78.3%) 93% of participants. Half of the male Ethnicity majority being <15 years of age Hispanic/Latino, % 9.0 12.3 (74%) (Table 4). participants (50%) and 17% of the Race female participants have a current White, % 88.7 87.1 diagnosis of ASD ( Table 5) (Pearson African American, 7.2 8.4 There is a wide range of ID and χ2; P < .0001). % of behavioral problems among Asian, % 2.0 2.6 individuals diagnosed with FXS, Other, % 2.2 1.9 and this is reflected by the patients DISCUSSION Age group, y 0–4, % 18.3 16.8 enrolled in FORWARD. Table 5–9, % 28.5 31.0 5 provides an overview of the The FXCRC was initiated by 10–14, % 26.2 28.4 cognitive function of participants clinicians and researchers to 15–19, % 13.1 13.5 using the clinician’s global form a research structure that 20–24, % 7.2 5.9 impression. For patients eventually would lead to better >24, % 6.8 4.5

Downloaded from www.aappublications.org/news by guest on September 27, 2021 PEDIATRICS Volume 139 , number s3 , June 2017 S189 TABLE 5 General Description of ID Level and ASD Diagnosis of Participants Diagnosed With FXS survey, will complement these clinic- Enrolled Between September 7, 2012 and August 31, 2014 in the FORWARD Longitudinal based data and collectively provide a Database more robust characterization of FXS Male Female and identify needs of individuals and Clinician’s summary of overall ID level families. Participants <7 y of age, N 162 41 % with developmental delay 100 70.7 Based on current data (Tables 2 Participants ≥7 y of age, N 362 106 and 4), FORWARD is probably No ID, % 0.6 21.7 missing a proportion of racial/ethnic Borderline ID, % 3.6 31.1 minorities either because they are

Mild ID, % 22.9 33.0 not diagnosed or because they are Moderate ID, % 59.9 12.3 Severe ID, % 12.4 1.9 not attending fragile X clinics. Many Profound ID, % 0.6 0 reasons for not attending a clinic can Current diagnosis of ASD be considered, such as: the lack of a Participants ≥3 y of age, N 449 136 clinical referral or awareness of the

% with ASD diagnosis 49.9 16.9 existence of a clinic; cost barriers related to travel to the clinic or lack of insurance to cover care beyond into research efforts to identify it may be that the most severely the diagnosis; language barriers; important pharmacologic, affected patients cannot be seen cultural or religious beliefs; and behavioral, and educational in clinic because their behavior many others. The FXCRC has relied interventions. prevents them from being brought on community support networks, in for medical care. Methods, such sponsored by the NFXF, to educate as the nonenrollment log described The FORWARD structure is stakeholders in their regions above, will help determine whether clinic-based, similar to that for about the benefits of the fragile 41 FORWARD represents those disorders such as spina bifida X clinics, and it hopes to increase 42 who attend fragile X clinics, but and cystic fibrosis. This structure the overall number and to have a cannot inform whether FORWARD differs from other clinical databases, wider distribution of racial/ethnic represents those diagnosed with FXS such as Duchenne Connect, that minority patients attending fragile in general. collect self-reported clinical X specialty clinics. Additionally, information from individuals with a to improve recruitment for the However, the data on the clinician’s specific disorder and their families Spanish-speaking population, most global impression of cognitive (eg, see ref 43). The advantage of of the parent-report FORWARD impairment and the presence of ASD the clinic-based system is that data materials have been translated in male and female participants in are collected by a clinician at the into Spanish and administered at FORWARD is comparable to that time of the clinic visit, maximizing clinics in locations that serve this observed in the literature and, thus, completeness and accuracy of these population. data. is encouraging in terms of being representative of individuals with The experience and tools used to A limitation of FORWARD is that FXS (Table 5). For example, the create FORWARD can serve as a enrollment occurs only through majority of male participants have model for other FXS studies in fragile X specialty clinics. This moderate ID and female participants other countries and for studies of enrollment only through clinics have borderline to mild ID ( Table 5), other ID disorders. For example, has the potential to lead to a similar to that reported previously.34 the data collection tools used in biased representation of family Also, results on the percent of FORWARD were shared with a demographics and severity of the patients with a current diagnosis of group of fragile X clinicians and syndrome. Families who have ASD are similar to those obtained researchers in Germany working access to more resources or live in from a national survey of parents to create a similar data resource, urban areas with increased access with children diagnosed with FXS. In referred to as EXPLAIN.44 The to clinicians specializing in FXS that survey, 46% of males and 16% of potential outcome will be the may be more represented in females with FXS had ASD by parent ability to compare and contrast FORWARD. Additionally, it may be report,30 and in FORWARD, 50% clinical outcomes of FXS in different that affected individuals who of males and 17% of females with clinical and cultural settings. Use attend fragile X specialty clinics FXS had ASD (Table 5). Use of other of the same tools and variables have more severe problems than data collection methods, such as in longitudinal studies of other those with milder symptoms, or Our Fragile X World’s parent-report neurologic disorders will also

Downloaded from www.aappublications.org/news by guest on September 27, 2021 S190 SHERMAN et al increase understanding of the providing a valuable resource to the ABBREVIATIONS commonalities among ID and FXS community. behavioral disorders and potentially ABC-C: Aberrant Behavior lead to new discoveries. Checklist–Community ACKNOWLEDGMENTS ASD: autism spectrum disorder We thank the NFXF for their support, CDC: Centers for Disease Control CONCLUSIONS encouragement, and commitment and Prevention DCC: Data Coordinating Center The FORWARD longitudinal database to establish the FXCRC. We thank FORWARD: Fragile X Online includes complete baseline data Don Bailey, Melissa Raspa, and Registry With on >900 individuals with FXS, Anne Wheeler for their input into Accessible Research representing the largest resource of FORWARD. We thank Rebecca Nash Database clinical data for the FXS population in for her assistance with graphics. FXCRC: Fragile X Clinical and the United States. These data can now Importantly, FORWARD can Research Consortium be used as a resource by the clinical only exist through the efforts of FXD: fragile X–associated disorder and research communities interested individuals who have FXS and their FXS: fragile X syndrome in advancing our understanding families and the clinicians and teams ID: intellectual disability of FXS, including the impact of who care for them. IRB: institutional review board cooccurring conditions, the impact To acknowledge the work of NC: national coordinator on the day-to-day life of individuals the fragile X specialty clinics NFXF: National Fragile X living with FXS and their families, and participating in FXCRC (25 of which Foundation short-term and long-term outcomes. have contributed data to FORWARD), SCQ: Social Communication The availability of longitudinal we list the clinical director(s), their Questionnaire data is currently limited; however, affiliation, and the year they joined SRS-2: Social Responsiveness the intent is to continue collecting the FXCRC. The list is alphabetical by Scale, Second Edition longitudinal data with the goal of state.

Accepted for publication Jan 24, 2017 Address correspondence to Stephanie L. Sherman, PhD, Department of Human Genetics, Emory University School of Medicine, 615 Michael St, Whitehead Building, Suite 301, Atlanta, GA 303022. E-mail: [email protected] PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2017 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: Dr Kaufmann is a consultant to Neuren, Edison, Newron, EryDel, Marinus, Anavex, and GW Pharmaceuticals; he has received research support from Novartis, Ipsen and Eloxx; EBK has received funding from Seaside Therapeutics, Novartis, Roche, Alcobra, Neuren, Cydan, Fulcrum and Neurotrope Pharmaceuticals to consult on trial design or development strategies and/or conduct clinical trials in FXS, Rett syndrome or Down syndrome, from Vtesse to conduct clinical trials in Niemann-Pick disease, type C, and from Asuragen Inc to develop testing standards for FMR1 testing. The other authors have indicated they have no fi nancial relationships relevant to this article to disclose. FUNDING: Supported by cooperative agreements 5U01DD000231 and 5U19DD000753-02 with the Centers for Disease Control and Prevention. POTENTIAL CONFLICT OF INTEREST: Dr Kaufmann is a consultant to Neuren, Edison, Newron, EryDel, Marinus, Anavex, and GW Pharmaceuticals; he has received research support from Novartis, Ipsen and Eloxx; EBK has received funding from Seaside Therapeutics, Novartis, Roche, Alcobra, Neuren, Cydan, Fulcrum and Neurotrope Pharmaceuticals to consult on trial design or development strategies and/or conduct clinical trials in FXS, Rett syndrome or Down syndrome, from Vtesse to conduct clinical trials in Niemann-Pick disease, type C, and from Asuragen Inc to develop testing standards for FMR1 testing. The other authors have indicated they have no potential confl icts of interest to disclose.

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Downloaded from www.aappublications.org/news by guest on September 27, 2021 FORWARD: A Registry and Longitudinal Clinical Database to Study Fragile X Syndrome Stephanie L. Sherman, Sharon A. Kidd, Catharine Riley, Elizabeth Berry-Kravis, Howard F. Andrews, Robert M. Miller, Sharyn Lincoln, Mark Swanson, Walter E. Kaufmann and W. Ted Brown Pediatrics 2017;139;S183 DOI: 10.1542/peds.2016-1159E

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