A randomized controlled trial of an online health tool about Down syndrome

The research plan was approved by the Partners Human Research Committee. Informed consent was obtained from all subjects and archived at Massachusetts General Hospital.

We conducted a national two-arm, randomized controlled trial of caregivers of individuals with DS to assess the efficacy of DSC2U in assuring adherence to evidence-based guidelines (ClinicalTrials.gov: NCT04227197; HSRProj number: HSRP20163014). The full protocol is available, on request, from the corresponding author.

Participants were recruited through online social media postings from MassGeneral Hospital and DS nonprofit organizations around the United States. We enrolled US-based caregivers between 3 October 2017 and 30 September 2018. We defined “caregivers” as parents, siblings, or other persons responsible for the care of an individual with DS whom they identify as a “dependent”. To be eligible, caregivers had to be English- or Spanish-speaking, live in the United States, and have a child/dependent with DS ≥ 1 year old, and not be an active patient in a DS specialty clinic. To strive for a more demographically diverse sample, we applied a quota system during enrollment based on the race and ethnicity of the individual with DS (Supplementary Materials S1, Figure S1). Additional recruitment measures were also implemented: (1) we reached out to the minority working groups of the DS organizations (e.g., National Down Syndrome Congress and Massachusetts Down Syndrome Congress); (2) we recontacted all of the DS local support groups in demographic areas of the country that have sizable black/African American and Spanish-speaking communities; (3) we asked African American caregivers who are influencers on social media to help recruit for our study; and (4) all of our recruitment materials, online and in print, were also available in Spanish. All caregivers provided informed consent.

DSC2U is a web-based tool, in English and Spanish, for families to get up-to-date, personalized health and wellness information, based on national guidelines and expert consensus, for a person with DS (Supplementary Materials S2 and S3). After the caregiver completed the DSC2U intake questionnaire, they received online access to a personalized caregiver checklist and PCP plan, also available in English and Spanish. These documents contained customized suggestions that were designed to help people with DS get health care tailored to their own specific needs. Also included in the documents was in-depth information about education, therapies, life skills, mental health/neurobehavioral conditions, and psychosocial supports with extensive links to curated online resources (Supplementary Materials S3, S16, S17). Caregivers were encouraged to share and discuss the PCP plan at the next wellness visit with the PCP.

Caregivers completed a baseline assessment survey (Supplemental Material S4, S20) no more than 8 weeks prior to the scheduled wellness visit with the PCP. This survey collected demographic data about the participant, their child or dependent, and their PCP; current health concerns and history; and health-care screening status. After the baseline assessment was received, caregivers were assigned in a 1:1 ratio to DSC2U or waitlist according to a computer-generated randomization schedule constructed with permuted blocks of size 2 and 4, stratified for traveling distance from PCP (three levels: <30 minutes, 30–59 minutes, and ≥60 minutes) and type of insurance (two levels: public and private). We emailed participants randomized to the intervention group a link to DSC2U, accessible with a 4-digit passcode so that they could return to DSC2U and complete it at their convenience. The DSC2U intake questionnaire contains ten sections for caregivers to complete, including current symptoms in their loved one with DS along with any past medical or behavioral diagnoses and any recent blood work or diagnostic testing. The DSC2U intake also contains optional questions about nutrition, education, therapies, life skills, and community resources (Supplementary Materials S3). The DSC2U intake questionnaire is distinct from the baseline assessment.

If the DSC2U intake questionnaire was not completed, we emailed reminders at 4, 3, and 2 weeks before the scheduled PCP appointment. Participants in the control group received usual care for 7 months after their next scheduled PCP appointment, after which they were offered access to DSC2U.

The primary outcome was adherence to five recommended health-care evaluations: celiac screen, sleep study, thyroid test, audiogram, and ophthalmology evaluation (Supplementary Materials S2, S7).^{,  ,  ,}  These five were selected from among those set forth by the AAP and adult consensus statements for DS because of the prevalence of the associated medical problems, the consequences of failing to treat appropriately, and the availability of treatments and therapies. We assessed the indications for each of the five evaluations for a given participant based on information reported in the baseline assessment (Supplementary Material S21). Our secondary outcomes were experience with the PCP visit, satisfaction with DSC2U (intervention group), and quality of life measures.

Primary outcomes were assessed by caregiver survey approximately 7 months after the PCP visit to allow time for recommended evaluations to be scheduled and completed. We asked caregivers whether the five evaluations were completed or recommended by the PCP (Supplementary Material S18). Primary outcome evaluations were measured along with other health-care evaluations to assess response bias. To validate caregiver responses, medical records were obtained from the first 20 caregivers who completed the study. We planned for validation of all caregiver reports if agreement was less than 90%.

Secondary outcomes measuring the experience with the PCP visit were gathered by caregiver survey approximately 2 weeks after the PCP visit for both the intervention and control participants (Supplementary Material S6, Figures S6, S7). Some measures of visit experience were taken or adapted from the Clinician Group Consumer Assessment of Healthcare Providers and Systems (CG-CAHPS) suite of instruments (Supplementary Material S19). We also asked the intervention group about their satisfaction with DSC2U at the 2-week and 7-month time points.

At baseline and then ~2 weeks and ~7 months after the PCP visit, six measures of quality of life were collected by caregiver self-report using age-appropriate versions of the PedsQL 2.0 Family Impact Module and PedsQL 4.0 parent-proxy, standard Short Form 15 Generic Core Scales (Supplementary Material S5).^{,  ,} 

PCP-reported measures, including experience with the patient visit and experience with DSC2U (intervention arm), were gathered by self-administered mail surveys sent 2 weeks after the visit (Supplementary Material S20). An incentive of $40 was enclosed with the survey.

Except where indicated otherwise, all caregiver communications, including survey requests, were by email. Reminder emails to nonrespondents were sent up to three times about two weeks apart, concluding with two phone calls in the eighth week, if needed. PCPs received their survey by mail, with an option to complete the survey electronically; reminders were sent by mail up to two times, two weeks apart, concluding with two phone calls in the sixth week, if needed. All study data were collected and managed using REDCap.^, Caregivers received up to $50 in incentives and an additional $20 if selected for validation.

The complete statistical analysis plan is available in Supplementary Materials S8 and S9. Based on previously published completion rates of indicated evaluations and to allow for up to a 14% dropout, we estimated that a sample of 200 total parents/caregivers would yield 80% power to detect an average increase of 0.6 completed or recommended evaluations. This sample would provide 80% power to detect treatment-specific improvements in secondary outcomes for effect sizes as small as 0.56. All analyses were performed on an intention-to-treat basis. All tests for significance were two-sided. Analyses were performed using SAS (version 9.4, SAS Institute, Cary, NC).

Significant benefit, defined a priori, was declared when the mean number of indicated evaluations that had been recommended or completed was greater among participants randomized to the intervention if two-sample t-test with a two-tailed p value for the treatment comparison was <0.05. For participants lost to follow-up and those reporting that they were not sure whether a given evaluation was completed or recommended by their PCP, we counted them as having not completed the evaluation. (In this intention-to-treat analysis, we treated loss to follow-up as fully informative about noncompletion.) On the other extreme, as part of our Supplementary Materials, we performed the same analyses but excluded any missing data. (In this case we treated loss to follow-up as wholly noninformative [i.e., completely at random] with respect to noncompletion). We confirmed our inference using a generalized linear model assuming beta-binomial distributed counts of recommended or completed evaluations among those indicated with parameters estimated by maximum likelihood and in a permutation test by direct randomization of assigned treatment labels.

We analyzed longitudinal changes in our secondary outcome measures using a shared-baseline repeated-measures analysis of variance (ANOVA) for each of six quality of-life outcomes derived from the two PedsQL instruments. Linear contrasts were used to test for treatment-specific improvements over time. As a sensitivity analysis, we also used simple two-group Wilcoxon rank-sum tests to compare changes from baseline to the 2-week and 7-month follow-ups individually. With six secondary outcomes, we tested each secondary outcome at ɑ = 0.008, two-tailed, to control for multiple comparisons.

We further analyzed the primary outcome for subgroup-dependent differences with linear models that included terms for subgroup membership, treatment group, and their interaction and that allowed for heteroscedastic variance by subgroup. Evidence of a subgroup-dependent difference in the efficacy of DSC2U was based on the significance of the subgroup x treatment group interaction (Supplementary Materials S13).

We assessed 645 caregivers for eligibility through the study website, and 281 were consented (Fig. 1). After accounting for the caregivers who did not complete the baseline survey, changed their PCP visit date outside of the study window, or self-withdrew, we randomized 230 consented caregivers to receive either DSC2U (117 participants) or “usual care” (113 participants).

At the 2-week follow-up, 101 (86.3%) of the 117 original caregivers in the intervention group and 108 (95.6%) of the 113 caregivers in the control group completed the surveys. At this same time point, 81.6% and 77.9% of the PCPs completed the surveys in the intervention and control groups, respectively.

At the 7-month follow-up, 103 (88.0%) of 117 original caregivers in the intervention group and 110 (97.3%) of 113 caregivers in the control group completed the surveys.

The ages of the individuals with DS ranged from 8 months to 56 years old (at the time of the caregivers’ completion of the baseline assessment), and 92.1% of caregivers were mothers. The two treatment groups of caregivers, patients, and PCPs were well balanced with respect to baseline characteristics and relationships (Table 1; S1, S2).

At the end of the 7-month follow-up period, the primary outcome—the number of indicated evaluations that were completed or recommended by the PCP—was greater among DSC2U participants (intervention group: M = 0.53, SD = 0.73; control group: M = 0.33, SD = 0.53; difference: 0.20, 95% confidence interval [CI]: 0.04 to 0.37, p = 0.016 by t-test, p < 0.011 by beta-binomial test, p = 0.012 by permutation test; Tables 2, 3). Participants in the intervention group had a 1.6-fold increase in the number of indicated evaluations that were completed or recommended by the PCP compared with the controls. The mean absolute difference was 0.20 evaluations across the five evaluation items between the intervention group and the control group. Put another way, the DSC2U participants had one more indicated evaluation that was recommended by their PCP or completed (versus control group) for every five PCP visits. All of these indicated evaluations were supported by the DS health-care guidelines.^{,,  ,} 

Of note, the intervention group was also more likely to complete nonindicated evaluations than the control group (Supplementary Materials S12) although the difference was not significant when classifying loss to follow-up as noncompletion in our intention-to-treat analysis (Tables 2, 3). None of the analyzed subgroups disproportionately benefited from DSC2U based on our primary outcome measure (Supplementary Materials S13). We validated the reports of five primary outcomes from 20 caregivers. Of these 100 parental reports, 95 were accurate based on medical records. We received five inconsistent responses from four caregivers.

Caregivers in both arms rated the PCP visits highly (Supplementary Table S2). On a 10-point Likert scale with “10” representing “most helpful” and “0” representing “least helpful”, caregivers reported high satisfaction with DSC2U at both the 2-week follow-up (M = 7.75, SD = 1.84) and 7-month follow-up (M = 7.79, SD = 1.82); satisfaction exhibited no significant decline over this time (p = 0.90, Table 4). PCPs also expressed high satisfaction with DSC2U at the 2-week follow-up (M = 7.80, SD = 1.86).

Analyses of secondary quality of life outcomes, as ascertained through the six PedsQL 4.0 parent-proxy and PedsQL 2.0 Family Impact Module summary scores, did not demonstrate a significant difference between the intervention and control groups at either the 2-week or 7-month time points (Supplementary Material S15, Table S10).

Of the caregivers in the intervention group who completed the 2-week follow-up (N = 101), all accessed the caregiver checklist in some capacity (viewing, downloading, and/or printing). Of these, 97% reported that the caregiver checklist recommendations were easy to understand (Table 4). All caregivers would recommend the checklist to another caregiver. About 76% would review their checklist more than twice per year after the 2-week time point, and 61% would access more than twice per year after the 7-month time point (p = 0.004, Table 4). At the 2-week time point, 96% of caregivers would recomplete DSC2U again in the future, which did not statistically lessen over time (Table 4).

When the plan was shared with the PCP, 93% of caregivers felt that the PCP seemed to be interested in the information, and 86% felt the PCPs agreed with the recommendations. At the 2-week follow-up, all PCPs who received the plan discussed the recommendations with the caregiver and were interested in the information. About 97% of PCPs who received the plan agreed with the recommendations.

None of the characteristics of the individual with DS, the caregiver, the PCP, the PCP’s practice, or the relationship between the PCP and caregiver was a statistically significant predictor for any of the dependent variables detailed above, when the p value was adjusted to account for multiple comparisons (Supplemental Material S14, Table S9).

B.G.S. occasionally consults on the topic of Down syndrome through Gerson Lehrman Group. He receives remuneration from Down syndrome nonprofit organizations for speaking engagements and associated travel expenses. B.G.S. receives annual royalties from Woodbine House, Inc., for the publication of his book, Fasten Your Seatbelt: A Crash Course on Down Syndrome for Brothers and Sisters. Within the past two years, he has received research funding from F. Hoffmann-La Roche, Inc. and LuMind Research Down Syndrome Foundation to conduct clinical trials for people with Down syndrome. B.G.S. is occasionally asked to serve as an expert witness for legal cases where Down syndrome is discussed. B.G.S. serves in a nonpaid capacity on the Honorary Board of Directors for the Massachusetts Down Syndrome Congress and the Professional Advisory Committee for the National Center for Prenatal and Postnatal Down Syndrome Resources. B.G.S. has a sister with Down syndrome. K.D. is an unpaid member of the Board of Directors of Bridges Associates, a private not-for-profit organization serving children and adults with learning disabilities in Barnstable County, Massachusetts. E.A.M. serves as a DSMB member for Novartis Pharmaceuticals and Shire Human Genetic Therapies; serves on a trial Steering Committee for Biogen; serves on the Executive Committee of the Parkinson Study Group; has recently consulted for Cerevance, InTrance, and Inventram; and his institution receives research funding on his behalf from ALS Finding A Cure, Amylyx Pharmaceuticals, Autism Speaks, Cedars-Sinai Research Institute, Farmer Family Foundation, GlaxoSmithKline, Mitsubishi Tanabe Pharmaceuticals, and the Salah Foundation. S.L.S. receives research funding from the LuMind Down Syndrome Foundation IDSC.  She is a nonpaid volunteer for the Medical and Scientific Advisory Council for the Massachusetts Down Syndrome Congress. S.B. is an employee of the Down Syndrome Association of Los Angeles and serves in a nonpaid capacity on the Self Determination Advisory Committee as a parent of an individual with disabilities for the North Los Angeles County Regional Center area. P.E.B. serves in a nonpaid capacity on the board of trustees of the Riverview School in East Sandwich, Massachusetts. P.E.B. has a daughter with Down syndrome. B.C. receives remuneration from Down syndrome nonprofit organizations for speaking engagements and associated travel expenses. B.C. receives annual royalties from Woodbine House, Inc., for the publication of his books, Mental Wellness in Adults with Down Syndrome and The Guide to Good Health for Teens and Adults with Down Syndrome. Within the past year, he has received research funding from LuMind Research Down Syndrome Foundation to conduct a clinical trial for people with Down syndrome. B.C. is occasionally asked to serve as an expert witness for legal cases where Down syndrome is discussed. B.C. serves in a nonpaid capacity on the Board of Directors for the Down Syndrome Medical Interest Group and the Professional Advisory Committee for the National Down Syndrome Society and the National Down Syndrome Congress.  B.C.’s great uncle had Down syndrome. J.M. speaks at conferences for Down syndrome and other disability organizations. Additionally, J.M. consults and facilitates the National Down Syndrome Congress Advocacy Training Boot Camp and does some other advocacy related consulting for them, and facilitates educational workshops for a local nonprofit, Inclusion Connections. J.M. currently serves on two boards, Disability Rights Center of Kansas (incoming Board President) and the City of Olathe Persons with Disabilities Advisory Board. J.M. has a child with Down syndrome. T.R. is a self-employed pediatrician. He also provides contract work for St. John’s Health in Jackson, Wyoming as a staff pediatrician and for the State of Wyoming and Teton County, Wyoming as County Health Officer.  He is a volunteer clinical faculty member of the University of Washington School of Medicine. M.S., L.M., P.E.B., S.B., J.M., and S.C. each have a child with Down syndrome. The other authors declare no conflicts of interest.