Comparing Treatment Options for Urea Cycle Disorders [Internet]

Excerpt

Background: Urea cycle disorders (UCDs) are rare genetic metabolic disorders resulting in deficiencies in liver enzymes required to detoxify ammonia. UCDs cause brain damage, cognitive delays, and death. There are 2 major treatment options for UCDs: (1) medical management (MM) with diet and medications and (2) liver transplantation (LT). Evidence comparing the outcomes of MM vs LT is sparse. Additionally, no research has been conducted on how families of patients with UCD choose between MM and LT.

Objectives:

1. Aim 1: To study 2 UCD patient cohorts, 1 treated with MM and the other treated by LT, comparing survival rate, neurocognitive function, and patient-reported quality of life (QOL).

2. Aim 2: To examine, through a representative sample of patient families and their providers, how UCD treatment decisions are made, describing the factors that influence a family's decision to continue conservative MM or proceed to an LT.

3. Aim 3: To develop a strategy to disseminate the study findings from aim 1 that align with the decision-making process illustrated through aim 2 and that is responsive to the expressed needs of patients with UCDs and their families.

Methods: We used a mixed-method comparative cohort study design using quantitative research methods in aim 1 and qualitative research methods in aim 2. Aim 1 data for MM and LT comparison were obtained primarily from the UCD Consortium natural history study. Eligible participants included neonatal-onset patients with LT-qualifying UCD subtypes. To maintain comparability and temporal alignment, we assigned an index age in the MM group that was comparable with the transplant age in the LT group. Data analyses relied on causal inference methods, covariate balanced propensity scoring, and risk-set matching to identify comparable MM and LT groups. These analyses estimated the average treatment effect in the treated (ATT) for survival, QOL, and neuropsychological development. In aim 2, individual and focus group interviews with caregivers and providers were used to determine drivers of treatment choice. Thematic content and framework analysis techniques were used to identify patterns within the data, explore relationships between key themes, and build a framework describing how UCD treatment decisions are reached. For aim 3, we developed a dissemination strategy after reviewing the aim 2 results and considering points to be emphasized for patients, families, and providers.

Results:

1. Aim 1: Despite selecting 283 participants with neonatal-onset UCDs who we believed to be transplant candidates, severity in the LT cohort was greater than that in the MM cohort, leading to considerable nonoverlap. To provide fair comparisons, analyses were thus restricted to patients of comparable intermediate severity, resulting in the exclusion of up to 41.7% (78/187) of the original sample, depending on the method. The aim 1 results therefore lack the statistical power needed to adequately test our hypotheses; however, they are useful for generating better-informed hypotheses to be evaluated in future research. The main expected advantage of LT was the absence of hyperammonemic events (HAEs) following transplant, whereas the MM group continued to experience HAEs. This benefit came at a price: ~40% of the LT cohort experienced complications, and ~8% to 10% required retransplantation. Causal inference analyses found no comparable LT benefit in survival, patient QOL, or neuropsychological development. However, positive differences between the LT and MM cohorts were consistently observed across different analytical methods in family QOL (3.6-30.3) and in intelligence quotient and global performance scores, especially in older children (7.8-16.7), suggest a potential LT advantage.

2. Aim 2: We elucidated factors influencing treatment choices for families affected by UCD and developed a novel conceptual framework interlinking the factors that together inform each family's perception of the risks and benefits of MM vs LT.

3. Aim 3: Guided by a new understanding of the experience of patients with UCD, we developed a strategy to disseminate the complex evidence produced by this study.

Conclusions: The aim 1 results confirmed that LT serves as a virtual cure for HAEs in neonatal-onset UCDs. However, this pronounced metabolic effect did not translate into evidence of the expected large posttransplant improvement in outcomes. Nevertheless, there were indications of beneficial effects on family QOL and on cognitive outcomes, including improved effects with earlier age of LT without evidence of increased mortality risk. The aim 2 results provided a clearer understanding of the factors that drive decision-making among UCD caregivers and providers. With an understanding of the aim 1 and 2 results, providers may be better positioned to anticipate and respond to the needs of families affected by UCD.

Limitations: The aim 1 study sample was limited to comparisons of neonatal survivors of intermediate severity connected to main metabolic centers. Follow-up losses and low rates of participation in neuropsychological testing led to considerable missing data. We cannot rule out potential bias from unknown and potentially unbalanced markers of severity. For aims 2 and 3, caregivers were recruited primarily through a UCD patient advocacy organization and may not represent the perspectives of the broader UCD community, including those of families of deceased children, whom we were unable to interview.