# Design and rationale of “Antecedents and correlates of well-being in young adults with congenital heart disease in the Boston Circulatory Arrest Study (BCAS-Adult)”

Michelle Gurvitz, Alexandra Roseman, Lori Sahakian, Johanna Calderon, Ai Wern Chung, Donna Duva, Borjan Gagoski, Clare Hobson, Jee Won Kang, Adrienne Kovacs, et al.

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## To cite this version:

Michelle Gurvitz, Alexandra Roseman, Lori Sahakian, Johanna Calderon, Ai Wern Chung, et al. Design and rationale of “Antecedents and correlates of well-being in young adults with congenital heart disease in the Boston Circulatory Arrest Study (BCAS-Adult)”. American Heart Journal, 2025, 289, pp.127-137. 10.1016/j.ahj.2025.05.012. hal-05086069

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# Design and rationale of "Antecedents and correlates of well-being in young adults with congenital heart disease in the Boston Circulatory Arrest Study (BCAS-Adult)"

Michelle Gurvitz¹, Alexandra Roseman², Lori Sahakian³, Johanna Calderon⁴, Ai Wern Chung⁵, Donna Duva⁶, Borjan Gagoski⁷, Clare Hobson⁸, Jee Won Kang⁹, Adrienne Kovacs¹⁰, Patricia Ibeziako¹¹, Michael Rivkin¹², David Bellinger¹¹, David Wypij¹³, Patricia Ellen Grant⁷, Jane W Newburger⁶

¹ Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts. Electronic address: Michelle.Gurvitz@cardio.chboston.org.

² Department of Psychology, Long Island University, Brooklyn, New York.

³ University of Massachusetts Chan Medical School, Worcester, Massachusetts.

⁴ National Institute of Health and Medical Research, INSERM, U1046 PhyMedExp, Cardiac Neurodevelopment Team, Montpellier, France; Division of Psychiatry and Behavioral Sciences, Harvard Medical School, Boston Children's Hospital, Boston, Massachusetts.

⁵ Fetal-Neonatal Neuroimaging and Developmental Science Center, Boston Children's Hospital; Division of Newborn Medicine, Department of Medicine, Boston Children's Hospital, Boston, Massachusetts.

⁶ Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts.

⁷ Fetal-Neonatal Neuroimaging and Developmental Science Center, Boston Children's Hospital; Department of Radiology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.

⁸ Loyola University, Stritch School of Medicine, Chicago, IL.

⁹ Department of Psychology, University of California, Los Angeles, Los Angeles, CA.

¹⁰ Equilibria Psychological Health, Toronto, Ontario, Canada.

¹¹ Division of Psychiatry and Behavioral Sciences, Harvard Medical School, Boston Children's Hospital, Boston, Massachusetts.

¹² Division of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA.

¹³ Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.

**Keywords:**
brain MRI; congenital heart disease; mental health; neuropsychological outcomes; transposition of the great arteries; well-being.

E-mail address:

Michelle.Gurvitz@cardio.chboston.org
# Abstract

**Objectives:**

Neurodevelopmental challenges are common among children and adolescents with congenital heart disease (CHD), affecting up to 50% of patients, and recent data suggests they are also present in adulthood. Longitudinal predictors of these challenges in adults have not been studied. The goal of this study was to assess well-being in adults with d-transposition of the great arteries (d-TGA) who had been enrolled in the Boston Circulatory Arrest Study (BCAS) where developmental follow-up was reported throughout childhood and adolescence with brain MRI imaging correlation in adolescence. Well-being was defined through neuropsychological, behavioral and mental health outcomes, quality of life, and social and educational attainment. Brain MRI metrics were also collected.

**Design and enrollment:**

Study participants were age 26-33 years and recruited from the BCAS cohort (n= 171 in neonatal cohort, n=139 age 16 years). We assessed neuropsychological, psychiatric, and lifestyle outcomes, and brain MRI features. In this paper, we detail the BCAS-Adult protocols for the study assessments and data collected, approaches, and challenges encountered. Key analyses proposed from this study and its outcomes are outlined including comparisons to local controls or national norms and longitudinal outcome predictors.

**Conclusions:**

The results from this study will elucidate neuropsychological performance, mental health status, and brain MRI patterns of the BCAS cohort in young adulthood, as well as the predictors and trajectory of these outcomes beginning in early infancy. Study results can inform screening and assessment, anticipatory guidance, and interventions to give children with CHD the best chance to maximize success in adulthood.
Introduction

Congenital heart disease (CHD) is the most common birth defect in the United States (US) and affects approximately 0.8% of live births. 1 Now, more than 85% of CHD patients survive to adulthood, with adults out-numbering children living with CHD. 2 Such dramatic improvements in life expectancy have exposed long-term cardiac and noncardiac morbidities, shifting the goals of care beyond survival to include dimensions of overall well-being. 2 Higher than expected rates of anxiety, depression, post-traumatic stress disorder, social difficulties, lower educational attainment, and underemployment are reported in adults with CHD, some studies have also described neurocognitive profiles and abnormalities in brain structure and function. 3–12 However, no recent studies have been able to assess longitudinal profiles and risk factors from early infancy that may underlie adverse adult psychosocial and cognitive outcomes.

In children and adolescents with CHD, neuropsychological and mental health impairments are the most frequent and often the most distressing comorbidity; over half of children with moderate or complex CHD carry a risk of executive function impairments and other neurodevelopmental deficits. 13, 14 Executive functions develop throughout childhood and adolescence, and are refined in young adulthood, paralleling the ongoing maturation of prefrontal structures and fronto-parietal and subcortical networks during the third decade of life. Executive function impairments in adolescents with CHD are associated with magnetic resonance imaging (MRI) connectome findings of increased modularity and small worldness and reduced global efficiency, suggesting that brain structure may be an important imaging biomarker for neuropsychological deficits. 13, 15 Executive dysfunction may have ongoing debilitating effects on measures of well-being including school achievement, employment, social adaptation, health maintenance, and quality of life. 16-19

The Boston Circulatory Arrest Study (BCAS) at Boston Children's Hospital (BCH) enrolled newborns with D-TGA from 1988 to 1992 and randomly assigned them to 1 of 2 methods of surgical vital organ support, deep hypothermic circulatory arrest or low-flow cardiopulmonary bypass, for their neonatal arterial switch operation. 20 Studied through the perioperative period and then serially at ages 1, 4, 8, and 16 years, comprehensive neurodevelopmental and mental health follow-up was conducted and reported throughout development, including a brain MRI at age 16. 21-29

As this cohort reached adulthood, there was an opportunity to explore adult outcomes and their predictors. The primary goal of the Antecedents and Cor- relates of Well-being in Young Adults with Congenital Heart Disease in the Boston Circulatory Arrest Study (BCAS-Adult) was to assess adult well-being by evaluating long-term neuropsychological and mental health out- comes and evaluating the concurrent relationship of executive function with quality of life, neuropsychological function, mental health, social relatedness, independence and educational attainment, in young adults with D- TGA. The study also aimed to determine potential relationships between these functional domains and MRI- derived measures of brain structure, function, and connectivity. In analyses using the comprehensive longitudinal data collected in this cohort, we plan to elucidate the association of adult well-being with patient factors, medical history, and earlier measures of childhood executive function, neuropsychological performance, mental health, and adolescent neuroimaging.
# Design and methods

## Project design and setting

Between 2017 and 2021, we invited adults with D-TGA initially enrolled in the BCAS study to return for evaluation. 12 BCAS-Adult was interrupted by the COVID-19 pandemic, resulting in adaptations to the assessment protocols. In the initial design, participants underwent a comprehensive onsite evaluation including neuropsychological assessment, psychiatric interview, behavioral and mental health questionnaires, and a brain MRI over a 2-day visit. Due to the COVID-19 pandemic, study visits were adjusted for validated remote administration except for the MRI portion of the study (Table 1 and Table 2). The BCH Institutional Review Board approved all study procedures.

## Sample and recruitment

D-TGA participants: Between 1988 and 1992, 171 neonates with D-TGA who underwent the arterial switch operation (ASO) enrolled in the Boston Circulatory Arrest Study, a prospective, randomized single-center trial to evaluate neurodevelopmental effects of 2 different cardiopulmonary bypass strategies. 20 All infants were randomly assigned to a predominant method of vital organ support (deep hypothermic circulatory arrest or low-flow cardiopulmonary bypass) using an alpha-stat pH strategy and crystalloid hemodilution to a hematocrit of ~20%. Details on postoperative management were presented in Bellinger et al. 23 Eligibility criteria of participants as neonates to BCAS included a diagnosis of D-TGA with either intact ventricular septum or ventricular septal defect (VSD), and an ASO performed by 3 months of age. Patients were excluded for birth weight of < 2.5 kilograms, a recognizable syndrome of congenital anomalies, an extra-cardiac anomaly of greater than minor severity, previous cardiac surgery, associated cardio-vascular anomalies requiring reconstruction of the aortic arch, or additional open surgical procedures. Of the 171 patients enrolled in infancy, 155 and 139 had participated in follow-up evaluations at ages 8 years and 16 years, respectively. For BCAS-Adult, the surviving D-TGA patients who completed the 8- or 16-year follow-up study and resided in the US were contacted by a letter to participants and parent(s). If there was no response, LexisNexisTM data analytics was used to obtain more recent contact information.

Control participants: We recruited a referent group of young adults to establish a comparison sample for the brain MRI analysis and for select portions of the neuropsychological evaluation that lacked population-based normative data. Control participants were recruited through local flyers and online classified advertisements. Exclusion criteria were the same as those used in the NIH study of normal brain development 23 and included a lack of fluency in English, a history of CHD, and known risk factors for brain disorders (e.g., intrauterine exposure to brain altering substances, history of a closed head injury with a loss of consciousness, diagnosis of a psychiatric disorder). Control participants were selected to approximate the age, sex, and handedness of the D-TGA participants and were screened for contraindications to the brain MRI.
## Data collection procedures

Patient factors and prior medical history for D-TGA participants were obtained from earlier BCAS data files. Re-search assistants obtained interim medical history by interview and review of medical records, including cardiac surgical procedures or catheterizations, the most recent appointment with a cardiologist, and questions to assess the New York Heart Association Functional Class. Control participants completed a separate medical history form. All participants were measured for height, weight, and head circumference. General data collection procedures were similar between D-TGA and control participants. Prior to the COVID-19 pandemic in March 2020, D-TGA participants traveled for an in-person 2-day study visit at BCH. Day 1 included informed consent, study questionnaires (Table 1), the Structured Clinical Interview for DSM-5 Disorders (SCID-RV-5), and the brain MRI. Local safety measures were in place with the BCH psychiatry team should the participant have expressed concerns or endorsed suicidal ideation during the SCID-RV-5. Day 2 included in-person neuropsychological assessments with a study team neuropsychologist. After neuropsychological testing was complete, a closing meeting was held with the participant, the research assistant, and a study investigator to review any questions or concerns. The control group followed a similar but shorter testing procedure that occurred over 1 day and included study questionnaires (Table 1), select neuropsychological testing, and the brain MRI.

<table><caption>**Table 1.** BCAS-adult non-MRI data collection before and after March 2020</caption><thead><tr><th rowspan="2">Measure</th><th rowspan="2">Construct(s) Measured</th><th colspan="2">Prior to March 2020</th><th colspan="2">After March 2020</th></tr><tr><th>d-TGA</th><th>Control</th><th>d-TGA</th><th>Control</th></tr></thead><tbody><tr><td>Medical history</td><td>Medical history, cardiac procedures, other medical conditions</td><td>X</td><td>X</td><td>X</td><td>X</td></tr><tr><td>Mental health</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Structured clinical interview for DSM-5 disorders, research version (DSM5-RV)</td><td>ADHD, PTSD, depression, anxiety</td><td>X</td><td></td><td>X</td><td></td></tr><tr><td>NIH toolbox emotional battery</td><td>Psychological well-being, social relationships, stress and self-efficacy</td><td>X</td><td></td><td>X</td><td></td></tr><tr><td>Connors' adult ADHD rating scales, screening version (CAARS-S:SV)</td><td>ADHD</td><td>X</td><td>X</td><td>X</td><td>X</td></tr><tr><td>Other patient reported outcomes</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Linear analog scale (LAS)</td><td>Quality of life</td><td>X</td><td>X</td><td>X</td><td>X</td></tr><tr><td>Quality of life scale (QOLS)</td><td>Quality of life</td><td>X</td><td>X</td><td>X</td><td>X</td></tr><tr><td>Hospital anxiety and depression scale (HADS)</td><td>Anxiety, Depression</td><td>X</td><td>X</td><td>X</td><td>X</td></tr><tr><td>Health behavior scale, sex behavior scale</td><td>Risk-taking behavior</td><td>X</td><td>X</td><td>X</td><td>X</td></tr><tr><td>Pittsburgh sleep quality index (PSQI)</td><td>Sleep</td><td>X</td><td>X</td><td>X</td><td>X</td></tr><tr><td>Brief illness perception questionnaire</td><td>Adult illness severity/health status</td><td>X</td><td></td><td>X</td><td></td></tr><tr><td>The resilience scale</td><td>Resilience</td><td>X</td><td>X</td><td>X</td><td></td></tr><tr><td>COVID-19 impact scale</td><td>Impact of COVID-19 on quality of life</td><td></td><td></td><td>X</td><td>X</td></tr><tr><td>Neuropsychological battery</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Wechsler adult intelligence scale, 4th edition (WAIS-IV)</td><td>Intellectual functioning</td><td>X</td><td>X</td><td>X</td><td>X</td></tr><tr><td>Delis-Kaplan executive function system (DKEFS)</td><td>Executive functions</td><td>X</td><td></td><td>X</td><td></td></tr><tr><td>Wechsler individual achievement test, 3rd edition (WIAT-III)</td><td>Academic achievement</td><td>X</td><td></td><td>X</td><td></td></tr><tr><td>Reading the mind in the eyes</td><td>Social cognition</td><td>X</td><td>X</td><td>X</td><td>X</td></tr><tr><td>Wechsler memory scale IV (WMS-IV)</td><td>Memory</td><td>X</td><td></td><td>X</td><td></td></tr><tr><td>Prospective-retrospective memory questionnaire (PRMQ)</td><td>Memory</td><td>X</td><td>X</td><td>X</td><td>X</td></tr><tr><td>Advanced clinical solutions for WAIS-IV and WMS-IV</td><td>Social cognition</td><td>X</td><td>X</td><td></td><td></td></tr><tr><td>Rey-Osterrieth complex figure test</td><td>Visual-spatial skills</td><td>X</td><td></td><td>X</td><td></td></tr><tr><td>Iowa gambling task (IGT)</td><td>Decision-making</td><td>X</td><td>X</td><td>X</td><td>X</td></tr><tr><td>Autism spectrum quotient (ASQ)</td><td>Social cognition</td><td>X</td><td>X</td><td>X</td><td>X</td></tr><tr><td>Behavior rating inventory of executive function for adults (BRIEF-A)</td><td>Every-day life executive functions</td><td>X</td><td>X</td><td>X</td><td>X</td></tr><tr><td>NIH toolbox cognitive battery</td><td>Executive functions, episodic memory, processing speed</td><td>X</td><td></td><td>X</td><td></td></tr></tbody></table>
<table><caption>**Table 2.** Order of administration for BCAS-adult data collection before and after March 2020</caption><thead><tr><th>Phase of study</th><th>Visit day</th><th>d-TGA participant</th><th>Control participant</th></tr></thead><tbody><tr><td rowspan="10">Before March 2020</td><td rowspan="10">Day 1</td><td>Informed consent</td><td>Informed consent</td></tr><tr><td>Medical history</td><td>Medical history</td></tr><tr><td>Height, weight, head circumference</td><td>Height, weight, head circumference</td></tr><tr><td>Urine-pregnancy test (if applicable)</td><td>Urine-pregnancy test (if applicable)</td></tr><tr><td>BRIEF-A</td><td>BRIEF-A</td></tr><tr><td>ASQ</td><td>ASQ</td></tr><tr><td>CAARS-S:SV</td><td>REDCap surveys</td></tr><tr><td>NIH Toolbox</td><td>Neuropsychological battery (see Table 1)</td></tr><tr><td>SCID-RV-5</td><td>Brain MRI</td></tr><tr><td>REDCap surveys</td><td>Brain MRI</td></tr><tr><td rowspan="10">After March 2020</td><td rowspan="10">Day 2</td><td>Neuropsychological battery (see Table 1)</td><td>N/A</td></tr><tr><td>Wrap-up meeting</td><td></td></tr><tr><td>Electronic informed consent</td><td>Electronic informed consent</td></tr><tr><td>Medical history</td><td>Medical history</td></tr><tr><td>ASQ</td><td>ASQ</td></tr><tr><td>CAARS-S:SV</td><td>REDCap surveys</td></tr><tr><td>SCID-RV-5</td><td></td></tr><tr><td>REDCap surveys</td><td></td></tr><tr><td>Neuropsychological battery via Zoom (see Table 1)</td><td>Neuropsychological battery via Zoom (see Table 1)</td></tr><tr><td>BRIEF-A</td><td></td></tr><tr><td>NIH toolbox</td><td></td></tr><tr><td rowspan="2">Day 3</td><td>Brain MRI (if in Massachusetts)</td><td>Brain MRI in person within 2-week period of completing day 2</td></tr><tr><td>IGT testing via Zoom</td><td>Radiology team obtains height, weight, head circumference</td></tr><tr><td>Day 4</td><td>N/A</td><td>Complete IGT testing via Zoom</td></tr></tbody></table>

ASQ, autism spectrum questionnaire; BRIEF-A, behavior rating inventory of executive function for adults; CAARS-S:SV, Connors' adult ADHD rating scales, screening version; DSM-5-RV, structured clinical interview for DSM-5 disorders, research version; IGT, Iowa gambling task.
In-person study visits were paused in March 2020 due to the COVID-19 pandemic. Remote testing procedures were developed and approved by the IRB over the sub- sequent 6 months and implemented in October 2020. To comply with public health and BCH guidelines during the COVID-19 pandemic, all study visits were conducted via a secure teleconferencing platform (BCH ZoomTM) except for brain MRI. Remote D-TGA case participation included 2-4 sessions scheduled no more than 2 weeks apart from day 1 of the first remote session. The first remote session included administration of study questionnaires and the SCID-5-RV. Prior to starting the SCID-5-RV interview, remote participants were asked to provide an emergency contact for safety measures and screened with the Columbia Suicide Severity Rating Scale (CSSRS). 30 The CSSRS was not given prior to COVID-19 as the SCID-5-RV was administered in-person and risk for suicide could be assessed at the time of study visit. The next study session included a neuropsychological assessment conducted virtually, in which remote versions of the original in-person battery were administered. Neuropsychological tests that were not validated for remote administration were excluded from the battery ( Table 1 ). Test administrators and order of assessment administration were also shifted for some aspects of the neuropsychological evaluation ( Table 2 ). Only in-state participants completed the in- person visit for the brain MRI (scheduled on a separate day) to comply with BCH and state guidelines regarding travel. Remote participation for con- trols included 2 to 4 sessions scheduled no more than 2 weeks from Day 1. Remote procedures for controls were identical to those of cases, and the brain MRI was scheduled for a separate day within 2 weeks after testing was completed.

Mental health and lifestyle evaluation

The primary assessment of mental health of D-TGA participants was the SCID-5-RV. D-TGA participants also completed the NIH Toolbox Emotion Battery, 31 which assessed emotion in 4 domains (psychological well-being, social relationships, stress and self-efficacy, and negative affect), as well as the Brief Illness Perception Questionnaire, which inquired about the participant's perception of the impact of their illness on daily activities. 26 Both D-

TGA and control participants completed a battery of self- reported questionnaires evaluating quality of life, anxiety and depression symptoms, risk-taking behaviors, sleep, health status, and resilience ( Table 1 ). 32-45 The COVID- 19 Impact Scale 46 was added to the battery of surveys after March 2020 and administered to all participants to evaluate the effects of the pandemic on quality of life.

Neuropsychological assessment

Neuropsychological batteries included measures of global intellectual functioning, executive functioning, decision-making, processing speed, social cognition and autism spectrum disorder traits, visual-spatial skills, mem- ory, and academic achievement (i.e., reading skills). The battery was designed to assess neurodevelopmental do- mains consistently reported to be affected in youth and adults with complex CHD. Most of the tests are nation- ally standardized, but tests for which national standards were not available or where the testing was important for group comparisons were also administered to the control group ( Table 1 ).
## Executive functioning

The Delis-Kaplan Executive Function System (D-KEFS) assessed inhibitory control, cognitive flexibility, planning abilities, and hypothesis generation within verbal and spatial modalities. 47 It includes 9 subtests: Trail-Making Test, Verbal Fluency, Design Fluency, Color-Word Interference, Sorting Test, Twenty Questions, Word Context, Tower, and Proverb. The expected population mean is 10 and SD is 3 for each subtest. A composite score averages the patient's standard score on the subtests and was our main executive function endpoint.

The NIH Toolbox Assessment of Neurological and Behavioral Function executive function battery was also administered to D-TGA participants. It is a set of computerized assessments that measure inhibitory control (Flanker Inhibitory Control and Attention Test), working memory (List Sorting Working Memory Test), and cognitive flexibility (Dimensional Change Card Sort Test). 31 The NIH Toolbox Pattern Comparison Processing Speed was used to assess the time it takes to process a set amount of information. 31 We also used the Picture Sequence Memory Test as a measure of episodic memory and the Picture Vocabulary Test to evaluate receptive vocabulary. The expected population mean is 100 and SD is 15 for each test.

The Behavior Rating Inventory of Executive Function for Adults (BRIEF-A) was administered to provide self-reports on executive functions in the home and school/work settings. 32 The BRIEF-A yields 2 broad indexes (Behavioral Regulation, Metacognition) and includes 2 validity scales (Inconsistency, Negativity). The Global Executive Composite (GEC) score was the main endpoint used. Specific Index and subscale scores were also examined as secondary endpoints. Scores are provided in T-scores with an expected population mean of 50 and SD of 10 for each subtest.

The Iowa Gambling Task (IGT) assessed the ability to make decisions under conditions of uncertainty, a higher-order executive function ability. 33

## Social cognition and autism spectrum

The Reading the Mind in the Eyes Test (revised) was given to assess mental state attribution. 36 In the computerized test, a person looks at 36 photographs of the region around the eyes and chooses 1 of 4 words of emotional valence that best describes what the person in the picture is thinking or feeling (e.g., nervous, interested, surprised, etc.).

The Advanced Clinical Solutions for WAIS-IV and WMS IV (ACS) assessed aspects of social cognition, such as affect labeling, affect recognition from faces and prosody, identification of sarcasm, and the ability to verbalize intent of a speaker. 48

The Autism Spectrum Quotient provided information about 5 domains of autism spectrum disorder (social skills, communication skills, imagination, attention to detail, and attention switching/tolerance of change). 37 A total score ranges from 0 to 50, with higher scores indicating more autism traits and scores > 25 showing a risk for autism spectrum disorders.
Memory

The NIH Toolbox Picture Sequence Memory Test evaluated episodic memory. 31 It involves recalling a series of illustrated objects and activities or increasing length that are presented via computer. The participant was asked to recall the sequence of pictures that is presented over 2 learning trials. The expected population mean is 100 and SD is 15.

The Wechsler Memory Scale IV (WMS-IV) provided a comprehensive evaluation of memory abilities, including auditory, visual, immediate, and delayed memory. 38 We administered the standard battery including 10 sub- tests. Five indexes were recorded: Immediate Memory, Delayed Memor y, Auditor y Memor y, Visual Memor y, and Visual Working Memory. Indexes have a mean of 100 and SD of 15.

*Visual-spatial Skills:* The Re y-Osterrieth Complex Figure Test 49 assessed immediate, short-
term, and delayed recall. The test involves copying and then reproducing a complex figure.

*Intelligence and Academic Achievement:* The Wechsler Adult Intelligence Scale-Fourth Edition (WAIS-IV) was given to participants as an intelligence test. 39 In addition to Full-Scale IQ, the test yields 4 index scores (Verbal Comprehension, Perceptual Reasoning, Working Memory, and Processing Speed). Our main endpoint was the Full-Scale IQ (expected mean of 100, SD of 15). Secondary outcomes included all index scores as well as individual subtests. Participants also completed the Wechsler Individual Achievement Test, 3rd edition (WIAT-III) Reading (expected mean of 100, SD of 15).

Brain magnetic resonance imaging

MRI scans were performed on a Siemens Skyra 3 Tesla scanner equipped with a 64-channel head coil. Our protocol included:

1. Structural T1 -weighted images were obtained us- ing a motion corrected Magnetization-Prepared RApid Gradient-Echo sequence (mocoMPRAGE) with prospective motion correction. 50 This sequence provided anatomical information which was used to obtain brain volumetrics and cortical parcellations. Total acquisition time was 6 minutes.

2. Structural T2 -weighted images were obtained with a 3D Sampling Perfection with Application optimized Contrast using different flip angle Evolution (SPACE) sequence. This provided anatomical information that was also used for cortical parcellations. Total acquisition time was 4.5 minutes.

3. Diffusion-weighted imaging (DWI) was performed using a Simultaneous Multi-Slice (SMS) sequence with an Echo-Planar Imaging (EPI) readout. 51 DWI provided quantitative measures of water diffusivity and its directionality in tissue (including white and gray matter) and was used to model structural connectivity in the brain. A total of 60 gradient directions were acquired (20 per $b = 1,000, 2,000$ and $3,000$ s/mm$^2$), and $5$ $b = 0$ s/mm$^2$ volumes. In addition, 2 pairs of $b = 0$ s/mm$^2$ volumes were acquired in the anterior-posterior and posterior anterior (AP/PA) direction for susceptibility distortion correction. Total acquisition time was 10.5 minutes.
4. Resting-state functional MRI (rsfMRI) was obtained with an SMS EPI sequence. rsfMRI allowed the measurement of temporal correlations in spontaneous blood oxygen level-dependent (BOLD) signals and served as a measure of functional connectivity. A total of 425 volumes were acquired. An additional 150 volumes were acquired in the opposite PA direction for susceptibility distortion correction. Total acquisition time was 11.5 minutes.

Sequences 1 to 4 were qualitatively assessed during scanning, and the sequence was repeated as necessary if excessive motion was detected. Additional sequences in our protocol included volumetric spectroscopic imaging, susceptibility weighted imaging, and a pseudo-continuous arterial spin labeling acquisition. All sequences and parameters for the entire protocol are detailed in Table 3. Total time of the MRI protocol is 60 minutes.

<table><caption>**Table 3.** Parameters for all sequences in the BCAS-Adult neuroimaging MRI protocol</caption><thead><tr><th>MRI sequence</th><th>Sequence type</th><th>Repetition time (TR)</th><th>Time to echo (TE)</th><th>Flip angle (°)</th><th>Voxel size</th><th>Field-of-view (FOV)</th><th># of slices</th><th>Acceleration factor</th><th>Duration (m – minutes; s – seconds)</th><th>Other parameters</th></tr></thead><tbody><tr><td>Structural T<sub>1</sub>-weighted</td><td>Motion mitigated magnetization-prepared RAPID gradient echo with prospective motion correction (mocoMPRAGE)</td><td>2,500 ms</td><td>2.24, 4.1, 5.96, 7.82 ms</td><td>7</td><td>1 × 1 × 1 mm<sup>3</sup></td><td>256 × 256 mm<sup>2</sup></td><td>176</td><td>R<sub>GRAPPA</sub> – 2</td><td>6 m, 9 s</td><td>Inversion time – 1,310 ms; 4 contrasts which are reconstructed in a root mean square way to produce 1 volume. Low resolution volumetric EPI-based navigators at 8 mm isotropic voxels were interleaved with the MPRAGE readouts for real-time motion information that was used for prospective motion correction<sup>51</sup></td></tr><tr><td>Structural T<sub>2</sub>-weighted</td><td>3D sampling perfection with application optimized contrast using different flip angle evolution (SPACE)</td><td>3,200 ms</td><td>351 ms</td><td>-</td><td>1 × 1 × 1 mm<sup>3</sup></td><td>256 × 256 mm<sup>2</sup></td><td>176</td><td>R<sub>GRAPPA</sub> – 2</td><td>4 m, 21 s</td><td>Turbo factor – 278; Echo train length – 827 ms</td></tr><tr><td>Diffusion-weighted imaging</td><td>Bipolar, simultaneous multislice (SMS) echo-planar imaging (EPI) readout<sup>51</sup></td><td>5,700 ms</td><td>114 ms</td><td>20</td><td>2 × 2 × 2 mm<sup>3</sup></td><td>256 × 256 mm<sup>2</sup></td><td>74</td><td>R<sub>GRAPPA</sub> – 2; R<sub>SMS</sub> – 2</td><td>7 m, 24 s</td><td>Partial Fourier encoding – 6/8; Echo-spacing – 0.7 ms. 20 gradient directions at 3 b-value shells (b – 1,000, 2,000, and 3,000 s/mm<sup>2</sup>). Five volumes at b – 0 s/mm<sup>2</sup>. Two pairs of were also acquired in AP/PA direction (duration – 1 m 30 s/ pair).</td></tr><tr><td>Resting-state functional</td><td>SMS gradient-echo EPI</td><td>1,130 ms</td><td>30 ms</td><td>65</td><td>3 × 3 × 3 mm<sup>3</sup></td><td>234 × 234 mm<sup>2</sup></td><td>51</td><td>R<sub>SMS</sub> – 3</td><td>8 m, 19 s</td><td>Echo-spacing – 0.51 ms. A total of 425 volumes were acquired. An additional 150 volumes were acquired in the opposite PA direction (duration – 3 m, 10 s).</td></tr><tr><td>Volumetric spectroscopic imaging</td><td>Accelerated 3D spectroscopy imaging with spiral k-space trajectories<sup>61, 62</sup></td><td>1,800 ms</td><td>30 ms</td><td>90</td><td>12.3 × 12.3 × 12.3 mm<sup>3</sup> – 2cc<sup>3</sup></td><td>X, Y – 160 mm; Z – 100.8mm; F – 1.2 KHz</td><td>8</td><td>-</td><td>7 m, 48 s</td><td>Number of averages – 8; Matrix size (x, y, z, f) – [13, 13, 8, 512], zero-padded to [16, 16, 8, 512]; An additional spectroscopy scan with no water suppression, with 1 average and TR – 1 s (duration – 36 s).</td></tr><tr><td>Susceptibility-weighted imaging</td><td>Gradient-recalled echo sequence</td><td>28 ms</td><td>20 ms</td><td>15</td><td>0.57 × 0.57 × 1.5 mm<sup>3</sup></td><td>X – 256 mm; Y – 200 mm; Z – 156 mm</td><td>112</td><td>R<sub>GRAPPA</sub> – 2</td><td>4 m, 57 s</td><td>Post labeling delay – 1,500 ms; Max G<sub>x</sub> – 6 mT/m; duration of the labeling RF train – 1,800 ms</td></tr><tr><td>Pseudo-continuous arterial spin labeling</td><td>Singe-shot EPI</td><td>4,200 ms</td><td>13 ms</td><td>90</td><td>3.8 × 3.8 × 5 mm<sup>3</sup></td><td>240 × 240 × 100 mm<sup>3</sup></td><td>20</td><td>-</td><td>5 m, 40 s</td><td></td></tr></tbody></table>

Images were quality-controlled off-line via a combination of visual assessment and appropriate software depending on the sequence. For example, assessment of the structural T1- and T2-weighted data used the Free surfer tool, 52 and included protocols outlined by the ENIGMA Consortium (enigma.usc.edu) and by QA-
tools (github.com/Deep-MI/qatools-python). Assessment of the DWI data included use of FMIRB Software Library's 53 "EDDY QC" frame-work, 54 in which pre- and postprocessed images were compared as part of our quality-control.

## Statistical methods and data analysis

The BCAS-Adult study evaluated the concurrent relationship of executive function to adult well-being measured by neuropsychological, behavioral, and mental health outcomes and the relationship of these domains to structural and functional brain MRI measures. To complete this evaluation, comparisons in outcomes between the D-TGA participants and either the control participants or population norms will be made. As most study endpoints, including neuropsychological outcomes and brain volumetrics, are measured outcomes, the analyses will include 1- and 2-sample *t*-tests, correlations, multivariable linear regression, and smoothing techniques. These analyses will be accompanied by graphical exploration of the data and screening for outlying and influential observations. Data transformations or nonparametric methods will be used whenever parametric assumptions are violated. For analyses of binary outcomes, including psychiatric diagnoses and clinical abnormalities on structural brain MRI, exact methods and logistic regression will be used. For analyses of ordinal outcomes, such as test findings coded by severity, exact trend tests and proportional odds regression models will be used. Appropriate multivariable regression model building techniques and careful consideration of possible confounding and effect modification will be performed. These methods have been used successfully in prior iterations of the BCAS study. 21-23, 27, 29, 55, 56 We will also compare sociodemographic and medical factors and neuropsychological outcomes in childhood and adolescence between D-TGA subjects who returned versus those who did not. If differences are found, weighted analyses to account for potential sample bias will be conducted with weights determined by bootstrapped classification trees.

With 100 D-TGA participants and 2-sided 0.05 level tests, we have 80% power to detect correlations of 0.28 between executive functions and other factors and 80% power to detect an effect size of 0.29 SD units for comparing executive functions with a standardization sample. With 100 D-TGA participants and 50 controls, we have 80% power to detect an effect size of 0.49 SD units (approximately 1/2 of a standard deviation). At age 16, the D-KEFS composite score was correlated with WIAT Reading (r = 0.78) and Math (r = 0.75) composites, General Memory Index (r = 0.66), and Reading the Mind in the Eyes (r = 0.54), among other measures, and was 0.47 SD units lower than the standardization sample. Thus, we expect high power to detect correlations and comparisons of interest at age 26-33 years.

Primary and secondary outcome variables have been specified to establish priorities among endpoints for hypothesis testing. For analysis purposes, the primary executive function outcome is the D-KEFS composite score. Primary adult well-being measures included Reading the Mind in the Eyes (social cognition), the NIH Toolbox Picture Sequence Memory Test (memory), and the WAIS-IV Full-Scale IQ (intelligence and academic achievement). As
a result, adjustment for multiple comparisons will not be made across the neuropsychological
domains, though we will look for consistency across findings and compare scores across
domains to identify types and levels of vulnerability. Other outcome variables will be used to
establish, with greater clarity and specificity, the nature and basis of neuropsychological
sequelae, mental health status, and neuroimaging studies of the D-TGA adults vs
standardization samples or controls and in associations across different measures with
executive function. When concern about inflation of Type I error rates across tests is
warranted, omnibus tests (comparing the multiple end- points as joint dependent variables
compared to the standardization or control sample means) will be run. If an omnibus test
indicates a significant difference between the D-TGA group and the standardization or control
samples, its source will be sought by comparing groups on the individual components.

Structural and functional brain MRI findings will be cor- related with the neuropsychological findings. The MRI results will focus on connectivity measures such as global efficiency, modularity, and hubs (which are key principles in connectomics 15, 57, 58) to understand brain organization in relation to D-TGA outcomes. Throughout, care- ful consideration will be given to the possible effects of sex, age, and socioeconomic status of study participants on outcomes and associations.

Longitudinal and clinical-risk stratification models for adult quality of life and other well-
being outcomes as a function of patient factors, medical history, prior neuropsychological
testing, mental health, and imaging will be developed using multivariable linear and logistic
regression, generalized additive models, and classification and regression trees. Given the
number of variables be- ing considered, appropriate consideration of collinearity, data
reduction (principal components, factor analysis), clustering, and use of bootstrapping and
cross-validation to ensure that goodness-of-fit estimates are not overly optimistic will be
made. For outcomes measured repeatedly over time, longitudinal models for change and
tracking will be fit.

Summary

Adults with CHD represent a growing population within the US and the world and this
population will continue to grow as survival of CHD remains high. While survival has
improved, these adults remain at risk for cardiac complications and comorbid cognitive,
psychosocial and lifestyle challenges. 3, 5, 6, 59, 60 Youth with CHD are known to be at
increased risk for neurodevelopmental deficits and mental health conditions. There remains a
large gap in knowledge between known deficits in childhood CHD and effects on components
of adult well-being. We pro- posed this longitudinal study of the BCAS cohort in adult- hood
to explore associations with adult CHD patient well-being.

The onset of the global COVID-19 pandemic in the middle of the study caused a 5-month
delay in enrollment and a requirement to rework our study methodology to meet the
challenges of isolation, travel restrictions, and masking. Fortunately, we were able to work
with the hospital for a secure remote platform for consent and test administration and we
performed several tests remotely which improved our recruitment for neuropsychological and
mental health testing. Being an in-person test only and subject to travel restrictions, the MRI
portion of the study faced the greatest impact and lower than predicted recruitment. Despite
these restrictions, this remains the largest longitudinal cohort of CHD patients studied for
neuropsychological and psychiatric outcomes.
Although this study was limited to patients with D-TGA, the childhood neuropsychological phenotype of D-TGA has been similar to that of children born with other forms of cyanotic heart disease operated in early infancy. The Boston Circulatory Arrest Study thus lays the ground- work for additional studies of broader CHD populations to better inform screening, guidance, and interventions in youth. By better understanding the well-being, neuropsychological function, mental health status, and brain MRI patterns of adults with CHD, combined with neurocognitive and MRI predictors of these outcomes from childhood, we can elucidate avenues for intervention to give persons with CHD the best chance to maximize success across the lifespan.

## Funding

The study was supported by the National Heart, Lung and Blood Institute (NIH R01HL135061). The authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the paper and its final contents.

## Declaration of Competing Interest

The authors have no additional conflicts of interest for this study.

## CRediT authorship contribution statement

**Michelle Gurvitz:**

Writing -review & editing, Writing -original draft, Supervision, Project administration, Methodology, Investigation, Funding acquisition, Formal analysis, Data curation, Conceptualization. **Alexandra Roseman:** Writing -review & editing, Writing -original draft, Project administration, Data curation. **Lori Sahakian:** Writing -review & editing, Data curation, Project administration **Johanna Calderon:** Writing -review & editing, Writing -original draft, Supervision, Formal analysis, Data curation, Conceptualization. **Ai Wern Chung:** Writing -review & editing, Writing -original draft, Investigation, Formal analysis, Data curation. **Donna Duva:** Supervision, Resources, Project administration, Data curation. **Borjan Gagoski:** Data curation, Formal analysis, Supervision, Conceptualization. **Clare Hobson:** Writing -review & editing, Project administration, Data curation. **Jee Won Kang:** Writing -review & editing, Project administration, Formal analysis, Data curation. **Adrienne Kovacs:** Writing -review & editing, Supervision, Methodology, Conceptualization. **Patricia Ibeziako:** Writing -review & editing, Writing -original draft, Supervision, Investigation, Formal analysis, Data curation. **Michael Rivkin:** Writing -review & editing, Supervision, Methodology, Data curation, Conceptualization. **David Bellinger:** Writing -review & editing, Supervision, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. **David Wypij:** Writing -review & editing, Supervision, Methodology, Data curation, Conceptualization. **Patricia Ellen Grant:**
Writing -review & editing, Writing -original draft, Supervision, Project administration, Methodology, Funding acquisition, Formal analysis, Data curation, Conceptualization. **Jane W. Newburger:** Writing -review & editing, Supervision, Methodology, Data curation, Conceptualization.

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