Trial Outcomes & Findings for North Carolina Genomic Evaluation by Next-generation Exome Sequencing, 2 (NCT NCT03548779)

NCT ID: NCT03548779

Last Updated: 2025-05-13

Results Overview

The Peds QL Measurement Model for the Pediatric Quality of Inventory measures the core dimensions of health as delineated by the World Health Organization as well as role (school) functioning. The 23-item PedsQL Core Scales (Physical Functioning, Emotional Functioning, Social Functioning, and School Functioning) are developmentally appropriate surveys (Ages 2-4, 5-7, 8-12, 13-18) designed for parent proxy report. The 23 items are grouped together on the questionnaire, and are answered on a scale of 0-4. Items are reversed scored and linearly transformed to a 0-100 scale (0=100, 1=75, 2=50, 3=25, 4=0), so that higher scores indicate better Health-Related Quality of Life (HRQOL). This questionnaire will be self-administered at home.

• Recruitment status: COMPLETED
• Study phase: NA
• Target enrollment: 548 participants
• Primary outcome timeframe: 4-6 weeks prior to clinic visit 1
• Results posted on: 2025-05-13

Participant Flow

927 children were eligible for recruitment, and of these 791 parents/caregivers were approached by phone prior to their clinic visit; 514 parents/caregivers were reached for a recruitment phone call, and a total of 417 dyads consisting of a child and their parent/caregiver were enrolled and consented to randomization. Of these, 274 baseline intake forms were obtained at a clinic visit and those dyads continued in the study, for a total of 548 individuals enrolled in the protocol.

Participant milestones

Measure	Parent/Caregiver Pre-visit Prep + Exome Dyads (parent/caregiver + child) that are randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Parent/Caregiver Pre-visit Prep + Usual Care Dyads (parent/caregiver + child) that are randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "usual care" arm are not offered additional exome sequencing.	Parent/Caregiver No Pre-visit Prep + Exome Dyads (parent/caregiver + child) that are randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Parent/Caregiver No Pre-visit Prep + Usual Care Dyads (parent/caregiver + child) that are randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "usual care" arm are not offered additional exome sequencing.	Child Pre-visit Prep + Exome Dyads (parent/caregiver + child) that are randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Child Pre-visit Prep + Usual Care Dyads (parent/caregiver + child) that are randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "usual care" arm are not offered additional exome sequencing.	Child No Pre-visit Prep + Exome Dyads (parent/caregiver + child) that are randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Child No Pre-visit Prep + Usual Care Dyads (parent/caregiver + child) that are randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "usual care" arm are not offered additional exome sequencing.
Clinical Study STARTED	64	72	63	75	64	72	63	75
Clinical Study Second Stage Randomization and Consent Discussion	0	0	0	0	53	70	59	68
Clinical Study COMPLETED	64	72	63	75	53	70	59	68
Clinical Study NOT COMPLETED	0	0	0	0	11	2	4	7
Health Care Records Analysis STARTED	0	0	0	0	53	70	59	68
Health Care Records Analysis 6 Month Data Pre and Post	0	0	0	0	26	36	32	38
Health Care Records Analysis COMPLETED	0	0	0	0	22	35	27	31
Health Care Records Analysis NOT COMPLETED	0	0	0	0	31	35	32	37

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

North Carolina Genomic Evaluation by Next-generation Exome Sequencing, 2

Baseline characteristics by cohort

Measure	Parent/Caregiver Pre-visit Prep + Exome n=64 Participants Dyads (parent/caregiver + child) randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Parent/Caregiver Pre-visit Prep + Usual Care n=72 Participants Dyads (parent/caregiver + child) randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads randomized to the "usual care" arm are not offered additional exome sequencing.	Parent/Caregiver No Pre-visit Prep + Exome n=63 Participants Dyads (parent/caregiver + child) randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Parent/Caregiver No Pre-visit Prep + Usual Care n=75 Participants Dyads (parent/caregiver + child) randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads randomized to the "usual care" arm are not offered additional exome sequencing.	Child Pre-visit Prep + Exome n=64 Participants Dyads (parent/caregiver + child) randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Child Pre-visit Prep + Usual Care n=72 Participants Dyads (parent/caregiver + child) randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads randomized to the "usual care" arm are not offered additional exome sequencing.	Child No Pre-visit Prep + Exome n=63 Participants Dyads (parent/caregiver + child) randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Child No Pre-visit Prep + Usual Care n=75 Participants Dyads (parent/caregiver + child) randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads randomized to the "usual care" arm are not offered additional exome sequencing.	Total n=548 Participants Total of all reporting groups
Age, Continuous	35.3 years STANDARD_DEVIATION 6.7 • n=5 Participants	35.8 years STANDARD_DEVIATION 7.0 • n=7 Participants	36.6 years STANDARD_DEVIATION 9.5 • n=5 Participants	35.3 years STANDARD_DEVIATION 9.3 • n=4 Participants	5.4 years STANDARD_DEVIATION 4.3 • n=21 Participants	5.1 years STANDARD_DEVIATION 4.3 • n=10 Participants	6.8 years STANDARD_DEVIATION 4.6 • n=115 Participants	6.2 years STANDARD_DEVIATION 4.1 • n=24 Participants	20.8 years STANDARD_DEVIATION 16.4 • n=42 Participants
Sex/Gender, Customized Female	59 Participants n=5 Participants	67 Participants n=7 Participants	58 Participants n=5 Participants	67 Participants n=4 Participants	28 Participants n=21 Participants	31 Participants n=10 Participants	24 Participants n=115 Participants	37 Participants n=24 Participants	371 Participants n=42 Participants
Sex/Gender, Customized Male	3 Participants n=5 Participants	3 Participants n=7 Participants	4 Participants n=5 Participants	6 Participants n=4 Participants	36 Participants n=21 Participants	41 Participants n=10 Participants	39 Participants n=115 Participants	38 Participants n=24 Participants	170 Participants n=42 Participants
Sex/Gender, Customized Did not answer	2 Participants n=5 Participants	2 Participants n=7 Participants	1 Participants n=5 Participants	2 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=10 Participants	0 Participants n=115 Participants	0 Participants n=24 Participants	7 Participants n=42 Participants
Race/Ethnicity, Customized American Indian, Native American, or Alaska Native	2 Participants n=5 Participants	4 Participants n=7 Participants	3 Participants n=5 Participants	4 Participants n=4 Participants	1 Participants n=21 Participants	4 Participants n=10 Participants	3 Participants n=115 Participants	2 Participants n=24 Participants	23 Participants n=42 Participants
Race/Ethnicity, Customized Asian	0 Participants n=5 Participants	2 Participants n=7 Participants	0 Participants n=5 Participants	2 Participants n=4 Participants	3 Participants n=21 Participants	2 Participants n=10 Participants	1 Participants n=115 Participants	3 Participants n=24 Participants	13 Participants n=42 Participants
Race/Ethnicity, Customized Black or African American	7 Participants n=5 Participants	11 Participants n=7 Participants	10 Participants n=5 Participants	5 Participants n=4 Participants	8 Participants n=21 Participants	14 Participants n=10 Participants	10 Participants n=115 Participants	7 Participants n=24 Participants	72 Participants n=42 Participants
Race/Ethnicity, Customized Native Hawaiian/Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=10 Participants	0 Participants n=115 Participants	0 Participants n=24 Participants	0 Participants n=42 Participants
Race/Ethnicity, Customized White or European American	52 Participants n=5 Participants	49 Participants n=7 Participants	49 Participants n=5 Participants	54 Participants n=4 Participants	49 Participants n=21 Participants	50 Participants n=10 Participants	48 Participants n=115 Participants	57 Participants n=24 Participants	408 Participants n=42 Participants
Race/Ethnicity, Customized Middle Eastern or North African/Mediterranean	1 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	1 Participants n=21 Participants	0 Participants n=10 Participants	0 Participants n=115 Participants	0 Participants n=24 Participants	2 Participants n=42 Participants
Race/Ethnicity, Customized Hispanic/Latino(a)	4 Participants n=5 Participants	5 Participants n=7 Participants	2 Participants n=5 Participants	10 Participants n=4 Participants	7 Participants n=21 Participants	7 Participants n=10 Participants	2 Participants n=115 Participants	13 Participants n=24 Participants	50 Participants n=42 Participants
Race/Ethnicity, Customized Prefer not to answer	0 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	1 Participants n=10 Participants	0 Participants n=115 Participants	0 Participants n=24 Participants	2 Participants n=42 Participants
Race/Ethnicity, Customized Unknown/none of these fully describe me	1 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	1 Participants n=21 Participants	1 Participants n=10 Participants	1 Participants n=115 Participants	0 Participants n=24 Participants	5 Participants n=42 Participants

PRIMARY outcome

Timeframe: 4-6 weeks prior to clinic visit 1

Population: This analysis is conducted among the parent/caregiver participants only.

The Peds QL Measurement Model for the Pediatric Quality of Inventory measures the core dimensions of health as delineated by the World Health Organization as well as role (school) functioning. The 23-item PedsQL Core Scales (Physical Functioning, Emotional Functioning, Social Functioning, and School Functioning) are developmentally appropriate surveys (Ages 2-4, 5-7, 8-12, 13-18) designed for parent proxy report. The 23 items are grouped together on the questionnaire, and are answered on a scale of 0-4. Items are reversed scored and linearly transformed to a 0-100 scale (0=100, 1=75, 2=50, 3=25, 4=0), so that higher scores indicate better Health-Related Quality of Life (HRQOL). This questionnaire will be self-administered at home.

Outcome measures

Measure	Parent/Caregiver Pre-visit Prep + Exome n=62 Participants Dyads (parent/caregiver + child) that are randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Parent/Caregiver Pre-visit Prep + Usual Care n=70 Participants Dyads (parent/caregiver + child) that are randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "usual care" arm are not offered additional exome sequencing.	Parent/Caregiver No Pre-visit Prep + Exome n=61 Participants Dyads (parent/caregiver + child) that are randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Parent/Caregiver No Pre-visit Prep + Usual Care n=72 Participants Dyads (parent/caregiver + child) that are randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "usual care" arm are not offered additional exome sequencing.
Initial Patient Pediatric Quality of Life (Peds QL) Score	64.37 score on a scale Standard Deviation 20.59	65.83 score on a scale Standard Deviation 18.00	60.04 score on a scale Standard Deviation 17.10	63.39 score on a scale Standard Deviation 18.49

PRIMARY outcome

Timeframe: 6 months after return of results

Population: This analysis is conducted among the parent/caregiver participants only.

The Peds QL Measurement Model for the Pediatric Quality of Inventory measures the core dimensions of health as delineated by the World Health Organization as well as role (school) functioning. The 23-item PedsQL Core Scales (Physical Functioning, Emotional Functioning, Social Functioning, and School Functioning) are developmentally appropriate surveys (Ages 2-4, 5-7, 8-12, 13-18) designed for parent proxy report. The 23 items are grouped together on the questionnaire, and are answered on a scale of 0-4. Items are reversed scored and linearly transformed to a 0-100 scale (0=100, 1=75, 2=50, 3=25, 4=0), so that higher scores indicate better HRQOL. This questionnaire will be interviewer administered by telephone.

Outcome measures

Measure	Parent/Caregiver Pre-visit Prep + Exome n=20 Participants Dyads (parent/caregiver + child) that are randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Parent/Caregiver Pre-visit Prep + Usual Care n=36 Participants Dyads (parent/caregiver + child) that are randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "usual care" arm are not offered additional exome sequencing.	Parent/Caregiver No Pre-visit Prep + Exome n=26 Participants Dyads (parent/caregiver + child) that are randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Parent/Caregiver No Pre-visit Prep + Usual Care n=30 Participants Dyads (parent/caregiver + child) that are randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "usual care" arm are not offered additional exome sequencing.
Final Patient Pediatric Quality of Life (Peds QL) Score	72.15 score on a scale Standard Deviation 17.95	75.74 score on a scale Standard Deviation 15.01	71.65 score on a scale Standard Deviation 17.10	68.90 score on a scale Standard Deviation 19.01

PRIMARY outcome

Timeframe: 4-6 weeks prior to clinic visit 1

Population: This analysis is conducted among the parent/caregiver participants only.

The Short-Form Health Survey (SF-12) questionnaire is a reliable measure of perceived health that describes the degree of general physical health status and mental health distress. It consists of 12 items, derived from the physical and mental domains. Scores have a range of 0 to 100 and were designed to have a mean score of 50 and a standard deviation of 10 in a representative sample of the US population, with higher scores indicating greater functioning. This questionnaire will be self-administered at home.

Outcome measures

Measure	Parent/Caregiver Pre-visit Prep + Exome n=50 Participants Dyads (parent/caregiver + child) that are randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Parent/Caregiver Pre-visit Prep + Usual Care n=55 Participants Dyads (parent/caregiver + child) that are randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "usual care" arm are not offered additional exome sequencing.	Parent/Caregiver No Pre-visit Prep + Exome n=48 Participants Dyads (parent/caregiver + child) that are randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Parent/Caregiver No Pre-visit Prep + Usual Care n=55 Participants Dyads (parent/caregiver + child) that are randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "usual care" arm are not offered additional exome sequencing.
Initial Caregiver QoL Score	50.14 score on a scale Standard Deviation 10.25	48.84 score on a scale Standard Deviation 8.14	51.30 score on a scale Standard Deviation 8.72	47.69 score on a scale Standard Deviation 9.59

PRIMARY outcome

Timeframe: 2 weeks after return of results

Population: This analysis is conducted among the parent/caregiver participants only.

The SF-12 questionnaire is a reliable measure of perceived health that describes the degree of general physical health status and mental health distress. It consists of 12 items, derived from the physical and mental domains. Scores have a range of 0 to 100 and were designed to have a mean score of 50 and a standard deviation of 10 in a representative sample of the US population, with higher scores indicating greater functioning. This questionnaire will be interviewer administered by telephone.

Outcome measures

Measure	Parent/Caregiver Pre-visit Prep + Exome n=19 Participants Dyads (parent/caregiver + child) that are randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Parent/Caregiver Pre-visit Prep + Usual Care n=28 Participants Dyads (parent/caregiver + child) that are randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "usual care" arm are not offered additional exome sequencing.	Parent/Caregiver No Pre-visit Prep + Exome n=24 Participants Dyads (parent/caregiver + child) that are randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Parent/Caregiver No Pre-visit Prep + Usual Care n=31 Participants Dyads (parent/caregiver + child) that are randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "usual care" arm are not offered additional exome sequencing.
Intermediate Caregiver QoL Score	51.48 score on a scale Standard Deviation 9.03	46.58 score on a scale Standard Deviation 9.68	50.66 score on a scale Standard Deviation 11.49	50.08 score on a scale Standard Deviation 7.52

PRIMARY outcome

Timeframe: 6 months after return of results

Population: This analysis is conducted among the parent/caregiver participants only.

The SF-12 questionnaire is a reliable measure of perceived health that describes the degree of general physical health status and mental health distress. It consists of 12 items, derived from the physical and mental domains. Scores have a range of 0 to 100 and were designed to have a mean score of 50 and a standard deviation of 10 in a representative sample of the US population, with higher scores indicating greater functioning. This questionnaire will be interviewer administered by telephone.

Outcome measures

Measure	Parent/Caregiver Pre-visit Prep + Exome n=20 Participants Dyads (parent/caregiver + child) that are randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Parent/Caregiver Pre-visit Prep + Usual Care n=38 Participants Dyads (parent/caregiver + child) that are randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "usual care" arm are not offered additional exome sequencing.	Parent/Caregiver No Pre-visit Prep + Exome n=26 Participants Dyads (parent/caregiver + child) that are randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Parent/Caregiver No Pre-visit Prep + Usual Care n=30 Participants Dyads (parent/caregiver + child) that are randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "usual care" arm are not offered additional exome sequencing.
Final Caregiver QoL Score	53.31 score on a scale Standard Deviation 5.41	50.38 score on a scale Standard Deviation 8.21	47.41 score on a scale Standard Deviation 11.44	47.46 score on a scale Standard Deviation 10.39

PRIMARY outcome

Timeframe: Immediately after clinic 1 day of visit 1

Population: This analysis is conducted among the parent/caregiver participants only.

Patient centeredness scale, which measures the caregiver's perception of the level of patient centeredness of their visit with their child's provider (developed by Little et al., 2001). Self-administered in the clinic, immediately after clinic visit 1. Item responses will be coded as: 1=Very strongly disagree; 2=Strongly disagree; 3=Moderately disagree; 4=Neither agree nor disagree; 5=Moderately agree; 6=Strongly agree; 7=Very strongly agree. Response values will be summed and divided by the total number of items (21) to obtain mean scores ranging from 0-7 where higher values indicate stronger perceptions of patient centeredness.

Outcome measures

Measure	Parent/Caregiver Pre-visit Prep + Exome n=49 Participants Dyads (parent/caregiver + child) that are randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Parent/Caregiver Pre-visit Prep + Usual Care n=56 Participants Dyads (parent/caregiver + child) that are randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "usual care" arm are not offered additional exome sequencing.	Parent/Caregiver No Pre-visit Prep + Exome n=51 Participants Dyads (parent/caregiver + child) that are randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Parent/Caregiver No Pre-visit Prep + Usual Care n=58 Participants Dyads (parent/caregiver + child) that are randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "usual care" arm are not offered additional exome sequencing.
Post-Clinic Visit 1 Mean Patient Centeredness Score	5.7 score on a scale Standard Deviation 0.8	5.7 score on a scale Standard Deviation 0.9	5.9 score on a scale Standard Deviation 0.7	5.8 score on a scale Standard Deviation 0.9

PRIMARY outcome

Timeframe: 2 weeks after return of results

Population: This analysis is conducted among the parent/caregiver participants only.

Patient centeredness scale, which measures the caregiver's perception of the level of patient centeredness of their visit with their child's provider (developed by Little et al., 2001). Self-administered in the clinic, immediately after clinic visit 1. Item responses will be coded as: 1=Very strongly disagree; 2=Strongly disagree; 3=Moderately disagree; 4=Neither agree nor disagree; 5=Moderately agree; 6=Strongly agree; 7=Very strongly agree. Response values will be summed and divided by the total number of items (21) to obtain mean scores ranging from 0-7 where higher values indicate stronger perceptions of patient centeredness.

Outcome measures

Measure	Parent/Caregiver Pre-visit Prep + Exome n=20 Participants Dyads (parent/caregiver + child) that are randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Parent/Caregiver Pre-visit Prep + Usual Care n=24 Participants Dyads (parent/caregiver + child) that are randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "usual care" arm are not offered additional exome sequencing.	Parent/Caregiver No Pre-visit Prep + Exome n=24 Participants Dyads (parent/caregiver + child) that are randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Parent/Caregiver No Pre-visit Prep + Usual Care n=22 Participants Dyads (parent/caregiver + child) that are randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "usual care" arm are not offered additional exome sequencing.
Post-Return of Results Mean Patient Centeredness Score	5.5 score on a scale Standard Deviation 0.9	5 score on a scale Standard Deviation 1.3	5 score on a scale Standard Deviation 1.1	4.8 score on a scale Standard Deviation 1.6

PRIMARY outcome

Timeframe: During clinic 1 day of visit 1

Population: This analysis is conducted among the parent/caregiver participants who attended a clinic visit that was transcribed (a subset of all dyads who completed Clinic Visit 1). The analysis populations only represent the first randomization (Pre-visit prep vs. No pre-visit prep) because the second randomization (Exome vs. Usual care) did not occur until after the clinic visit was completed, and was therefore not germane to this specific outcome measure.

Count of number of questions caregiver asks provider in the audio recording of clinic visit 1. Coded by trained study staff.

Outcome measures

Measure	Parent/Caregiver Pre-visit Prep + Exome n=59 Participants Dyads (parent/caregiver + child) that are randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Parent/Caregiver Pre-visit Prep + Usual Care n=53 Participants Dyads (parent/caregiver + child) that are randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "usual care" arm are not offered additional exome sequencing.	Parent/Caregiver No Pre-visit Prep + Exome Dyads (parent/caregiver + child) that are randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Parent/Caregiver No Pre-visit Prep + Usual Care Dyads (parent/caregiver + child) that are randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "usual care" arm are not offered additional exome sequencing.
Number of Questions Caregiver Asks in Clinic Visit 1	4.36 Number of questions asked Standard Deviation 4.66	2.83 Number of questions asked Standard Deviation 3.03	—	—

PRIMARY outcome

Timeframe: 1 year prior to return of results

Population: This analysis includes the subset of child participants with 12 months of EHR data available before and after study results were returned.

Count of number of in-patient hospital admissions among child participants during 1 year prior to return of results using data obtained from the Electronic Medical Record. Coded by trained study staff. Admissions were summed across all participants.

Outcome measures

Measure	Parent/Caregiver Pre-visit Prep + Exome n=22 Participants Dyads (parent/caregiver + child) that are randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Parent/Caregiver Pre-visit Prep + Usual Care n=35 Participants Dyads (parent/caregiver + child) that are randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "usual care" arm are not offered additional exome sequencing.	Parent/Caregiver No Pre-visit Prep + Exome n=27 Participants Dyads (parent/caregiver + child) that are randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Parent/Caregiver No Pre-visit Prep + Usual Care n=31 Participants Dyads (parent/caregiver + child) that are randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "usual care" arm are not offered additional exome sequencing.
Number of In-patient Hospital Admissions Among Child Participants 1 Year Prior to Return of Results	0 In-patient hospital admissions	3 In-patient hospital admissions	4 In-patient hospital admissions	2 In-patient hospital admissions

PRIMARY outcome

Timeframe: 1 year after return of results

Population: This analysis includes the subset of child participants with 12 months of EHR data available before and after study results were returned.

Count of number of in-patient hospital admissions among child participants during 1 year after return of results using data obtained from the Electronic Medical Record. Coded by trained study staff. Admissions were summed across all participants.

Outcome measures

Measure	Parent/Caregiver Pre-visit Prep + Exome n=22 Participants Dyads (parent/caregiver + child) that are randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Parent/Caregiver Pre-visit Prep + Usual Care n=35 Participants Dyads (parent/caregiver + child) that are randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "usual care" arm are not offered additional exome sequencing.	Parent/Caregiver No Pre-visit Prep + Exome n=27 Participants Dyads (parent/caregiver + child) that are randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Parent/Caregiver No Pre-visit Prep + Usual Care n=31 Participants Dyads (parent/caregiver + child) that are randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "usual care" arm are not offered additional exome sequencing.
Number of In-patient Hospital Admissions Among Child Participants 1 Year After Return of Results	1 In-patient hospital admissions	1 In-patient hospital admissions	8 In-patient hospital admissions	2 In-patient hospital admissions

PRIMARY outcome

Timeframe: 1 year prior to return of results

Population: This analysis includes the subset of child participants with 12 months of EHR data available before and after study results were returned.

Count of number of in-patient hospital days among child participants during 1 year prior to return of results using data obtained from the Electronic Medical Record. Coded by trained study staff. Days were summed across all participants.

Outcome measures

Measure	Parent/Caregiver Pre-visit Prep + Exome n=22 Participants Dyads (parent/caregiver + child) that are randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Parent/Caregiver Pre-visit Prep + Usual Care n=35 Participants Dyads (parent/caregiver + child) that are randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "usual care" arm are not offered additional exome sequencing.	Parent/Caregiver No Pre-visit Prep + Exome n=27 Participants Dyads (parent/caregiver + child) that are randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Parent/Caregiver No Pre-visit Prep + Usual Care n=31 Participants Dyads (parent/caregiver + child) that are randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "usual care" arm are not offered additional exome sequencing.
Number of In-patient Hospital Days Among Child Participants 1 Year Prior to Return of Results	0 In-patient hospital days	13 In-patient hospital days	22 In-patient hospital days	1 In-patient hospital days

PRIMARY outcome

Timeframe: 1 year after return of results

Population: This analysis includes the subset of child participants with 12 months of EHR data available before and after study results were returned.

Count of number of in-patient hospital days among child participants during 1 year after return of results using data obtained from the Electronic Medical Record. Coded by trained study staff. Days were summed across all participants.

Outcome measures

Measure	Parent/Caregiver Pre-visit Prep + Exome n=22 Participants Dyads (parent/caregiver + child) that are randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Parent/Caregiver Pre-visit Prep + Usual Care n=35 Participants Dyads (parent/caregiver + child) that are randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "usual care" arm are not offered additional exome sequencing.	Parent/Caregiver No Pre-visit Prep + Exome n=27 Participants Dyads (parent/caregiver + child) that are randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Parent/Caregiver No Pre-visit Prep + Usual Care n=31 Participants Dyads (parent/caregiver + child) that are randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "usual care" arm are not offered additional exome sequencing.
Number of In-patient Hospital Days Among Child Participants 1 Year After Return of Results	5 In-patient hospital days	5 In-patient hospital days	148 In-patient hospital days	11 In-patient hospital days

PRIMARY outcome

Timeframe: 1 year prior to return of results

Population: This analysis includes the subset of child participants with 12 months of EHR data available before and after study results were returned.

Count of number of long-term care admissions among child participants during 1 year prior to return of results using data obtained from the Electronic Medical Record. Coded by trained study staff. Admissions were summed across all participants.

Outcome measures

Measure	Parent/Caregiver Pre-visit Prep + Exome n=22 Participants Dyads (parent/caregiver + child) that are randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Parent/Caregiver Pre-visit Prep + Usual Care n=35 Participants Dyads (parent/caregiver + child) that are randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "usual care" arm are not offered additional exome sequencing.	Parent/Caregiver No Pre-visit Prep + Exome n=27 Participants Dyads (parent/caregiver + child) that are randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Parent/Caregiver No Pre-visit Prep + Usual Care n=31 Participants Dyads (parent/caregiver + child) that are randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "usual care" arm are not offered additional exome sequencing.
Number of Long-term Care Admissions Among Child Participants 1 Year Prior to Return of Results	0 Long-term care admissions	0 Long-term care admissions	4 Long-term care admissions	0 Long-term care admissions

PRIMARY outcome

Timeframe: 1 year after return of results

Population: This analysis includes the subset of child participants with 12 months of EHR data available before and after study results were returned.

Count of number of long-term care admissions among child participants during 1 year after return of results using data obtained from the Electronic Medical Record. Coded by trained study staff. Admissions were summed across all participants.

Outcome measures

Measure	Parent/Caregiver Pre-visit Prep + Exome n=22 Participants Dyads (parent/caregiver + child) that are randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Parent/Caregiver Pre-visit Prep + Usual Care n=35 Participants Dyads (parent/caregiver + child) that are randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "usual care" arm are not offered additional exome sequencing.	Parent/Caregiver No Pre-visit Prep + Exome n=27 Participants Dyads (parent/caregiver + child) that are randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Parent/Caregiver No Pre-visit Prep + Usual Care n=31 Participants Dyads (parent/caregiver + child) that are randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "usual care" arm are not offered additional exome sequencing.
Number of Long-term Care Admissions Among Child Participants 1 Year After Return of Results	0 Long-term care admissions	0 Long-term care admissions	3 Long-term care admissions	0 Long-term care admissions

PRIMARY outcome

Timeframe: 1 year prior to return of results

Population: This analysis includes the subset of child participants with 12 months of EHR data available before and after study results were returned.

Count of number of long-term care days among child participants during 1 year prior to return of results using data obtained from the Electronic Medical Record. Coded by trained study staff. Days were summed across all participants.

Outcome measures

Measure	Parent/Caregiver Pre-visit Prep + Exome n=22 Participants Dyads (parent/caregiver + child) that are randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Parent/Caregiver Pre-visit Prep + Usual Care n=35 Participants Dyads (parent/caregiver + child) that are randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "usual care" arm are not offered additional exome sequencing.	Parent/Caregiver No Pre-visit Prep + Exome n=27 Participants Dyads (parent/caregiver + child) that are randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Parent/Caregiver No Pre-visit Prep + Usual Care n=31 Participants Dyads (parent/caregiver + child) that are randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "usual care" arm are not offered additional exome sequencing.
Number of Long-term Care Days Among Child Participants 1 Year Prior to Return of Results	0 Long-term care days	0 Long-term care days	29 Long-term care days	0 Long-term care days

PRIMARY outcome

Timeframe: 1 year after return of results

Population: This analysis includes the subset of child participants with 12 months of EHR data available before and after study results were returned.

Count of number of long-term care days during 1 year after return of results using data obtained from the Electronic Medical Record. Coded by trained study staff. Days were summed across all participants.

Outcome measures

Measure	Parent/Caregiver Pre-visit Prep + Exome n=22 Participants Dyads (parent/caregiver + child) that are randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Parent/Caregiver Pre-visit Prep + Usual Care n=35 Participants Dyads (parent/caregiver + child) that are randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "usual care" arm are not offered additional exome sequencing.	Parent/Caregiver No Pre-visit Prep + Exome n=27 Participants Dyads (parent/caregiver + child) that are randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Parent/Caregiver No Pre-visit Prep + Usual Care n=31 Participants Dyads (parent/caregiver + child) that are randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "usual care" arm are not offered additional exome sequencing.
Number of Long-term Care Days Among Child Participants 1 Year After Return of Results	0 Long-term care days	0 Long-term care days	17 Long-term care days	0 Long-term care days

PRIMARY outcome

Timeframe: 1 year prior to return of results

Population: This analysis includes the subset of child participants with 12 months of EHR data available before and after study results were returned.

Count of number of ER visits during 1 year prior to return of results using data obtained from the Electronic Medical Record. Coded by trained study staff. Visits were summed across all participants.

Outcome measures

Measure	Parent/Caregiver Pre-visit Prep + Exome n=22 Participants Dyads (parent/caregiver + child) that are randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Parent/Caregiver Pre-visit Prep + Usual Care n=35 Participants Dyads (parent/caregiver + child) that are randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "usual care" arm are not offered additional exome sequencing.	Parent/Caregiver No Pre-visit Prep + Exome n=27 Participants Dyads (parent/caregiver + child) that are randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Parent/Caregiver No Pre-visit Prep + Usual Care n=31 Participants Dyads (parent/caregiver + child) that are randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "usual care" arm are not offered additional exome sequencing.
Number of ER Visits Among Child Participants 1 Year Prior to Return of Results	15 ER visits	25 ER visits	35 ER visits	35 ER visits

PRIMARY outcome

Timeframe: 1 year after return of results

Population: This analysis includes the subset of child participants with 12 months of EHR data available before and after study results were returned.

Count of number of ER visits during 1 year after return of results using data obtained from the Electronic Medical Record. Coded by trained study staff. Visits were summed across all participants.

Outcome measures

Measure	Parent/Caregiver Pre-visit Prep + Exome n=22 Participants Dyads (parent/caregiver + child) that are randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Parent/Caregiver Pre-visit Prep + Usual Care n=35 Participants Dyads (parent/caregiver + child) that are randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "usual care" arm are not offered additional exome sequencing.	Parent/Caregiver No Pre-visit Prep + Exome n=27 Participants Dyads (parent/caregiver + child) that are randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Parent/Caregiver No Pre-visit Prep + Usual Care n=31 Participants Dyads (parent/caregiver + child) that are randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "usual care" arm are not offered additional exome sequencing.
Number of ER Visits Among Child Participants 1 Year After Return of Results	10 ER visits	29 ER visits	20 ER visits	23 ER visits

PRIMARY outcome

Timeframe: 1 year prior to return of results

Population: This analysis includes the subset of child participants with 12 months of EHR data available before and after study results were returned.

Count of number of specialists visits during 1 year prior to return of results using data obtained from the Electronic Medical Record. Coded by trained study staff. Visits were summed across all participants.

Outcome measures

Measure	Parent/Caregiver Pre-visit Prep + Exome n=22 Participants Dyads (parent/caregiver + child) that are randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Parent/Caregiver Pre-visit Prep + Usual Care n=35 Participants Dyads (parent/caregiver + child) that are randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "usual care" arm are not offered additional exome sequencing.	Parent/Caregiver No Pre-visit Prep + Exome n=27 Participants Dyads (parent/caregiver + child) that are randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Parent/Caregiver No Pre-visit Prep + Usual Care n=31 Participants Dyads (parent/caregiver + child) that are randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "usual care" arm are not offered additional exome sequencing.
Number of Specialists Visits Among Child Participants 1 Year Prior to Return of Results	202 Specialist visits	665 Specialist visits	663 Specialist visits	332 Specialist visits

PRIMARY outcome

Timeframe: 1 year after return of results

Population: This analysis includes the subset of child participants with 12 months of EHR data available before and after study results were returned.

Count of number of specialists visits during 1 year after return of results using data obtained from the Electronic Medical Record. Coded by trained study staff. Visits were summed across all participants.

Outcome measures

Measure	Parent/Caregiver Pre-visit Prep + Exome n=22 Participants Dyads (parent/caregiver + child) that are randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Parent/Caregiver Pre-visit Prep + Usual Care n=35 Participants Dyads (parent/caregiver + child) that are randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "usual care" arm are not offered additional exome sequencing.	Parent/Caregiver No Pre-visit Prep + Exome n=27 Participants Dyads (parent/caregiver + child) that are randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Parent/Caregiver No Pre-visit Prep + Usual Care n=31 Participants Dyads (parent/caregiver + child) that are randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "usual care" arm are not offered additional exome sequencing.
Number of Specialists Visits Among Child Participants 1 Year After Return of Results	220 Specialist visits	556 Specialist visits	650 Specialist visits	273 Specialist visits

SECONDARY outcome

Timeframe: 4-6 weeks prior to clinic visit 1

Population: This analysis is conducted among the parent/caregiver participants only. The parent/caregiver completes this measure as a proxy for the child.

This is a single item measure from the Peds QL that will be answered on a scale of 0-4. Items are reversed scored and linearly transformed to a 0-100 scale (0=100, 1=75, 2=50, 3=25, 4=0), so that higher scores indicate better HRQOL for this single measure. This questionnaire will be self-administered at home.

Outcome measures

Measure	Parent/Caregiver Pre-visit Prep + Exome n=36 Participants Dyads (parent/caregiver + child) that are randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Parent/Caregiver Pre-visit Prep + Usual Care n=40 Participants Dyads (parent/caregiver + child) that are randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "usual care" arm are not offered additional exome sequencing.	Parent/Caregiver No Pre-visit Prep + Exome n=42 Participants Dyads (parent/caregiver + child) that are randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Parent/Caregiver No Pre-visit Prep + Usual Care n=50 Participants Dyads (parent/caregiver + child) that are randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "usual care" arm are not offered additional exome sequencing.
Initial Average Peds QL Score for "Missing School for Not Feeling Well"	70.8 score on a scale Standard Deviation 29.8	80.6 score on a scale Standard Deviation 20.5	65.5 score on a scale Standard Deviation 28.3	73 score on a scale Standard Deviation 28.7

SECONDARY outcome

Timeframe: 6 months after return of results

Population: This analysis is conducted among the parent/caregiver participants only. The parent/caregiver completes this measure as a proxy for the child.

This is a single item measure from the Peds QL that will be answered on a scale of 0-4. Items are reversed scored and linearly transformed to a 0-100 scale (0=100, 1=75, 2=50, 3=25, 4=0), so that higher scores indicate better HRQOL for this single measure. This questionnaire will be interviewer-administered by telephone.

Outcome measures

Measure	Parent/Caregiver Pre-visit Prep + Exome n=12 Participants Dyads (parent/caregiver + child) that are randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Parent/Caregiver Pre-visit Prep + Usual Care n=23 Participants Dyads (parent/caregiver + child) that are randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "usual care" arm are not offered additional exome sequencing.	Parent/Caregiver No Pre-visit Prep + Exome n=19 Participants Dyads (parent/caregiver + child) that are randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Parent/Caregiver No Pre-visit Prep + Usual Care n=20 Participants Dyads (parent/caregiver + child) that are randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "usual care" arm are not offered additional exome sequencing.
Final Average Peds QL Score for "Missing School for Not Feeling Well"	77.1 score on a scale Standard Deviation 23.8	82.6 score on a scale Standard Deviation 22.6	78.9 score on a scale Standard Deviation 23.3	81.3 score on a scale Standard Deviation 22.2

SECONDARY outcome

Timeframe: 4-6 weeks prior to clinic visit 1

Population: This analysis is conducted among the parent/caregiver participants only. The parent/caregiver completes this measure as a proxy for the child.

This is a single item measure from the Peds QL that will be answered on a scale of 0-4. Items are reversed scored and linearly transformed to a 0-100 scale (0=100, 1=75, 2=50, 3=25, 4=0), so that higher scores indicate better HRQOL for this single measure. This measure will be included in the questionnaire that will be self-administered at home.

Outcome measures

Measure	Parent/Caregiver Pre-visit Prep + Exome n=36 Participants Dyads (parent/caregiver + child) that are randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Parent/Caregiver Pre-visit Prep + Usual Care n=40 Participants Dyads (parent/caregiver + child) that are randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "usual care" arm are not offered additional exome sequencing.	Parent/Caregiver No Pre-visit Prep + Exome n=41 Participants Dyads (parent/caregiver + child) that are randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Parent/Caregiver No Pre-visit Prep + Usual Care n=50 Participants Dyads (parent/caregiver + child) that are randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "usual care" arm are not offered additional exome sequencing.
Initial Average Peds QL Score for "Missing School for Doctors Visit"	59.7 score on a scale Standard Deviation 28.4	65 score on a scale Standard Deviation 27.8	54.9 score on a scale Standard Deviation 27.2	60 score on a scale Standard Deviation 26.9

SECONDARY outcome

Timeframe: 6 months after return of results

Population: This analysis is conducted among the parent/caregiver participants only. The parent/caregiver completes this measure as a proxy for the child.

This is a single item measure from the Peds QL that will be answered on a scale of 0-4. Items are reversed scored and linearly transformed to a 0-100 scale (0=100, 1=75, 2=50, 3=25, 4=0), so that higher scores indicate better HRQOL for this single measure. This measure will be interviewer administered by telephone.

Outcome measures

Measure	Parent/Caregiver Pre-visit Prep + Exome n=12 Participants Dyads (parent/caregiver + child) that are randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Parent/Caregiver Pre-visit Prep + Usual Care n=23 Participants Dyads (parent/caregiver + child) that are randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "usual care" arm are not offered additional exome sequencing.	Parent/Caregiver No Pre-visit Prep + Exome n=19 Participants Dyads (parent/caregiver + child) that are randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Parent/Caregiver No Pre-visit Prep + Usual Care n=20 Participants Dyads (parent/caregiver + child) that are randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "usual care" arm are not offered additional exome sequencing.
Final Average Peds QL Score for "Missing School for Doctors Visit"	77.1 score on a scale Standard Deviation 23.8	82.6 score on a scale Standard Deviation 21.4	78.9 score on a scale Standard Deviation 23.3	82.5 score on a scale Standard Deviation 19.5

SECONDARY outcome

Timeframe: 4-6 weeks prior to clinic visit 1

Population: This analysis is conducted among the parent/caregiver participants only.

This is a single item measure that will be answered on a scale of 1-6 where 1=None, 2=Less than a week, 3=Between 1 and 4 weeks, 4= Between 4 and 8 weeks, 5=Between 8 and 12 weeks, 6=I stopped working altogether. Higher scores indicate greater amounts of work missed because of the child's condition or treatments. This measure will be included in the questionnaire that will be self-administered at home.

Outcome measures

Measure	Parent/Caregiver Pre-visit Prep + Exome n=62 Participants Dyads (parent/caregiver + child) that are randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Parent/Caregiver Pre-visit Prep + Usual Care n=70 Participants Dyads (parent/caregiver + child) that are randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "usual care" arm are not offered additional exome sequencing.	Parent/Caregiver No Pre-visit Prep + Exome n=61 Participants Dyads (parent/caregiver + child) that are randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Parent/Caregiver No Pre-visit Prep + Usual Care n=72 Participants Dyads (parent/caregiver + child) that are randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "usual care" arm are not offered additional exome sequencing.
Initial Amount of Work Missed Because of Child's Condition or Treatments Score	2.3 score on a scale Standard Deviation 1.7	2.4 score on a scale Standard Deviation 1.9	2.5 score on a scale Standard Deviation 1.8	2 score on a scale Standard Deviation 1.4

SECONDARY outcome

Timeframe: 6 months after return of results

Population: This analysis is conducted among the parent/caregiver participants only.

This is a single item measure that will be answered on a scale of 1-6 where 1=None, 2=Less than a week, 3=Between 1 and 4 weeks, 4= Between 4 and 8 weeks, 5=Between 8 and 12 weeks, 6=I stopped working altogether. Higher scores indicate greater amounts of work missed because of the child's condition or treatments. This measure will be interviewer-administered by telephone.

Outcome measures

Measure	Parent/Caregiver Pre-visit Prep + Exome n=20 Participants Dyads (parent/caregiver + child) that are randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Parent/Caregiver Pre-visit Prep + Usual Care n=38 Participants Dyads (parent/caregiver + child) that are randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "usual care" arm are not offered additional exome sequencing.	Parent/Caregiver No Pre-visit Prep + Exome n=26 Participants Dyads (parent/caregiver + child) that are randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Parent/Caregiver No Pre-visit Prep + Usual Care n=28 Participants Dyads (parent/caregiver + child) that are randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "usual care" arm are not offered additional exome sequencing.
Final Amount of Work Missed Because of Child's Condition or Treatments Score	2.3 score on a scale Standard Deviation 1.7	2.3 score on a scale Standard Deviation 1.8	2.5 score on a scale Standard Deviation 1.8	2.6 score on a scale Standard Deviation 2

SECONDARY outcome

Timeframe: 4-6 weeks prior to clinic visit 1

Population: This analysis is conducted among the parent/caregiver participants only.

This is a single item measure that will be answered on a scale of 1-5, where 1=Not at all, 2=A little bit, 3=Somewhat, 4=Quite a bit, 5=Very much. Higher scores indicate greater difficulty finishing normal work (including both work outside of the home and housework) because of child's condition or treatments. This measure will be included in the questionnaire that will be self-administered at home.

Outcome measures

Measure	Parent/Caregiver Pre-visit Prep + Exome n=62 Participants Dyads (parent/caregiver + child) that are randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Parent/Caregiver Pre-visit Prep + Usual Care n=70 Participants Dyads (parent/caregiver + child) that are randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "usual care" arm are not offered additional exome sequencing.	Parent/Caregiver No Pre-visit Prep + Exome n=62 Participants Dyads (parent/caregiver + child) that are randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Parent/Caregiver No Pre-visit Prep + Usual Care n=72 Participants Dyads (parent/caregiver + child) that are randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "usual care" arm are not offered additional exome sequencing.
Initial Difficulty With Finishing Normal Work (Including Both Work Outside of the Home and Housework) Because of Child's Condition or Treatments Score	2.7 score on a scale Standard Deviation 1.4	2.5 score on a scale Standard Deviation 1.3	2.7 score on a scale Standard Deviation 1.2	2.4 score on a scale Standard Deviation 1.2

SECONDARY outcome

Timeframe: 2 weeks after return of results

Population: This analysis is conducted among the parent/caregiver participants only.

This is a single item measure that will be answered on a scale of 1-5, where 1=Not at all, 2=A little bit, 3=Somewhat, 4=Quite a bit, 5=Very much. Higher scores indicate greater difficulty finishing normal work (including both work outside of the home and housework) because of child's condition or treatments. This measure will be interviewer-administered by telephone.

Outcome measures

Measure	Parent/Caregiver Pre-visit Prep + Exome n=20 Participants Dyads (parent/caregiver + child) that are randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Parent/Caregiver Pre-visit Prep + Usual Care n=28 Participants Dyads (parent/caregiver + child) that are randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "usual care" arm are not offered additional exome sequencing.	Parent/Caregiver No Pre-visit Prep + Exome n=23 Participants Dyads (parent/caregiver + child) that are randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Parent/Caregiver No Pre-visit Prep + Usual Care n=31 Participants Dyads (parent/caregiver + child) that are randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "usual care" arm are not offered additional exome sequencing.
Intermediate Difficulty With Finishing Normal Work (Including Both Work Outside of the Home and Housework) Because of Child's Condition or Treatments Score	1.9 score on a scale Standard Deviation 1.1	2 score on a scale Standard Deviation 1.1	2.3 score on a scale Standard Deviation 1.3	2.1 score on a scale Standard Deviation 1.1

SECONDARY outcome

Timeframe: 6 months after return of results

Population: This analysis is conducted among the parent/caregiver participants only.

This is a single item measure that will be answered on a scale of 1-5, where 1=Not at all, 2=A little bit, 3=Somewhat, 4=Quite a bit, 5=Very much. Higher scores indicate greater difficulty finishing normal work (including both work outside of the home and housework) because of child's condition or treatments. This measure will be interviewer-administered by telephone.

Outcome measures

Measure	Parent/Caregiver Pre-visit Prep + Exome n=20 Participants Dyads (parent/caregiver + child) that are randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Parent/Caregiver Pre-visit Prep + Usual Care n=38 Participants Dyads (parent/caregiver + child) that are randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "usual care" arm are not offered additional exome sequencing.	Parent/Caregiver No Pre-visit Prep + Exome n=26 Participants Dyads (parent/caregiver + child) that are randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Parent/Caregiver No Pre-visit Prep + Usual Care n=28 Participants Dyads (parent/caregiver + child) that are randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "usual care" arm are not offered additional exome sequencing.
Final Difficulty With Finishing Normal Work (Including Both Work Outside of the Home and Housework) Because of Child's Condition or Treatments Score	2.1 score on a scale Standard Deviation 1.4	2.1 score on a scale Standard Deviation 1.3	2.1 score on a scale Standard Deviation 1.1	2.1 score on a scale Standard Deviation 1.2

SECONDARY outcome

Timeframe: 2 weeks after return of results

Population: This analysis is only performed in the subset of parent/caregiver participants whose child was randomized to receive exome sequencing and received an interpretation of their exome data from a provider.

Concordance between caregiver and provider reports of whether patients' diagnostic results were positive, negative, or uncertain. Coded as a dichotomous variable: 0=discordant diagnostic reports; 1=concordant diagnostic reports. Results are given as the number of parent/caregiver participant responses for each group that were concordant with the provider's diagnostic interpretation of the exome results.

Outcome measures

Measure	Parent/Caregiver Pre-visit Prep + Exome n=11 Participants Dyads (parent/caregiver + child) that are randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Parent/Caregiver Pre-visit Prep + Usual Care n=18 Participants Dyads (parent/caregiver + child) that are randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "usual care" arm are not offered additional exome sequencing.	Parent/Caregiver No Pre-visit Prep + Exome Dyads (parent/caregiver + child) that are randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Parent/Caregiver No Pre-visit Prep + Usual Care Dyads (parent/caregiver + child) that are randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "usual care" arm are not offered additional exome sequencing.
Percent Concordance of Caregiver and Provider Reports of Genetic or Genomic Test Results	9 participants	12 participants	—	—

SECONDARY outcome

Timeframe: 4-6 weeks prior to clinic visit 1

Population: This analysis is conducted among the parent/caregiver participants only.

Self-efficacy scale, which measures caregivers' confidence in communicating with their child's provider. Self-administered as part of the intake questionnaire. Measured with adapted Decision Self Efficacy Scale (developed by O'Connor, 1995). Adapted wording from the original scale so items refer to general communication, as opposed to a specific decision. Shorted scale to 7 items from 11 since not all items were applicable to this study. Item responses will be coded as: 1=Not at all confident; 5=Very confident. Mean scores will be calculated by summing the response values and dividing by the total number of items (7). Higher scores indicate higher confidence in communicating with their child's provider.

Outcome measures

Measure	Parent/Caregiver Pre-visit Prep + Exome n=72 Participants Dyads (parent/caregiver + child) that are randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Parent/Caregiver Pre-visit Prep + Usual Care n=70 Participants Dyads (parent/caregiver + child) that are randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "usual care" arm are not offered additional exome sequencing.	Parent/Caregiver No Pre-visit Prep + Exome n=62 Participants Dyads (parent/caregiver + child) that are randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Parent/Caregiver No Pre-visit Prep + Usual Care n=73 Participants Dyads (parent/caregiver + child) that are randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "usual care" arm are not offered additional exome sequencing.
Mean Baseline Self Efficacy Score	4.5 score on a scale Standard Deviation 0.5	4.5 score on a scale Standard Deviation 0.6	4.6 score on a scale Standard Deviation 0.4	4.6 score on a scale Standard Deviation 0.5

SECONDARY outcome

Timeframe: Immediately before Clinic Visit 1

Population: This analysis is conducted among the parent/caregiver participants only.

Self-efficacy scale, which measures caregivers' confidence in communicating with their child's provider. Self-administered as part of the intake questionnaire. Measured with adapted Decision Self Efficacy Scale (developed by O'Connor, 1995). Adapted wording from the original scale so items refer to general communication, as opposed to a specific decision. Shorted scale to 7 items from 11 since not all items were applicable to this study. Item responses will be coded as: 1=Not at all confident; 5=Very confident. Mean scores will be calculated by summing the response values and dividing by the total number of items (7). Higher scores indicate higher confidence in communicating with their child's provider.

Outcome measures

Measure	Parent/Caregiver Pre-visit Prep + Exome n=20 Participants Dyads (parent/caregiver + child) that are randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Parent/Caregiver Pre-visit Prep + Usual Care n=28 Participants Dyads (parent/caregiver + child) that are randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "usual care" arm are not offered additional exome sequencing.	Parent/Caregiver No Pre-visit Prep + Exome n=24 Participants Dyads (parent/caregiver + child) that are randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Parent/Caregiver No Pre-visit Prep + Usual Care n=31 Participants Dyads (parent/caregiver + child) that are randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "usual care" arm are not offered additional exome sequencing.
Mean Pre-Clinic Visit 1 Self Efficacy Score	4.6 score on a scale Standard Deviation 0.5	4.4 score on a scale Standard Deviation 0.8	4.5 score on a scale Standard Deviation 0.5	4.4 score on a scale Standard Deviation 0.6

SECONDARY outcome

Timeframe: 2 weeks after return of results

Population: This analysis is conducted among the parent/caregiver participants only.

Subscale of the Feeling About genomiC Testing Results measure assesses caregivers' level of uncertainty about their child's genetic test results (developed by Gallego et al., 2014). Interviewer administered by telephone. Item responses will be coded as: 1=Not at all; 2=A little; 3=Somewhat; 4=A good deal; 5=A great deal. Mean scores will be calculated by summing the response values and dividing by the total number of items (3). Higher scores indicate greater uncertainty about their child's genetic test results.

Outcome measures

Measure	Parent/Caregiver Pre-visit Prep + Exome n=20 Participants Dyads (parent/caregiver + child) that are randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Parent/Caregiver Pre-visit Prep + Usual Care n=24 Participants Dyads (parent/caregiver + child) that are randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "usual care" arm are not offered additional exome sequencing.	Parent/Caregiver No Pre-visit Prep + Exome n=23 Participants Dyads (parent/caregiver + child) that are randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Parent/Caregiver No Pre-visit Prep + Usual Care n=21 Participants Dyads (parent/caregiver + child) that are randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "usual care" arm are not offered additional exome sequencing.
Post-Return of Results Mean FACToR Uncertainty Subscale Score	1.7 score on a scale Standard Deviation 0.6	2.4 score on a scale Standard Deviation 1.1	2.3 score on a scale Standard Deviation 1	2.2 score on a scale Standard Deviation 1.1

SECONDARY outcome

Timeframe: Final follow-up, up to approximately three years after clinic visit 1

Population: Child participants for whom sufficient data was available to determine vital status at follow-up

Based on NC Vital Statistics, the child's vital status will be reported as living or deceased.

Outcome measures

Measure	Parent/Caregiver Pre-visit Prep + Exome n=28 Participants Dyads (parent/caregiver + child) that are randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Parent/Caregiver Pre-visit Prep + Usual Care n=39 Participants Dyads (parent/caregiver + child) that are randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "usual care" arm are not offered additional exome sequencing.	Parent/Caregiver No Pre-visit Prep + Exome n=35 Participants Dyads (parent/caregiver + child) that are randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Parent/Caregiver No Pre-visit Prep + Usual Care n=36 Participants Dyads (parent/caregiver + child) that are randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "usual care" arm are not offered additional exome sequencing.
Vital Status at Final f/u Living	28 Participants	38 Participants	35 Participants	36 Participants
Vital Status at Final f/u Deceased	0 Participants	1 Participants	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Final follow-up, up to approximately three years after clinic visit 1

Population: One child participant died during the course of the study follow-up period, unrelated to the study intervention. Cause of death was multiple organ failure and septic shock.

Child causes of death related to the primary condition based on NC Vital Statistics, child causes of death will be reported as related to the disorder of the child or not related to the disorder of the child.

Outcome measures

Measure	Parent/Caregiver Pre-visit Prep + Exome Dyads (parent/caregiver + child) that are randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Parent/Caregiver Pre-visit Prep + Usual Care n=1 Participants Dyads (parent/caregiver + child) that are randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "usual care" arm are not offered additional exome sequencing.	Parent/Caregiver No Pre-visit Prep + Exome Dyads (parent/caregiver + child) that are randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Parent/Caregiver No Pre-visit Prep + Usual Care Dyads (parent/caregiver + child) that are randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "usual care" arm are not offered additional exome sequencing.
Number of Child Participants With Causes of Death Unrelated to the Study	0 Participants	1 Participants	0 Participants	0 Participants

Adverse Events

Child Pre-visit Prep + Exome

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Child Pre-visit Prep + Usual Care

Serious events: 1 serious events

Other events: 0 other events

Deaths: 1 deaths

Child No Pre-visit Prep + Exome

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Child No Pre-visit Prep + Usual Care

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Serious adverse events

Measure	Child Pre-visit Prep + Exome n=53 participants at risk Dyads (parent/caregiver + child) that are randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Child Pre-visit Prep + Usual Care n=70 participants at risk Dyads (parent/caregiver + child) that are randomized to the "pre-visit prep" arm receive a study packet with educational materials and a question prompt list. The parent/caregiver is instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to the child's clinic visit 1 appointment. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "usual care" arm are not offered additional exome sequencing.	Child No Pre-visit Prep + Exome n=59 participants at risk Dyads (parent/caregiver + child) that are randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "exome" arm are offered exome sequencing in addition to tests ordered by the physician at that visit. The parent/caregiver may decline for their child to have exome sequencing at this point.	Child No Pre-visit Prep + Usual Care n=68 participants at risk Dyads (parent/caregiver + child) that are randomized to the "no pre-visit prep" arm receive a mailed card reminding them about their upcoming clinic visit. During the clinic visit 1 evaluation, the physician orders any tests deemed clinically appropriate. After completing the clinic visit, dyads that are randomized to the "usual care" arm are not offered additional exome sequencing.
General disorders Septic Shock	0.00% 0/53 • Up to 3 years	1.4% 1/70 • Number of events 1 • Up to 3 years	0.00% 0/59 • Up to 3 years	0.00% 0/68 • Up to 3 years

Other adverse events

Adverse event data not reported

Additional Information

Jonathan Berg, MD, PhD

University of North Carolina at Chapel Hill

Phone: 919-966-7043

Email: jonathan_berg@med.unc.edu

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place