Choosing between medical management and liver transplant in urea cycle disorders: A conceptual framework for parental treatment decision-making in rare disease.

Urea cycle disorders (UCD) are rare inherited metabolic disorders caused by deficiencies of enzymes and transporters required to convert neurotoxic ammonia into urea. These deficiencies cause elevated blood ammonia, which if untreated may result in death, but even with optimal medical management, often results in recurrent brain damage. There are two major treatments for UCD: medical management or liver transplantation. Both are associated with mortality and morbidity but the evidence comparing outcomes is sparse. Thus, families face a dilemma: should their child be managed medically, or should they undergo a liver transplant? To (a) describe the factors that contribute to treatment choice among parents of children diagnosed with UCD and to (b) organise these factors into a conceptual framework that reflects how these issues interrelate to shape the decision-making experience of this population. Utilising grounded theory, qualitative data were collected through semi-structured interviews with parents (N = 35) and providers (N = 26) of children diagnosed with UCD and parent focus groups (N = 19). Thematic content analysis and selective and axial coding were applied. The framework highlights the life-cycle catalysts that frame families' personal perceptions of risks and benefits and describes the clinical, personal, social, and system factors that drive treatment choice including disease severity, stability, and burden, independence, peer experiences, and cost, coverage and access to quality care. Findings equip providers with evidence upon which to prepare for productive patient interactions about treatment options. They also provide a foundation for the development of patient-centred outcome measures to better evaluate effectiveness of treatments in this population.

INTRODUCTION

Urea cycle disorders (UCD) are rare inherited disorders of metabolism caused by deficiencies of one of six enzymes and two transporters required for ammonia detoxification and urea synthesis. Disruption of the urea cycle can result in hyperammonaemia which precipitates cytotoxic brain oedema and may result in death. In those who recover from acute hyperammonaemia, intellectual and developmental disabilities are common.1, 2, 3, 4, 5, 6

Despite significant improvements in medical management (MM) following the wider availability of alternative pathway medications, most individuals with UCD remain at high risk of hyperammonaemia.7, 8 Thus, an increasing number of patients have been undergoing liver transplantation (LT) as a procedure that “cures” the hyperammonaemia.9, 10, 11, 12, 13 However, LT is a complicated surgical procedure, which carries risk of mortality and morbidity and requires a life‐long regimen of immunosuppression.

Most patients with UCD are at elevated risk for disability or death at various times in their lives.14 This risk, although always present, is not easily quantified, especially among mild‐moderately affected patients. This ambiguity can make treatment decisions, like if and/or when to pursue LT, particularly challenging for patients. In other medical conditions, the decision to perform transplantation is often made because organ function has failed. However, for patients with UCD, the decision can be more complex as outcomes from medical therapy vary widely and because transplantation is ideally initiated when patients are stable rather than critically ill. There is also limited empirical evidence to support clinical guidance on treatment alternatives for patients with UCD, introducing ambiguity and personal judgement to the process of making treatment decisions. Clinicians involved in the diagnosis and treatment of UCD have long relied on non‐comparative research findings in combination with expert opinion to guide clinical practice and treatment counselling for these disorders.15 Thus, they have been unable to help patients and families weigh available treatment alternatives against key health outcomes like survival, neurocognitive status, and quality of life.3, 6, 16, 17, 18, 19, 20 A more detailed description of currently available treatment guidance and evidence to support treatment decision making in UCD is available in the appendix (Table A1).

Despite its complexity, no research has been conducted on how families of UCD patients make treatment choices in the absence of definitive evidence and clinical guidance, and the issues that influence their decision to pursue one option over another. This article describes the findings from an adapted grounded theory study that combines qualitative interview and focus group data to examine the decision‐making experience of families affected by UCD to (a) identify key factors families consider in evaluating and reaching a treatment choice and (b) build a conceptual framework that explores how these factors interrelate to drive treatment decision making in this population.

METHODS

Approach

This study utilised an adapted grounded theory approach, borrowing from Strauss and Corbin's systematic procedures for grounded theory.21

Data sources and collection

Qualitative data were collected from parents of children affected by UCD (N = 35) and their clinical providers (N = 26) through semi‐structured phone interviews lasting 45 to 90 minutes. Two in‐person parent focus groups (N = 19), lasting 90 minutes each, were conducted to validate interview findings. Interviews and focus groups were recorded and transcribed verbatim for use in analysis.

Interview guides were developed by integrating findings from a limited relevant evidence base on parent health care decision‐making in paediatric illnesses where transplant is offered as a treatment.22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37 Guides were augmented with additional information from key informants including patient advocates and metabolic physicians. They were revised in response to patient review.

Sampling

Stratified purposeful sampling was used to recruit an initial pool of parent participants whose children were born in the United States after 1996 (ie, post‐FDA approval of alternative pathway medications) and diagnosed with one of four UCDs (argininosuccinate lyase deficiency [ALD], argininosuccinate synthetase deficiency [ASD], carbamylphosphate synthetase deficiency [CPSI], and ornithine transcarbamylase deficiency [OTC]) for which LT is a consideration. Parent recruitment was conducted through the National Urea Cycle Disorders Foundation (NUCDF) via listserv, social media, discussions boards, and one‐on‐one outreach. Parent participants varied in terms of their child's (a) disease severity and (b) treatment course at the time of recruitment. Stratified sampling was also utilised to recruit a national cross‐section of UCD providers through the Urea Cycle Disorders Consortium (UCDC) listserv and via one‐on‐one outreach, reflecting variation in location and provider type. After an initial round of recruitment, subsequent study participants were selected through theoretical sampling. Characteristics of interview and focus group participants are summarised in Tables 1 and 2. Limitations of our study sample are discussed in the appendix (Table A2).

Table 1

Characteristics of urea cycle disorder (UCD) parent interview and focus group participants

		Interviews (N = 35)	Focus groups (N = 19)	Total (N = 54)
Gender‐caretaker	Male	11% (4)	21% (4)	15% (8)
	Female	89% (31)	79% (15)	85% (46)
Sex‐child	Male	53% (19)	63% (12)	56% (30)
	Female	47% (16)	37% (7)	44% (24)
Age‐caretakera	21‐29	9% (3)	6% (1)	7% (4)
	30‐39	54% (19)	44% (8)	51% (27)
	40‐49	23% (8)	22% (4)	23% (12)
	50+	14% (5)	28% (5)	19% (10)
Age‐child	0–1	3% (1)	11% (2)	6% (3)
	2‐5	31% (11)	31% (6)	31% (17)
	6‐11	34% (12)	11% (2)	26% (14)
	12‐18	23% (8)	36% (7)	28% (15)
	>18	9% (3)	11% (2)	9% (5)
Disease severity‐child	Neonatal onset	71% (25)	68% (13)	70% (38)
	Late onset	29% (10)	32% (6)	30% (16)
Treatment status‐child	Medical management	40% (14)	42% (8)	41% (22)
	Liver transplant	60% (21)	58% (11)	59% (32)
Age at transplant‐child (if applicable)b	0–1	68% (14)	55% (6)	62% (20)
	2–5	16% (3)	18% (2)	16% (5)
	6–11	11% (2)	18% (2)	13% (4)
	12–18	0% (0)	0% (0)	0% (0)
	>18	5% (1)	9% (1)	6% (2)
Race‐caretaker	White	91% (32)	95% (18)	92% (50)
	Black	6% (2)	0% (0)	4% (2)
	Other	3% (1)	5% (1)	4% (2)
Hispanic or Latino‐caretaker	Yes	9% (3)	5% (1)	7% (4)
	No	91% (32)	95% (18)	93% (50)
Highest level of education‐caretakera	Less than high school degree	0% (0)	0% (0)	0% (0)
	High school degree	3% (1)	0% (0)	2% (1)
	Some college	11% (4)	11% (2)	11% (6)
	Associate degree	6% (2)	6% (1)	6% (3)
	Bachelor's degree	40% (14)	39% (7)	40% (21)
	Graduate degree	40% (14)	44% (8)	41% (22)
Employment status caretakera	Employed, part‐time	34% (12)	28% (5)	32% (17)
	Employed, full‐time	37% (13)	50% (9)	41% (22)
	Not employed	23% (8)	17% (3)	21% (11)
	Retired	3% (1)	0% (0)	2% (1)
	Disabled, not able to work	3% (1)	5% (1)	4% (2)
Household incomea	<$25 000	9% (3)	6% (1)	8% (4)
	$25 000–$49 999	8% (3)	6% (1)	7% (4)
	$50 000–$74 999	3% (1)	11% (2)	6% (3)
	$75 000–$99 999	17% (6)	22% (4)	19% (10)
	$100 000‐$149 000	40% (14)	43% (8)	41% (22)
	$150 000–$200 000	14% (5)	6% (1)	11% (6)
	> $200 000	9% (3)	6% (1)	8% (4)

n = 18 for focus group characteristic; n=53 total; 1 focus group participants failed to respond to all questions.

n = 20 for interviews; n = 11 for focus groups; n = 31 total.

Table 2

Characteristics of urea cycle disorder (UCD) provider interview participants (N = 26)

Gender	Male	34% (9)
	Female	66% (17)
Age	31‐36	23% (6)
	37‐42	23% (6)
	43‐48	15% (4)
	49‐54	15% (4)
	55‐60	8% (2)
	>60	16% (4)
Clinical degree	MD	76% (20)
	Registered Nurse/Nurse Practitioner	8% (2)
	Genetic counselling	12% (3)
	Nutrition	4% (1)
Race	White	88% (23)
	Black	0% (0)
	Other	12% (3)
Hispanic or Latino	Yes	8% (2)
	No	92% (24)
Years of clinical practice in UCD	<3	8% (2)
	4‐6	25% (7)
	7‐10	16% (4)
	>10	47% (12)
	Do not know/not sure	4% (1)

Data analysis

Thematic content analysis was utilised to categorise data into recurrent themes. Initial data abstraction was accomplished through line‐by‐line open coding of a cross‐section of 14 interview transcripts by 3–4 coders. Open coding was utilised to generate a preliminary codebook and refined through team consensus until a final structure of codes emerged. This coding structure was applied across all transcripts. Data collection and analysis were conducted through an iterative process until analytic saturation was reached.

Selective and axial coding were applied to move beyond a typology of participant accounts to identify core concepts and explore the relationship between key themes. To facilitate this level of analysis, common qualitative analysis techniques such as charting and mapping and interpretation were employed.38

All interview and focus group data were managed using QSR International NVivo (v. 11) software.39

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 (5). Informed consent was obtained from all patients and providers for being included in the study.

This article does not contain any studies with animal subjects performed by any of the authors.

RESULTS

Context of limited empirical evidence

Interviews and focus groups captured a context of insufficient evidence and ill‐defined clinical guidelines with regard to the choice between MM and LT. Parents and providers described challenges of treatment decision‐making against a backdrop of high uncertainty and detailed a decision‐making experience largely defined by this context (Appendix, Box 1, [1a‐c]). The decision‐making framework was constructed within this landscape.

A framework for treatment choice in UCD

Key themes were positioned within a framework that illustrates how factors interrelate and collectively influence the decision between MM and LT (Figure 1).

Figure 1

A conceptual framework describing the key factors that contribute to the decision between MM and LT among families whose children are diagnosed with UCD, within a context of insufficient clinical evidence and poorly defined clinical guidance

Weighing the relative risks and benefits

Consideration of the relative risks and benefits of MM vs LT was a central component of the decision‐making experience and thus, positioned at the core of the framework. Parent participants described their efforts to understand and compare risks and benefits (Appendix, Box 2, [2a]) while struggling to weigh treatment alternatives in the absence of evidence‐based guidance (Appendix, Box 2, [2b‐d]).

In the absence of uniform clinical guidance, families relied on experience (their own, their providers', and their peer's') as inputs of imperfect information. Participants discussed these inputs as an inter‐related collection of complex clinical, personal, social, and system factors. These factors, found on the four cardinal points of the framework, inform each family's personal perception of the risks and benefits of MM vs LT, and ultimately, their decision to pursue or not pursue LT as a treatment for their child.

Tipping point

Parents who had chosen LT as a treatment for their child all reached a “tipping point” in their evaluation of the risks and benefits of LT vs MM. Ultimately, these families felt unable to continue managing their child's disorder through diet and medication, prompting (ie, “tipping”) them to pursue LT (Appendix, Box 3 [3a]). Interviews highlighted variation in how families approach this decision and the conditions under which they entertain transplant as a viable treatment alternative. If, when, how, and for what reason families reach this conclusion varied within the study cohort. Some described their “tipping point” shortly after diagnosis, some never reached a point where transplant was a true consideration, and others faced their “tipping point” after years of MM and key changes in circumstance (Appendix, Box 3, [3b‐d]). The family's tolerance for the uncertainty that accompanies MM (Appendix, Box 3, [3e]), the child's clinical status, the personal burden of disease, the social implications of the illness, and the patient's experience with the health‐care system each factored into this timeline to various degrees. Together, these represent the landscape within which families affected by UCD evaluate available treatment choices and reach or do not reach a “tipping point” in favour of LT.

Clinical factors

Disease severity

The severity of the child's diagnosis was cited as a key consideration in the choice between MM and LT. For patients with neonatal‐onset UCD, who are presumed to have virtually zero enzyme function, LT was often presented as the more evident choice. In these cases, parents and providers described transplant as the child's “only option” or “best chance at long‐term survival” (Appendix, Box 4, [4a‐b]).

It is important to note, however, that despite what most participants described as a compelling clinical argument in favour of LT for the most severe patients, some families still expressed hesitation in pursuing LT and continue to evaluate the potential complications of surgery against the risks of MM (Appendix, Box 4, [4c]).

In cases of late‐onset UCD or partial enzyme function, where MM is presented as a viable treatment alternative, participants described a much more subjective evaluation of the pros and cons driven by factors outside that of the child's diagnosis (Appendix, Box 4, [4d]).

Disease stability

Study participants differentiated between the child's disease severity, determined by their diagnosis, and the stability of their disease, reflected in the family's ability to control the child's ammonia through diet and medications. Parents often pointed to a period of frequent hyperammonemia and hospitalizations as a catalyst for transplant (Appendix, Box 5, [5a]). In some cases, disease control was never truly established (Appendix, Box 5, [5b]). Other families described a sudden loss of control over their child's ammonia (Appendix, Box 5, [5d]).

Among children who experienced fewer hospitalizations, some parents viewed LT as a last resort (Appendix, Box 5, [5e]) while others considered transplant as a preventive measure to avoid future complications. In these cases, parents did not interpret past disease stability as a predictor of future disease control, citing the unpredictable and potentially devastating nature of high ammonia as a driving force in their decision to pursue LT (Appendix, Box 5, [5f‐g]).

Personal factors

Burden on family

Parent participants extensively discussed the day‐to‐day challenges of managing their child's illness and the ways the disorder has altered their family life. Parents called attention to 24/7 medical caregiving, the impact of fear and worry on the family's emotional health, and the family's altered relationship to “normal” life comforts like food and travel. For many, these daily burdens provided a compelling reason to consider LT (Appendix, Box 6, [6a‐c]). For other parents, day‐to‐day challenges, although present, were not enough to prompt them to pursue transplant. In these cases, parents often described reaching a point of mastery and comfort in their child's MM routine and cited concerns about the new and unfamiliar risks of post‐transplant life (Appendix, Box 6, [6e‐f]).

Burden on child

Parents also discussed the burden of illness on their child's quality of life. Many participants expressed deep concern over how UCD impacts their child's intellectual and social development. Parent's often labelled their children's demeanour in immeasurable terms such as “foggy,” “unfocused,” “disorganised,” or “cloudy,” and worried their child was suffering due to heightened levels of ammonia. Those who considered LT often believed the surgery could offer their child an opportunity at a “normal” and better‐quality life (Appendix, Box 7, [7a‐c]). Among those who did not pursue LT, some described a much more optimistic picture of their child's current intellectual and social growth, including participation in school and sports (Appendix, Box 7, [7e‐f]).

Social factors

Peer‐to‐peer interaction

Parents reflected on conversations with other families affected by UCD and the role their peers played in shaping their own treatment choices. Most parents interacted, to varying degrees, with other families affected by UCD. While many pursued connections to other parents for the specific purpose of informing treatment choice, others connected organically through the UCD community. Regardless of how connections were made, many parents described being influenced by others' experiences with MM and LT. Parents were motivated to transplant based on the positive surgical and post‐surgical experiences of some families (Appendix, Box 8, [8a‐c]) and the negative outcomes shared by others who had delayed or foregone transplant (Appendix, Box 8, [8d]). Other parents were deterred from LT by stories of surgical complication (Appendix, Box 8, [8e‐f]) and/or encouraged to continue MM by others who had done so with success (Appendix, Box 8, [8 g]).

Consideration for child's independence

Parent participants often discussed their child's independence as a point of continuous concern. Parents considered shorter‐term steps towards independence like participating in school programs as well as longer‐term goals like living outside the home and attending college. Most parents did not trust others to manage their child's strict dietary regimen. Others worried that rising ammonia levels would impede their child's ability to recognise a crisis and take appropriate action. For many parents, transplant represented the only viable way to remove the threat of hyperammonaemia and ultimately, afford their child independence (Appendix, Box 9, [9a‐b]).

Other parent participants offered a different perspective on living independently with UCD. These parents described incremental efforts aimed at teaching their child to manage their medical needs. They shared a belief that their children could live safe and independent lives with UCD and thus, were not driven to pursue LT by these specific concerns (Appendix, Box 9, [9c‐d]).

System factors

Access to quality metabolic care

Parents considered their level of access to quality metabolic care when weighing treatment options. Parents who lacked confidence in their local metabolic team often pursued transplant to address what they perceived as inadequacies in their child's long‐term and emergency medical care (Appendix, Box 10, [10a‐b]). This issue was further framed by the family's geographic residence and their relative proximity to specialised UCD services. Families who lived farther from a hospital centre with expertise in UCD worried about timely and appropriate rescue care during hyperammonaemia. In some cases, this fear was a key driver in the parents' decision to pursue LT (Appendix, Box 10, [10c‐d]).

Parents who conveyed satisfaction with the local long‐term and emergency metabolic care options available to them expressed greater confidence in their physician's ability to help control their child's ammonia and in the hospital's capacity to address medical crises. These parents were often less motivated to explore alternatives to MM (Appendix, Box 10, [10e]).

Metabolic physician approach to treatment and guidance

Physician approach to treatment guidance held influence on parent treatment choice. Many parents described the relationship with their metabolic doctor as critical to their child's care and welfare. Thus, guidance from the metabolic doctor in favour of or against LT was highly valued by many parents (Appendix, Box 11, [11a‐b]). In the absence of information specifying the conditions for one treatment path over another, physician approach to treatment varied substantially from person to person. Our data suggest that these differences are driven, in part, by the physician's previous experiences with LT, the location of their training and that institution's general position on LT for UCD, and the outcomes they observed among their MM patient pool (Appendix, Box 11, [11c]).

Some families credited their physician's staunch opposition as a major deterrent to transplant, even in circumstances they now feel may have warranted it (Appendix, Box 11, [11d‐e]). Other parents were encouraged by their physician to explore transplant as an alternative treatment choice, leading some to pursue it (Appendix, Box 11, [11f]). Still, other providers described a position neither for nor against transplant. Some families valued this impartial approach, feeling empowered to explore both treatment options with the support of their metabolic doctor (Appendix, Box 11, [11 g]). Others described feeling paralysed by their provider's ambivalence and wished that their doctor had done more to assist them in weighing treatment alternatives (Appendix, Box 11, [11 h‐j]).

Cost and coverage of treatment

Parents cited costs of care and the burden of navigating insurance coverage as a major challenge. Qualitative data highlighted clear differences in the cost and coverage of MM vs LT. Parents described transplant as a fully covered procedure with little out‐of‐pocket cost for surgery, hospital stay, short‐, and long‐term post‐transplant medications, and follow ups (Appendix, Box 12, [12a‐b]). In contrast, parents described on‐going struggles with the cost and coverage of their child's pharmaceutical and nutritional needs under MM. Parents cited time‐consuming disputes over coverage for medications, metabolic formulas and medical foods, and indirect financial costs related to travel for medical care and reduced time at work (Appendix, Box 12, [12c‐d]). Despite these differences, parents did not point directly to finances as a driving force behind their treatment choices. However, for many participants, these financial implications contribute to the overall burden of disease and the context within which treatment decisions were made.

Phases of childhood and developmental milestones

Qualitative data demonstrated that changes during key developmental milestones precipitate new and/or aggravate existing challenges associated with the MM of UCD, acting as a catalyst for parents to consider for the first time or reconsider LT as a viable treatment choice. For example, as a child moves from infancy to early childhood, parents contend with new feeding challenges, including a transition to solid foods (Appendix, Box 13, [13a‐b]). They also face adherence issues once their child is able to refuse medications, formulas or other forms of nutrition (Appendix, Box 3, [3c]). Parents have an increasingly difficult time protecting their child from viral exposures as they transition to school age (Appendix, Box 13, [13d]) and face new challenges managing UCD in a school setting, including concerns about forging peer relationships and participating in “normal” childhood activities (Appendix, Box 13, [13e]). During adolescence and early adulthood, parents cited new adherence issues (Appendix, Box 13, [13f]), questions about their child's long‐term independence, and rising concerns about their child's ability to manage their own medical needs (Appendix, Box 13, [13 g‐h]). Data suggests that the clinical, personal, social, and system factors that influence treatment choice, manifest differently across these key phases of childhood. Thus, we include these major developmental transitions and milestones on the “x‐” and “y‐axes” of the framework to indicate that they may change priorities and re‐frame the parent's perception of risks and benefits.

Table 3 provides a summary of the key concepts outlined above with select exemplary quotes to reflect the perspectives of parent and provider participants. Additional quotes to support our analysis can be found in the Appendix (Box 1‐13).

Table 3

Summary of key concepts related to the treatment decision‐making experience of families affected by UCD and exemplary patient and provider quotes

Concept/domain		Exemplary quote
Context of limited empirical evidence		Provider: “We need to get more data to know what we are doing…I think it's lack of data and knowing if we are doing the right thing for this child or if we are actually harming them more than we are helping.”
Weighing risks and benefits of treatment alternatives		Parent: “It's the same thing as a risk benefit. You're making a pro and con list, and it's an unknown number of hyperammonemic episodes vs unknown complications from liver transplant.”
Clinical	Disease Severity	Provider: “I think in the severe neonatal onsets; I think that's less of a question at this point. That's really the only way to save them…In the later onsets, where it's a little bit less clear‐cut, I think—we have extensive conversations.”
	Disease Stability	Parent: “Initially, we were not for transplant…I just saw all the complications and the constant taking of medication…We thought, oh, we can keep him managed, but basically, it started getting to the point where [he] was beginning to have to be hospitalised every couple of months for illness.”
Personal	Burden on Family	Parent: “It really impedes your life, your family, and I would not want that for any new family. If we could protect them and they do not ever have to go through it, and if transplant is safe…That's the best option…the lack of sleep and constant worry, completely sleep deprived because you check to make sure they are fine all night long. The stress of what if something happens, that takes many years off your life.”
	Burden on Child	Parent: “He learned how to count money, and that was a huge thing because he worked and worked at it. Then he had a high ammonia level…He remembered that he knew how to count money, but he could not count it anymore. We thought, oh, that quality of life's horrible…He had to work so hard to learn it more than just a normal kid, and then to lose that functionality was devastating for him. That played into [the decision to transplant] too.”
Social	Peer to peer interaction	Parent: “A good friend of mine lived nearby in. Their daughter was transplanted. She died…That left a bad taste in my mouth…for a long time we did not even really give [transplant] much thought.”
	Consideration for child's independence	Parent: “For her independence, a transplant is necessary…when her ammonia level starts to rise, she cannot make decisions on how to help herself…. Living on her own and going away to college was not going to be an option.”
System	Access to quality metabolic care	Parent: “We're here…with very limited access to a decent metabolic geneticist …It seems that there are only a handful of specialists throughout the country, and if you are not in that location, you are really subject to pretty subpar care…I think the question had to do with local—not having local access to good physicians. We never felt like they had our backs here…so that was a huge stress for me knowing that we were basically on our own.”
	Physician approach to treatment and guidance	Provider: “People have very different approaches at different institutions…. I think it has a lot to do with, especially if you only have a few cases and then you have even fewer cases who decide to go through transplant, what happens to them afterwards. If you see a bad outcome or two that can totally change your impression for the next 20 years vs if you see some who do really, really great, then that may also change your referral pattern.”
	Cost and coverage of treatment	Parent: “In the very beginning I had to do a lot of navigating with [my child's] medication…They did not want to cover it…I spent many hours on the phone…The actual cost and coverage with [his] transplant, we have not had to worry about that at all. That was covered.”
Phases of childhood and developmental milestones		Provider: “Especially with the older children…who's going to manage the child who does not have a liver transplant after you are dead and gone or if you become incapacitated?…With the younger patients, I usually do not take that approach, but as the patients get into their teenage years, it's a question of, well, who is going to manage this?…That's something that really is important to think about.”
Tipping point		Provider: “Finally, push came to shove where it was the kids were coming in too frequently, or their ammonias were being too problematic, difficult to treat. Then we finally made the decision when that balance or the scale seemed to tip.”

DISCUSSION

This paper presents an original framework that reflects various inputs to a highly complex and dynamic personal evaluation of the risks and benefits of treatment alternatives among families affected by UCD. This study is novel in that it examines an understudied area of rare disease and provides a model for research around treatment decision making in rare disorders that may be applied to other conditions.

Although there have been no commensurate publications examining treatment decision making among families affected by UCD, several of the factors identified through this work, including the influence of peer‐to‐peer interactions, provider recommendations, and developmental milestones, align with and augment previous research on decision‐making in paediatric transplant.25, 26, 35, 37 A description of this previous research and its alignment with concepts identified through this study can be found in the appendix (Table A3).

This study also contributes new evidence supporting the role of other factors, not previously described, in driving treatment decisions in UCD. This study distinguishes between the function of disease severity and disease stability in mediating treatment choice, expounds on the implications of disease for the family and the child and its role in treatment decision‐making, and explores issues of health care quality, cost, and access as they relate to the choice between MM and LT.

Since no previously published studies have examined these factors in terms of their impact on treatment choice in UCD, providers have relied on anecdotal experience in guiding their understanding of how these issues bear on treatment choice. The role of these factors, particularly those unrelated to clinical markers of disease severity and stability, such as coverage, cost and access to medical vs surgical treatment generally function outside the purview of the clinician and so are likely underweighted by many medical providers. Thus, the results from this analysis hold practice implications for members of the patient care team. This framework equips providers with an evidence‐based account of the patient experience so that they may better address the concerns, needs, and expectations of patients and families during treatment counselling.

Patient‐centred outcome measures (PCOMs) are characterised by our ability to evaluate outcomes that reflect patient needs and priorities.40 Historically, the effectiveness of most rare disease interventions has been determined by the evaluation of surrogate clinical outcomes that may not reflect the benefits that patients most value.41 The treatment decision‐making framework constructed through this analysis begins to meet the objectives of PCOM development in rare disease by defining what families value most in terms of alleviation.42, 43 Future studies may build on this research to develop quality of life metrics that better capture the unique personal, clinical, social and system burdens of UCD and its related therapies. If developed, these outcome metrics could offer more meaningful estimations of patient benefit and thereby reduce uncertainty over the effectiveness of treatments for UCD.40

CONFLICT OF INTEREST

The authors declare no potential conflict of interest.

AUTHOR CONTRIBUTIONS

M. T. G. led the development of the study design and protocol, collection of interview and focus group data, qualitative analysis, and manuscript preparations for this research. A. R. M. participated in all aspects of this research including providing guidance on study design and protocol, groundwork for data collection and analysis and substantial manuscript revisions. K. Z. G. provided substantial research support in the analysis and interpretation of qualitative data and participated in manuscript revisions. D.M.S. provided substantial guidance in the interpretation of qualitative data and significant contributions during manuscript revisions. C.L.M. provided substantial guidance in the conception of the study and protocol design, supported recruitment of study subjects, and provided manuscript revisions. J. B. supported the development of the study protocol, co‐led recruitment of study subjects, and provided manuscript revisions. N.A.M. was PI for this study, providing guidance on all aspects of study design and protocol and substantial manuscript revisions. All authors will provide approval for the final version of this manuscript prior to publication and agrees to be accountable for the accuracy and integrity of this work.

Intervention type	Content of clinical guidelines	Evidence to support effectiveness
Medical therapeutic interventions for UCD	Current treatment guidelines focus on clinical diagnosis of UCD, management of acute hyperammonaemia, long‐term management through diet, medications, and amino acid supplementation, monitoring of patients, and cognitive outcomes and psychosocial issues. These guidelines were developed through professional consensus using the GRADE methodology for scoring evidence levels. However, the evidence available to support UCD guidelines are predominantly non‐analytical (eg, case series analysis, case reports).15	A few key large retrospective and prospective cohort analyses in UCD have aimed to determine the effect of medical therapeutic interventions for UCD on various outcomes including survival and cognitive function. 3, 6, 16, 17, 46 Results of these clinical studies must be compared with caution, since disease severity within study cohorts often differ and treatment combinations vary widely across providers and institutions.
Liver transplant as treatment for UCD	Current guidelines discuss liver transplantation as the only available curative treatment for UCD and suggest that transplant be considered for patients with severe UCDs who are not responding to medical therapy, experience recurrent metabolic decompensations requiring hospitalization, report poor quality of life, and are without severe neurological damage. 15	Although liver transplantation is performed in increasing frequency to treat UCD and survival rates seem to have improved over time with surgical advances, 18 there is not a great deal of data on neurocognitive function post‐transplant among patients with UCD or a robust evidence‐base comparing the relative value of liver transplant over conventional medical management techniques. The psychological, social, and health problems resulting from successful childhood transplants are also only beginning to be studied and recognized. The life expectancy among young children who have been transplanted is not well documented and little information is available on long‐term complications and quality of life in this group. 19, 20

Characteristics of sample	Limitation
Most caretaker recruitment was conducted via NUCDF, a non‐profit advocacy organisation for UCD patients and a resource of information and education for families affected by UCD.	Study sample may not capture the perspective of individuals who have not engaged on some level with this organisation.
Parent participant sample is skewed towards a predominantly white, educated, and affluent demographic.	The experience of these individuals may differ systematically from the experience of those who were interviewed. In the future, recruitment source and strategy should be diversified to capture the perspective of traditionally underserved and vulnerable populations affected by UCD, which are currently under‐represented in our sample.
Given the sensitive nature of their experience, parents whose child had passed away from complications related to UCD or liver transplant were not interviewed.	Study sample may not capture the perspective of individuals who lost a child in response to either treatment choice. Thus, may omit key elements of their experience.

Concept	Alignment with previous research
Peer‐to‐peer interaction	Dellon et al and Higgins & Kayser‐Jones both described engaging with other affected families and prior transplant recipients as an element of decision making among patients with cystic fibrosis and complex heart conditions, respectively. 26, 35 These types of peer‐to‐peer interactions are also reflected in this study's framework as a key driver of treatment choice in UCD.
Metabolic physician approach to treatment and guidance	Dellon et al, Hankins et al, and Pentz et al described trust in the recommendations of medical providers as another common factor for transplant related decision‐making in cystic fibrosis, sick cell anemia, and pediatric cancer patients. 25, 35, 41 This concept is discussed in the framework in terms of the metabolic physician's relationship with the family and the impact of their opinion and approach on the parent's perception of LT vs MM. Together with the previously published literature, study findings further support the notion that guidance from providers greatly influences treatment choice in complex, chronic pediatric conditions like UCD where transplant is a consideration.
Phases of childhood and developmental milestones	Previously published qualitative studies addressing patient and family experiences with inherited metabolic disorders identified life‐transitions as a major challenge for children and families. One such study cited problems with adherence to diet for phenylketonuria patients during adolescence. 47 Others highlighted social transitions across the lifespan as a challenge for patients diagnosed with various inherited metabolic disorders. 48–50 The existing literature does not explicitly discuss the role of life‐transitions in influencing treatment decisions but rather, highlights these transitions as a challenge for patients and families. Findings from this study expand on the existing literature by describing not only the inherent challenges of childhood transitions in rare disease but the ways in which developmental milestones frame treatment choice among families affected by inherited metabolic disorders like UCD.