Pharmacogenomics for Prader-Willi syndrome: caregiver interest and planned utilization

Introduction

Approximately 97% of the world's population has a genetic polymorphism that can affect medication efficacy [1]. Pharmacogenomics (PGx), the study of how an individual's genetic polymorphisms can contribute to medication response, provides great potential for a tailored pharmaceutical approach for patient healthcare [1]. Providers can utilize PGx results to provide patient-specific medication and dosage recommendations to maximize drug efficacy and minimize adverse drug reactions (ADRs) [1]. ADRs are a medication response that is ‘noxious, unintended and occurs at doses normally used in man' [2]. ADRs are a significant cause of morbidity and mortality, accounting for 6% of hospital admissions and 2% of deaths annually, and can also result in financial burden, delayed treatment and loss of confidence in medical management [2]. Research focused on PGx utilization to potentially mitigate the negative outcomes of ADRs has primarily concentrated on the healthcare provider’s perspective to identify deficits in knowledge, interpretation, and management of PGx information [3–5].

Recently, research has begun to include patient perspectives on PGx. Overall, trends have identified limited understanding and a desire for more thorough explanations about the practical implications of PGx results in terms of medical management [1,6]. However, this patient-perspective research has focused predominantly on the general population and medications for common health concerns such as pain management and depression [7]. Limited understanding of how PGx can be used for genetic conditions with a high prevalence of polypharmacy, or the concurrent use of two or more medications, can increase the risk of ADRs due to medication interactions and may further stall effective treatment of the underlying condition [8].

One group prone to polypharmacy that may benefit from PGx information are individuals with Prader-Willi syndrome (PWS). PWS is a rare genetic condition caused by loss of gene expression from the paternally inherited chromosome 15q11.2-13 region due to microdeletion (60% of cases), maternal uniparental disomy (35% of cases) or imprinting center defects (<5% of cases) [9–11]. Symptoms that develop in early childhood include endocrine dysfunction, hyperphagia, global developmental delay, mild-to-moderate intellectual disability and behavioral issues. The behavioral phenotype includes impulsivity, temper outbursts, self-injury, cognitive rigidity and obsessive-compulsive disorder, which are difficult to treat with behavior modification alone and often require trying multiple medications with potential adverse side effects [12]. Individuals with PWS are also susceptible to mental illness as they enter adulthood, including psychosis, which is markedly more common in those with PWS due to maternal uniparental disomy than major depression, more common in those with PWS due to microdeletion [9,10].

Among individuals with PWS, multiple medications are used often to manage their array of symptoms, with some prescribed over ten separate medications, which increases ADR likelihood [10,13]. Recently, Forster et al. investigated PGx variants for individuals with PWS and demonstrated prescription medications at standard doses were more likely to result in ADRs in individuals with PWS [8,14]. However, to date, no studies have been reported that examine the perception of PWS caregivers with respect to understanding and potential application of PGx information.

To better understand the impact of PGx testing and knowledge on this population of individuals, PGx testing was offered to individuals participating in a larger study utilizing whole-genome and RNA sequencing to identify genetic variants that contribute to the variable clinical phenotype of PWS. A PGx report template was developed to include the PGx results, general information about PGx, limitations of PGx, and resources for both healthcare providers and participants. This study aimed to assess PWS caregiver interest and planned utilization of the PGx results prior to receiving the PGx report. We hypothesized caregivers would be highly interested in PGx testing for medication decision-making and that they would plan to discuss the report with their family's medical providers to inform medication discussions.

Materials & methods

Overview

Caregivers were surveyed on their interest and planned utilization of the PGx report 9 months prior to receiving their child's PGx report. Survey responses were analyzed, and descriptive statistics were performed. All protocols, surveys, caregiver-facing recruitment materials and the PGx report template were reviewed and approved by the North Star Review Board.

Caregivers & recruitment

This study included data from individuals with PWS (verified by genetic diagnosis) whose caregivers (legally authorized representatives) consented to a larger study entitled ‘Whole Genome and RNA Sequencing Analysis in Prader-Willi Syndrome’ and consented to receive pharmacogenetic testing results [9]. Individuals with PWS were between the ages of 10 and 65 years old, resided in the USA, and were enrolled in and their caregivers had completed the medical history information section in the Global Prader-Willi Syndrome Registry [9]. The current study focused on assessing the attitudes of the caregiver who would receive the PGx report; consent was provided under the larger study protocol.

Development of pre-results survey

Caregivers were invited to complete the pre-results survey via email. The survey was developed by the authors and informed by: 1) a relevant literature review; 2) a genetic counselor with PGx expertise; and 3) a focus group of three PWS caregivers not included in the study. Discussion with the focus group took place after the three caregivers received access to the PGx report template and surveys. Questions and comments from the focus group were utilized to refine these documents.

The survey was administered via SurveyMonkey^® and questions consisted of multiple choice, ranking, select all that apply, a five-point Likert scale and fill in the blank for the answer choice ‘other’. Survey questions utilized branching logic to remain relevant to caregiver responses. The pre-results survey consisted of 41 total questions. Information collected included PGx interest, predicted utilization of the PGx report and caregiver demographics. The survey is available in the Supplementary data.

Email invitations to complete the pre-survey were sent to caregivers in July 2022 via the FPWR's secure email. A reminder email was sent to caregivers who had not yet completed the surveys 2 weeks after each initial survey invitation was sent. All surveys remained open to caregiver responses for approximately 2 months after the initial request. No identifying information was collected in the surveys; caregivers entered their genome study identification number from the larger pilot study to pair the survey data together and collect deidentified responses.

Data analysis

Survey data was downloaded from SurveyMonkey and demographic data (age, reported gender and PWS subtype for individuals with PWS) was downloaded from the Global PWS Registry and exported to Excel (Version 16.66). In one instance, two caregivers for the same child in the same family each completed the survey; therefore, only nonidentical responses regarding caregiver preference or demographics were included in the data analysis; identical responses, such as number of medications the child was on, were only counted once. Descriptive statistics were used to analyze and summarize responses to all questions in each survey. Responses to the five-point Likert scale questions were collapsed into three categories: negative (not at all and not so much), neutral (somewhat) and positive (very and extremely) to more clearly express caregiver answers. Fill in the blank responses were reported verbatim. Due to branching logic utilization, response number varied by question; therefore, percentages were calculated to reflect the varying sample sizes for each question.

Results

Participant characteristics

To better understand caregiver interest in and plans to utilize a PGx report, 50 caregivers were invited to complete an online survey prior to receiving their child's PGx results. A total of 48 caregivers completed the survey, including two caregivers for the same child in the same family. Demographic characteristics of the caregivers are detailed in Table 1. Most caregivers were biological or adopted mothers (85.4%), over the age of 50 years (77.1%), non-Hispanic/Latino (93.8%), White (95.8%) and had some college education or more (91.7%).

Characteristics about individuals with PWS, referred to as the caregivers' children henceforth, were also collected (Table 2). The genetic subtype of PWS was a paternal deletion for 55.3% of children, 57.4% were between 10 and 18 years old, 55.3% were female and 53.2% were taking seven or more drugs, including prescription, over the counter and/or supplements (Supplementary Figure 1).

Current strategies regarding drug changes

To explore the current drug experiences of caregivers and their children, we asked caregivers a series of questions to describe their child's drug usage and efficacy. Over the past 2 years, 35 children (74.5%) had prescription drug changes (use or dosage) with a median response of two to three drugs changing. When given multiple choices, the most common reason for a drug change was due to the drug not working (38.3%), followed by a new symptom (36.2%), side effects (25.5%) or the drug was no longer needed (14.9%).

Caregivers were also asked to rate the effectiveness of their child's drugs in treating and managing both their medical and behavioral symptoms over the past 2 years. For medical symptom management, 51.1% of caregivers reported their child's drug(s) to be somewhat effective and 48.9% reported their child's drug(s) to be very effective. For behavioral symptom management, 21.3% of caregivers reported their child's drug(s) to not be effective, 59.6% reported somewhat effective and 19.1% reported very effective.

To expand upon drug efficacy, caregivers were asked to select which drug classes they preferred to see recommendations for on their child's PGx report (Table 3). Caregivers were most interested in recommendations for behavior drugs (89.6%) and least interested in drug types that are not directly related to PWS treatment but may be helpful for future health concerns (e.g., chemotherapy drug recommendations for cancer treatment; 27.1%).

Previous awareness & utilization of pharmacogenomic testing

When asked about previous experiences with PGx, 29 (60.4%) caregivers had heard about PGx testing before participating in this study, with 16 (55.2%) of those individuals hearing about it from the PWS community (Figure 1). In the subset of children whose caregivers had heard about PGx testing before this study, nine children (31.0%) had previously received PGx testing. Of these, eight (88.9%) received testing through a specialist provider's office, and one (11.1%) received testing by requesting it directly through a company.

Current interest & desired outcome of pharmacogenomic testing

After enrollment in this study and an explanation of PGx and how it could be utilized, 45 (93.8%) caregivers reported being very interested in receiving a PGx report for their child. Caregivers were asked to rank five possible reasons they decided to receive the PGx report from most important (1) to least important (5; Supplementary Figure 2). Caregivers ranked their top choice as wanting to determine which drugs or dosage would be best in the future, should new drugs be needed. The lowest ranked choice was cost, which was free as part of this research study.

Prior to receiving their child's PGx report, caregivers were asked what they expected would be the most valuable outcome from the PGx testing. The top-rated outcomes were increasing the effectiveness of the drugs their child takes or may take in the future (47.9%) and decreasing trial and error in prescribing (31.3%; Table 4). The lowest ranked choice was decreasing the cost of the drugs their child takes or may take (0.0%).

Plans to utilize pharmacogenomic reports

As part of the larger study, caregivers will receive a PGx report customized to their child. When asked about their plans to utilize the PGx report, 47 (97.9%) caregivers planned to discuss their child's PGx report with one of their child's healthcare providers. Figure 2 represents the likelihood caregivers would bring the PGx report to different healthcare providers. The top three providers that caregivers plan to share their child's PGx report with were their child's endocrinologist (95.7%), primary care physician or pediatrician (89.4%) and psychiatrist (87.8%). Of note, the providers that caregivers reported they would be least likely to share their child's PGx report with were the dermatologist (31.0%), pharmacist (28.6%) and genetic counselor (25.0%).

When asked about their comfort level in using the PGx report to discuss changing drugs or dosage with their child's healthcare provider(s), 83.3% of caregivers felt very comfortable. However, only 47.9% felt confident that their child's healthcare provider would use the PGx report when prescribing drugs (Figure 3).

Discussion

This study assessed the extent of PWS caregiver interest in and planned utilization of PGx results prior to receiving a PGx report for their child. Although this study focuses on the caregiver perspectives and their interest in PGx for their children, its findings are in line with prior research showing high interest in PGx by the general population in the USA [1]. Findings support the hypothesis that caregivers in this study were most interested in PGx information for current or future drug decisions for their children. However, novel findings in this study suggest that while PWS caregivers appear comfortable discussing these results with their healthcare providers, they are not confident their providers will use this information when prescribing drugs.

PGx is a relatively new area in healthcare, and previous studies have indicated low level awareness and understanding of PGx by the public [3,6,7]. Despite this, more than half of caregivers in this study had heard about PGx, primarily through the PWS community and to a lesser extent through their child's medical healthcare provider(s). The PWS community appears to play an important role in raising awareness of PGx to the caregivers of this study. This finding may be more representative of the awareness within the rare disease caregiver community in general.

Based on the study's findings, caregivers were seeking PGx information for current and/or future drug management, especially for behavioral issues through drug intervention. Throughout the literature, behavioral issues among individuals with PWS are difficult to treat and may require the trial and error of psychotropic drugs [8,9,14]. Prescribing drugs that impact behavior can be a complex process due to the number of drug choices (SSRIs, antipsychotics, stimulants, etc.) available. Among this cohort's children, most caregivers (80.9%) believed their child's behavioral drugs were only somewhat effective or not effective at all, and most caregivers (74.5%) reported their child had required one or more drug or dosage changes in the past 2 years. These responses suggest PGx testing might be particularly helpful for the PWS population.

Caregivers consistently ranked cost for PGx testing of low importance for proceeding to gain PGx information, although this does not eliminate it as an important factor for consideration. In previous studies of the general population, regardless of financial status, cost was a major factor and sometimes considered a barrier for testing [4,7,15]. Since known literature focuses on the perspectives of the general population who likely take fewer drugs but with overall greater efficacy than individuals with PWS, it could be argued that in the PWS caregiver population, where multiple drugs and dosages may be tried and taken for treatment, the cost of testing has a lower impact than other variables when deciding whether or not to pursue PGx testing.

Regardless of the variables that impact caregiver pursuit for PGx testing prior to this study, our findings underscore that many caregivers would be comfortable discussing their child's PGx report with healthcare providers. However, they appear less confident that healthcare providers would utilize the PGx report when it comes to prescribing drugs. In previous studies, people varied in their plans and comfort level when sharing their PGx results with their healthcare providers but overall showed greater confidence in the drugs their healthcare providers would prescribe after they reviewed their PGx information [1,15–17]. PWS caregivers and their children attend healthcare provider visits more frequently. Therefore, we speculate that the familiarity experienced in these relationships may help facilitate the consequential comfort to discuss PGx testing. This is further supported by the finding that nearly all caregivers (95.7%) planned to share the PGx reports with their child's endocrinologist, a provider that is of utmost importance in the PWS community for management of endocrine health concerns, which occur early in life and require continuous management. Strong relationships with those providers may motivate sharing of the PGx report, even if the caregivers have limited confidence that the endocrinologist would utilize the PGx information.

Overall, there may be multiple reasons that caregivers in this study show limited confidence that providers would utilize the PGx report when prescribing drugs for their children. In the literature, medical providers often have limited training in interpretation and management of PGx results and likely choose not to discuss PGx testing if they do not know how to clinically use it [1,3]. Surprisingly, healthcare providers known to have the most training and course(s) in PGx, such as pharmacists and genetic counselors, were among the providers caregivers were least likely to share the PGx results [1]. In addition, while research has been promising, the scarcity of randomized clinical trials and lack of generalizability by meta-analyses regarding the clinical utility of PGx testing contribute to the challenges medical providers face in determining whether or not to use PGx information in the clinical setting [18]. Moreover, research in precision medicine has shown some physicians show concern for losing the communication and decision making style in traditional doctor–patient relationships by shifting from patient-centered, feelings-based communication to paternalistic data-driven decisions made by medical providers [19]. Combined, the current barriers and ethical quandaries medical providers face contribute to a reduced likelihood providers will use PGx information in patient care. We suggest that by including information about resources and providers that can help interpret PGx reports, prescribing providers may feel more comfortable discussing PGx which, in turn, may increase caregiver confidence in PGx utilization. Therefore, we also suggest more frequent interactions between PGx knowledge-based providers and prescribing providers. PGx knowledge-based providers can be consulted to explain PGx results and their possible implications so prescribing providers can apply this insight for clinical treatment decisions.

Limitations & future perspectives

This study is limited by the small sample size of caregivers. Furthermore, the caregivers, recruited from the Global PWS Registry to participate in a genomics study, are more educated and less representative (the majority were non-Hispanic White females) than the US population [9]. Therefore, while our findings may accurately represent PWS caregivers from the Global PWS Registry, they likely do not represent all PWS caregivers. Likewise, the ages of the children adjacently involved in this study are skewed toward 18 years or younger group. They may face different health issues than other age groups and, therefore, the caregivers may have different concerns and relationships with different healthcare providers such as endocrinologists as mentioned above. Future research with a larger cohort of more evenly distributed ages of individuals with PWS and more diverse PWS caregivers is needed.

Moreover, although we provided a brief explanation of what PGx is and how it can impact healthcare prior to the start of our survey, no assessments of the caregivers' knowledge were made afterwards. We did not evaluate the accuracy nor explanation of PGx provided by outside sources (PWS community, medical providers, etc.). In addition, we learned that 39.6% of caregivers had not even heard about PGx prior to this study. Therefore, the results in this study may indicate varying levels of PGx understanding. Since PGx is a relatively new and somewhat complicated medical subject, understanding could be considered crucial to interest and utilization. Future research into caregiver interest may benefit from incorporating and assessing knowledge of PGx testing and utilization.

Finally, our study lacks data to address why caregivers had limited confidence in their child's healthcare provider to use the PGx report when prescribing drugs. Further research is needed to establish reasons for the relatively low confidence. Moreover, we speculate caregivers may not know which healthcare providers would be the best for PGx result interpretation. As part of our future research studies, we plan to provide educational information and resources on a PGx report we designed. In this PGx report, we will provide caregivers information on how to follow-up with PGx experts (such as PGx genetic counselors). We plan to distribute future surveys to assess if caregivers, after receiving this PGx report, feel more confident about sharing it with healthcare providers. These findings may impact future healthcare provider/caregiver interactions and PGx testing for individuals with PWS.

Conclusion

PWS caregivers are highly interested in PGx testing primarily for current or future behavioral drug changes. Furthermore, as PWS communities play important roles in bringing awareness to PGx testing, more emphasis can be placed on ensuring that their information is accurate and comprehensive. Finally, providing educational resources with the PGx report, including how to locate knowledgeable providers for PGx interpretation, may result in increased caregiver confidence in the report being fully utilized. Future research is necessary to study PGx information dissemination among PWS caregivers to better understand how the findings are implemented in clinical care and perceived value of PGx testing. The findings from this study may also reflect those in the larger rare disease caregiver community where the likelihood of polypharmacy is high.