What was the research about?
Urea cycle disorders, or UCDs, are rare health disorders in which the body can’t get rid of ammonia. Ammonia is a substance the body produces as it breaks down protein in food. Ammonia builds up in the bloodstream as a result of UCDs. This build-up can lead to brain damage, disability, or death.
One way to treat UCDs is with medical management. This treatment involves a low-protein diet and medicine that helps the body break down ammonia. Another way is with liver transplant.
In this study, the research team looked at the medical histories of patients with severe UCDs. The team wanted to learn if the health of patients who had liver transplants and those on medical management differed over time. They also wanted to see how families and doctors made the difficult decision about which treatment to use.
What were the results?
The research team didn’t find major differences in survival, mental ability, or quality of life between patients who had liver transplants and those on medical management. For patients who had liver transplant sooner, the team saw a trend toward higher family quality of life and better mental ability. But the data didn’t show these effects for sure.
In interviews, the research team learned that families and doctors considered many personal, social, and medical factors when deciding on treatment.
What did the research team do?
The research team looked at medical data from 187 patients with UCD. All went to the hospital for UCD within 28 days of birth. The team collected medical histories from a UCD database and also from patients referred by study partners.
To make sure the study looked at patients who were comparable, the team matched liver transplant and medically managed patients based on their
- Decade of birth
- UCD type
- Method of diagnosis
- Type of symptoms at diagnosis
- Age when symptoms started
- Age at first health problem due to ammonia, and highest ammonia level during that health problem
All patients with the most severe UCDs had liver transplants, and all patients with the least severe UCDs had medical management. The research team excluded these patients because they couldn’t be matched up. The final data set included 109 patients.
To learn about how they decided which treatment to choose, the research team also interviewed parents and healthcare professionals.
Patient advocates, researchers, and healthcare professionals provided feedback throughout the study.
What were the limits of the study?
The low number of matched patients in the study limited how well the research team could see if the two groups differed.
Future studies could continue to look into how treatments for UCDs affect patients’ health.
How can people use the results?
Patients and their doctors can use these results when considering treatment for UCDs.
To compare survival rate, neurocognitive function, and quality of life in patients with neonatal onset urea cycle disorders (UCDs) who received liver transplants versus those managed medically
|Design||Observational: cohort study|
|Population||187 patients with neonatal-onset UCDs|
|Outcomes||Survival rate, neurocognitive function, quality of life|
|Timeframe||Up to 10-year follow-up for study outcomes|
UCDs are rare hereditary disorders that cause deficiencies in the liver’s ability to process ammonia. As a result, ammonia builds up in the bloodstream, which can lead to brain damage, disability, or death.
This retrospective cohort study compared survival rate, neurocognitive function, and quality of life in patients with neonatal onset UCDs who received either liver transplant or medical management. Medical management includes a low-protein diet to reduce ammonia in the body and medicine to improve the processing of ammonia. The choice between liver transplant and medical management involves complex trade-offs between transplantation risks and ongoing demands of dietary management and timely treatment of ammonia elevations that occur during illnesses and infections.
The research team analyzed more than 10 years of natural history data for 187 patients with neonatal onset UCDs. The team extracted study outcome data from the Urea Cycle Disorders Consortium, part of the Rare Disease Clinical Research Network. They supplemented the data with information from patients recruited by the team’s research partners. Patients in the study developed UCD symptoms within 28 days of birth and had one of the four most severe forms of neonatal onset UCDs.
The research team used propensity scoring to match liver transplant patients with medically managed patients with similar risk profiles. Matching characteristics included patients’ decade of birth, UCD type, method of diagnosis, type of symptoms at diagnosis, age at UCD onset, age at first hyperammonemic event (HAE), and maximum ammonia level during the first HAE. The team included patients’ pretransplant outcome data in the medical management group. The team excluded patients with the most and least severe cases of UCD because those with the most severe cases all had liver transplants and those with the least severe cases were all managed medically. The final analytic sample included 109 patients.
Patient advocates, researchers, and clinicians helped recruit patients and provided feedback throughout the study.
Among the 109 patients, those who received liver transplants and those managed medically did not differ significantly in survival rate, neurocognitive function, or quality of life. Although not significant, analyses revealed a general trend toward higher family quality of life and better neurocognitive function among patients who received liver transplants sooner.
Qualitative analyses identified the clinical, social, personal, and systemic factors that families and clinicians considered when choosing between liver transplant and medical management.
The low number of comparable patients in the study limited the research team’s ability to draw conclusions on the effect of liver transplant on study outcomes.
Conclusions and Relevance
The study did not find significant differences in survival rate, neurocognitive function, or quality of life among patients with neonatal onset UCDs who received liver transplants and those managed medically.
Future Research Needs
Future research could continue to examine the health outcomes of UCD treatment options.
Final Research Report
View this project's final research report.
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Peer review of PCORI-funded research helps make sure the report presents complete, balanced, and useful information about the research. It also assesses how the project addressed PCORI’s Methodology Standards. During peer review, experts read a draft report of the research and provide comments about the report. These experts may include a scientist focused on the research topic, a specialist in research methods, a patient or caregiver, and a healthcare professional. These reviewers cannot have conflicts of interest with the study.
The peer reviewers point out where the draft report may need revision. For example, they may suggest ways to improve descriptions of the conduct of the study or to clarify the connection between results and conclusions. Sometimes, awardees revise their draft reports twice or more to address all of the reviewers’ comments.
Peer reviewers commented and the researchers made changes or provided responses. Those comments and responses included the following:
- The reviewers commented on the lack of statistically significant results and warned the researchers not to attribute the lack of significance entirely to lower than expected sample size, since statistical significance in a larger sample was likely but might not be clinically meaningful. The reviewers cautioned against inferring too much from suggestive but not significant findings. The researchers acknowledged that it is tricky to convey an appropriate message from a study that failed to produce statistically significant results, but they felt that it would be a disservice to merely state that results were not significant and leave it at that. For example, they felt it was important to point out when large expected differences did not materialize, while for other parameters observed differences suggested clinically meaningful findings that can be tested in the future in larger, comparable samples. The researchers felt that it was important to lay out suggestive results and observations, with caveats about their significance, for a community in search of answers about best practices where there currently are none.
- The reviewers commented that the researchers did not achieve their third aim, which was to develop a strategy for disseminating findings. They suggested the researchers do more to come up with practical and useful applications of their findings. The researchers said the results of their quantitative analysis were complex, nuanced, and sometimes surprising. They expected to find more clinical benefits to liver transplantation than they did, but they said some of the challenges they faced, mainly that their two groups were not as comparable as they wished, reduced their ability to draw conclusions. The researchers explained that instead they would be collaborating with patients and families to determine the best ways to share study information with the community of patients with urea cycle disorders.
Conflict of Interest Disclosures
Study Registration Information
^Mendel Tuchman, MD, was the original Principal Investigator on this project.
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