Patient preferences in genetic newborn screening for rare diseases: study protocol.

INTRODUCTION: Rare diseases (RDs) collectively impact over 30 million people in Europe. Most individual conditions have a low prevalence which has resulted in a lack of research and expertise in this field, especially regarding genetic newborn screening (gNBS). There is increasing recognition of the importance of incorporating patients' needs and general public perspectives into the shared decision-making process regarding gNBS. This study is part of the Innovative Medicine Initiative project Screen4Care which aims at shortening the diagnostic journey for RDs by accelerating diagnosis for patients living with RDs through gNBS and the use of digital technologies, such as artificial intelligence and machine learning. Our objective will be to assess expecting parent's perspectives, attitudes and preferences regarding gNBS for RDs in Italy and Germany. METHODS AND ANALYSIS: A mixed method approach will assess perspectives, attitudes and preferences of (1) expecting parents seeking genetic consultation and (2) 'healthy' expecting parents from the general population in two countries (Germany and Italy). Focus groups and interviews using the nominal group technique and ranking exercises will be performed (qualitative phase). The results will inform the treatment of attributes to be assessed via a survey and a discrete choice experiment (DCE). The total recruitment sample will be 2084 participants (approximatively 1000 participants in each country for the online survey). A combination of thematic qualitative and logit-based quantitative approaches will be used to analyse the results of the study. ETHICS AND DISSEMINATION: This study has been approved by the Erlangen University Ethics Committee (22-246_1-B), the Freiburg University Ethics Committee (23-1005 S1-AV) and clinical centres in Italy (University of FerraraCE: 357/2023/Oss/AOUFe and Hospedale Bambino Gesu: No.2997 of 2 November 2023, Prot. No. _902) and approved for data storage and handling at the Uppsala University (2022-05806-01). The dissemination of the results will be ensured via scientific journal publication (open access).

From Qualitative Research to Quantitative Preference Elicitation: An Example in Invasive Meningococcal Disease.

BACKGROUND: Qualitative research is fundamental for designing discrete choice experiments (DCEs) but is often underreported in the preference literature. We developed a DCE to elicit preferences for vaccination against invasive meningococcal disease (IMD) among adolescents and young people (AYP) and parents and legal guardians (PLG) in the United States. This article reports the targeted literature review and qualitative interviews that informed the DCE design and demonstrates how to apply the recent reporting guidelines for qualitative developmental work in preference studies. METHODS: This study included two parts: a targeted literature review and qualitative interviews. The Medline and Embase databases were searched for quantitative and qualitative studies on IMD and immunization. The results of the targeted literature review informed a qualitative interview guide. Sixty-minute, online, semi-structured interviews with AYP and PLG were used to identify themes related to willingness to be vaccinated against IMD. Participants were recruited through a third-party recruiter's database and commercial online panels. Interviews included vignettes about IMD and vaccinations and three thresholding exercises examining the effect of incidence rate, disability rate, and fatality rate on vaccination preferences. Participant responses related to the themes were counted. RESULTS: The targeted literature review identified 31 concepts that were synthesized into six topics for the qualitative interviews. Twenty AYP aged 16-23 years and 20 PLG of adolescents aged 11-17 years were interviewed. Four themes related to willingness to be vaccinated emerged: attitudes towards vaccination, knowledge and information, perception of IMD, and vaccine attributes. Most participants were concerned about IMD (AYP 60%; PLG 85%) and had positive views of vaccination (AYP 80%; PLG 60%). Ninety percent of AYP and 75% of PLG always chose vaccination over no vaccination, independent of IMD incidence rate, disability rate, or fatality rate. CONCLUSION: Willingness to be vaccinated against IMD was affected by vaccine attributes but largely insensitive to IMD incidence and severity. This article provides an example of how to apply the recent reporting guidelines for qualitative developmental work in preference studies, with 21 out of 22 items in the guidelines being considered.

Priority Outcomes in Sickle Cell Disease Treatment: Co-Creation and Implementation of a Preference Exercise With Patients and Caregivers to Inform Drug Development.

Involving patients as co-leaders and co-creators in research is key to reflecting the patient's voice in decision-making. However, co-creation of patient-centered data to inform decisions is rare, especially in early drug development where patient input is critical to prioritizing patient-relevant outcomes and endpoints for use in clinical trials. Despite the industry's growing commitment to patient centricity, most patients are excluded from sharing their expertise in research; more inclusive methods of engaging patients as research partners are needed. We describe a collaboration between a pharmaceutical company and a patient organization in co-leading and co-creating a program to understand priorities of patients and caregivers for treatment features and outcomes in sickle cell disease to inform endpoint selection in clinical development. The results of this program will be used as a basis for continued interaction between patients and the sponsor and to inform ongoing clinical development and evidence-generation activities. This case study demonstrates an approach to meaningful collaborations between patient organizations and pharmaceutical companies aimed at including the patient's voice early in the medical product lifecycle.

Impact of Potential Symptoms and Risks Associated with Acid Sphingomyelinase Deficiency on Patients and Caregivers: A Best-Worst Scaling Study.

Purpose: Acid sphingomyelinase deficiency (ASMD) is a rare, progressive, and potentially fatal disease affecting major organs; its symptoms present heterogeneously. Data on the most bothersome symptoms for patients with ASMD types B or A/B and their caregivers or parents are limited. We conducted a survey to quantify the relative impact of potential ASMD symptoms and risks for patients and parents/caregivers. Patients and Methods: Twenty respondents, recruited via National Niemann-Pick Disease Foundation (United States) and Niemann-Pick United Kingdom, took a preference survey: 11 patients who had a self-reported diagnosis of ASMD types B or A/B and 9 parents who had a child with ASMD types B or A/B. Using object-case best-worst scaling, we explored the most and least bothersome among a set of 15 ASMD symptoms/risks selected based on clinical input and qualitative research with patients and caregivers. In 15 experimentally designed questions containing five items each, respondents ranked the symptoms/risks, irrespective of their experiences with them. Data were analyzed using a conditional multinomial logit model. Results: Patients reported constant abdominal pain, severe pain in bones and joints, and severe fatigue to be the most bothersome potential symptoms or risks, followed by a chance of bleeding in the spleen. The next most bothersome potential symptom was constant shortness of breath. Easy bruising and noticeable abdominal enlargement were among the least bothersome symptoms. The most bothersome symptom for parents was bleeding in the spleen. Conclusion: Patients and parents had similar perceptions of the most bothersome potential symptoms/risks. Despite the small sample size typical of rare disease studies, understanding patient preferences is important for such diseases and can inform shared decision-making.

Risk thresholds for patients to switch between daily tablets and biweekly infusions in second-line treatment for advanced hepatocellular carcinoma: a patient preference study.

BACKGROUND: Historically, high hepatocellular carcinoma (HCC)-related mortality has been, in part, due to lack of effective therapies; however, several systemic therapies have been recently approved for HCC treatment, including regorafenib and ramucirumab. These two treatments utilize different routes of administration (four daily tablets and biweekly intravenous infusions, respectively) and have different risks of adverse events (AEs). However, we lack data on patient preferences in balancing the route of administration and risk of AEs in patients with HCC. We aimed to determine patient preferences and trade-offs for second-line treatment in patients with HCC.  METHODS: Patients with advanced or metastatic HCC were recruited through their physicians for this study. Patient preferences were assessed by using a modified threshold technique (TT) design in which respondents were asked two direct-elicitation questions before (assuming same safety and efficacy and only varying mode of administration) and after (incorporating the safety profiles of ramucirumab and regorafenib) the TT series on seven risks of clinically relevant AEs. RESULTS: In total, of the 157 patients recruited by their physicians, 150 were eligible and consented to participate. In the first elicitation question (assuming risk and efficacy were equivalent), 61.3% of patients preferred daily tablets. However, 76.7% of patients preferred the biweekly infusion when the safety profiles of the two available second-line therapies were included. The TT analysis confirmed that preferences for oral administration were not strong enough to balance out the risk of AEs that differentiate the two therapies. DISCUSSION: We found that when patients were asked to choose between a daily, oral medication and a biweekly IV medication for HCC, they were more likely to choose a daily, oral medication if efficacy and safety profiles were the same. However, when risks of AEs representing the safety profiles of two currently available second-line treatments were introduced in a second direct-elicitation question, respondents often selected an IV administration with a safety profile similar to ramucirumab, rather than oral tablets with a safety profile similar to regorafenib. Our findings indicate that the risk profile of a second-line treatment for HCC may be more important than the mode of administration to patients.

Patient Preferences for Pharmaceutical and Device-Based Treatments for Uncontrolled Hypertension: Discrete Choice Experiment.

BACKGROUND: Discrete choice experiment is a survey method used to understand how individuals make decisions and to quantify the relative importance of features. Using discrete choice experiment methods, we quantified patient benefit-risk preferences for hypertension treatments, including pharmaceutical and interventional treatments, like renal denervation. METHODS: Respondents from the United States with physician-confirmed uncontrolled hypertension selected between treatments involving a procedure or pills, using a structured survey. Treatment features included interventional, noninterventional, or no hypertension treatment; number of daily blood pressure (BP) pills; expected reduction in office systolic BP; duration of effect; and risks of drug side effects, access site pain, or vascular injury. The results of a random-parameters logit model were used to estimate the importance of each treatment attribute. RESULTS: Among 400 patients completing the survey between 2020 and 2021, demographics included: 52% women, mean age 59.2±13.0 years, systolic BP 155.1±12.3 mm Hg, and 1.8±0.9 prescribed antihypertensive medications. Reduction in office systolic BP was the most important treatment attribute. The remaining attributes, in decreasing order, were duration of effect, whether treatment was interventional, number of daily pills, risk of vascular injury, and risk of drug side effects. Risk of access site pain did not influence choice. In general, respondents preferred noninterventional over interventional treatments, yet only a 2.3 mm Hg reduction in office systolic BP was required to offset this preference. Small reductions in office systolic BP would offset risks of vascular injury or drug side effects. At least a 20% risk of vascular injury or drug side effects would be tolerated in exchange for improved BP. CONCLUSIONS: Reduction in systolic BP was identified as the most important driver of patient treatment preference, while treatment-related risks had less influence. The results indicate that respondents would accept interventional treatments in exchange for modest reductions in systolic BP compared with those observed in renal denervation trials.

Travelers' preferences for tick-borne encephalitis vaccination.

BACKGROUND: This study aimed to quantify preferences and risk tolerance for a tick-borne encephalitis (TBE) vaccination. RESEARCH DESIGN AND METHODS: A stated-preference survey instrument was administered to international travelers living in the United States to elicit preferences for a no-cost TBE vaccine when planning an international trip, conditional upon four different qualitative levels of endemic TBE risk. RESULTS: The likelihood of choosing the vaccine increased with a destination's level of endemic risk. Most respondents (94%) would choose to receive the vaccine at the highest risk level presented in the survey (i.e. when multiple TBE cases among humans are reported year after year); 6% of the sample would choose not to receive the vaccine at any risk level. Respondents who engage in outdoor activities were twice as likely as the average respondent to choose vaccination rather than opting out of vaccination, and were one-third more likely than the average respondent to choose to receive the vaccine at the lowest risk level. CONCLUSIONS: Respondents were highly interested in a TBE vaccine, assuming no cost, and most were willing to be vaccinated at all qualitative TBE risk levels. Respondents who participated in outdoor activities were more likely than the average respondent to choose the vaccine.

Patient Preferences for Treating "OFF" Episodes in Parkinson's Disease: A Discrete Choice Experiment.

INTRODUCTION: Several on-demand treatments are available for management of "OFF" episodes in patients with Parkinson's disease (PD). We evaluated patients' preferences for features of theoretical on-demand treatment options. METHODS: In a discrete choice experiment, US adults with self-reported PD of ≥5 years, or <5 years with "OFF" episodes, taking oral carbidopa/levodopa, selected between pairs of theoretical on-demand treatments that varied by mode of administration (with and without mode-specific adverse events [AEs]), time to FULL "ON," duration of "ON," and out-of-pocket cost for a 30-day supply. Data were analyzed with a random parameters logit model; results were used to calculate relative importance of treatment attributes, preference shares, and willingness to pay. RESULTS: Among 300 respondents, 98% had "OFF" episodes. Across the range of attribute levels included in the survey, avoiding $90 cost was most important to respondents, followed by a preferable mode of administration with associated AEs and decreasing time to FULL "ON." Duration of "ON" was relatively less important. On average, respondents preferred a theoretical dissolvable sublingual film versus other theoretical treatments with alternative modes of administration. Respondents were willing to pay $28-$52 US dollars to switch from least- to more-preferred mode of administration with associated AEs, $58 to reach FULL "ON" in 15 versus 60 min, and $9 to increase duration of FULL "ON" from 1 to 2 h. CONCLUSION: Respondents with PD valued lower out-of-pocket cost and a sublingual mode of administration with its associated AEs when choosing an on-demand treatment for "OFF" episodes.

Parent and Pediatrician Preferences for Type 1 Diabetes Screening in the U.S.

OBJECTIVE: The purpose of this study was to use a discrete-choice experiment methodology to understand the relative importance of the attributes of screening tests for type 1 diabetes among parents and pediatricians in the U.S. RESEARCH DESIGN AND METHODS: Online surveys presented hypothetical screening test profiles from which respondents chose their preferred test profile. Survey attributes were based on likely screening test options and included the mode of administration, where and when the test was conducted, the type of education and monitoring available to lower the risk of diabetic ketoacidosis (DKA), and whether a treatment was available that would delay onset of insulin dependence. Data were analyzed using random-parameters logit models. RESULTS: Parents placed the highest relative importance on monitoring programs that could reduce the risk of DKA to 1%, followed by treatment to delay onset of insulin dependence by 1 or 2 years, and, finally, avoiding a $50 out-of-pocket cost. Pediatricians placed equal importance on monitoring programs that reduced a patient's risk of DKA to 1% and on avoiding a $50 out-of-pocket cost for the screening test, followed by the option of a treatment to delay the onset of insulin dependence. The mode of administration and location and timing of the screening were much less important to parents and pediatricians. CONCLUSIONS: Parents and pediatricians preferred screening tests that were accompanied by education and monitoring plans to reduce the risk of DKA, had available treatment to delay type 1 diabetes, and had lower out-of-pocket costs.

Using the Threshold Technique to Elicit Patient Preferences: An Introduction to the Method and an Overview of Existing Empirical Applications.

Patient preference information (PPI) is a topic of interest to regulators and industry. One of many known methods for eliciting PPI is the threshold technique (TT). However, empirical studies of the TT differ from each other in many ways and no effort to date has been made to summarize them or the evidence regarding the performance of the method. We sought to describe the TT and summarize the empirical applications of the method. Forty-three studies were reviewed. Most studies estimated the minimum level of benefit required to make a treatment worthwhile, and over half estimated the maximum level of risk patients would accept to achieve a treatment benefit. The evidence demonstrates that the TT can be used to elicit multiple types of thresholds and can be used to explore preference heterogeneity and preference non-linearity. Some evidence suggests that the method may be sensitive to anchoring and shift-framing effects; however, no evidence suggests that the method is more or less sensitive to these potential biases than other stated-preference methods. The TT may be a viable method for eliciting PPI to support regulatory decision-making; however, additional understanding of the performance of this method may be needed. Future research should focus on TT performance compared with other stated-preference methods, the extent to which results predict patient choice, and the ability of the TT to inform individual treatment decisions at the point of healthcare delivery.

A retrospective audit of the characteristics and treatment outcomes in patients with diabetes-related charcot neuropathic osteoarthropathy.

AIMS: To review the characteristics, management and outcomes one year after diagnosis in patients with diabetes related charcot neuropathic osteoarthropathy (CN) treated at the Diabetes Podiatry service, Waitemata District Health Board (WDHB) between 2000-2014. METHODS: Patients with diabetes and recorded diagnosis of CN were identified from the podiatry service records. Clinical details were retrospectively obtained from WDHB databases and patient medical records. RESULTS: Forty-one patients were included, 31 had type 2 diabetes, 10 had type 1 diabetes. At presentation, the median duration of all-type diabetes was 15 years. The median time from symptom onset to diagnosis was 17 weeks. Symptoms at presentation were: oedema (49%), warmth (73%), erythema (17%), swelling (90%) and pain (60%). Concomitant ulcers were present in 32%, deformities 83%, osteomyelitis 2% and septic arthritis 2%. Mean time to ambulation in modified shoes was 21.3 weeks (±11.5). Complication rates one year from diagnosis for ulcers, osteomyelitis, amputations and all-cause mortality were 34%, 2%, 2% and 5% respectively. CONCLUSION: Time to diagnosis of CN was shorter than previously reported, though the high rate of deformities still suggests a significant delay in diagnosis. Increased education of healthcare professionals and people with diabetes-related neuropathy is important to ensure early diagnosis and appropriate management to reduce deformities and complications.