Introduction

A disease is considered rare in the European Union if it affects one person in every 2,000 [1]. Due to their low prevalence, scientific and medical knowledge in the field of rare diseases is limited, creating challenges in the search for diagnosis, treatment, and care options. The European Reference Networks (ERNs) were established with the goal of addressing this shortage and providing the best diagnostic and treatment options for patients suffering from rare diseases. These networks link healthcare providers throughout Europe in order to address medical conditions that require highly specialised treatment and a concentration of knowledge and resources. At present, 24 networks participate in the initiative. Through these networks, reliable Clinical Practice Guidelines (CPGs) and tools to support clinical decision-making must be developed to ensure that people with rare diseases and their caregivers receive safer and more efficient care throughout the European Union. CPGs developed for rare diseases must address the challenges associated with a lack of sufficient scientific evidence as most methodological approaches, such as GRADE [2], require this evidence to make recommendations.

In the aforementioned context, the European Commission (EC) issued a tender in 2018 (DG SANTE/2018/B3/030) with two primary objectives: (i) to assist ERNs and their health care providers in developing, evaluating, and implementing CPGs and other clinical decision support tools; and (ii) to contribute to the ERNs’ and their members’ capacity for producing and adhering to high-quality CPGs and tools in their area of specialisation. The tender was won by a consortium coordinated by the Andalusian Public Foundation for Progress and Health (FPS) and comprised two specialised health training institutions (the Andalusian School of Public Health and the Open University of Catalonia) and five health technology assessment agencies that are members of RedETS (the Spanish National Network for Health Technology Assessment), including AETSA (Andalusian Health Technology Assessment Area). One work package of the project aims to methodically assist ERNs in the development, evaluation and adaptation of CPGs. To accomplish this, each of the consortium’s five agencies supports different ERNs. The study presented here is part of this work package and is contextualised within the AETSA’s support for the European Reference Network on Neurological Diseases (ERN-RND) in developing the first CPG for the management of NKX2-1-related disorders.

NXK2-1-related disorders are considered rare due to their low prevalence (1:500,000) [3]. Choreoathetosis, hypothyroidism and neonatal respiratory distress are all symptoms of this condition (OMIM*600635). Variants in the NKX2-1 gene (formerly known as TITF1) or a deletion in 14q13.3, even if the NKX2-1 gene is not involved, can cause it [4]. Additional signs and symptoms such as tremor, myoclonus, dystonia, ataxia, sensorineural hearing loss, hypotonia and motor developmental delay, attention deficit and hyperactivity, hypodontia, short stature, and psychiatric, cardiovascular and genitourinary abnormalities may occur in patients with NKX2-1-related disorders [5, 6]. The onset and progression of symptoms, as well as their association with other symptoms, are highly variable in this condition. The entire brain-lung-thyroid syndrome is present in half of patients. Chorea typically begins in early childhood or around the age of one year, or in late childhood or adolescence, and progresses into the second decade, when it remains stable or remits. The second most common manifestation is pulmonary disease, which can manifest itself in newborns as respiratory distress syndrome, in young children as interstitial lung disease, or in the elderly as pulmonary fibrosis. In young adults with an NKX2-1-related disease, the risk of developing lung cancer is increased. Thyroid dysfunction caused by dysembryogenesis can manifest as primary congenital hypothyroidism [3]. Although numerous reports have been published on adult-onset cancer associated with NKX2-1-related disorders, including large cell lung carcinoma, glioblastoma multiforme and papillary thyroid cancer [7–9], there are conflicting recommendations for follow-up for these patients, ranging from no controls [10] to annual lung X-rays or CT scans [3], as well as thyroid palpation. As a result, NKX2-1-related disorders affect a variety of organs and systems, and patients with this disorder also face an increased risk of developing cancer.

For this condition to be addressed comprehensively in the CPG, in addition to the topics to which clinicians attach most importance, it is necessary to give a voice to the patients themselves and to the people who accompany them in their processes, such as their caregivers or representatives, in order to identify the key issues for the people affected. To meet this objective, two main recommendations are supported by the “Guideline International Network Public Toolkit: patient and public involvement in guidelines” [11]. The first of these recommended actions is the inclusion of patients and/or patient representatives in the guideline development group which has been addressed (listed in the acknowledgements section). The second recommended action is to use research methods to ask patients, which is what this study is about. Thus, within this collaborative framework, and to comply with the above-mentioned indications, it is necessary to identify patient values, preferences and information needs in order to incorporate them in the development of the CPG and address them in the patient information booklet incorporating the relevant information of the CPG. The CPG will be developed based on the handbook entitled “Methodology for the elaboration of Clinical Practice Guidelines for rare diseases” [12], developed within the framework of the ERNs Guidelines project and based on the GRADE approach. The GRADE approach involves the Evidence-to-Decision framework, which considers patient values and preferences as a criterion for formulating recommendations [13, 14]. The patient document aims to provide high-quality information based on available evidence and best clinical practices in accessible layman’s language [15, 16]. The document will be developed based on the handbook entitled “Methodology for the Elaboration of Patient Information Booklets for rare diseases” [17], which was also developed as part of the ERNs Guidelines project.

Aim

The overall goal is to explore, using qualitative research methods, the values, preferences and information needs of patients with NKX2-1-related disorders, their caregivers, and/or representatives in order to identify elements that:

1. ➢ are relevant from a patient perspective, in addition to those considered important by clinicians, in order to avoid their omission from the CPG;
2. ➢ can be incorporated into the patient information booklet to address the identified information gaps.

Methods and analysis

Data collection

Both the focus group and the interviews will take place virtually via the Microsoft Teams platform, and audio and video recorders will be used. The rationale for conducting the study virtually is to facilitate the participation of individuals who are in different geographical locations, as well as to avoid any unexpected situation resulting from the current COVID-19 context. Given the European dimension of the project, the study will include a focus group with participants who can converse fluently in Spanish, as well as semi-structured interviews with participants who can converse fluently in Spanish, English, German or French. An interpreter will translate the conversation between the participant and the researcher during the semi-structured interviews in German or French; the interpreter has a background in research and will sign the confidentiality form.

A structured script will be used to guide the dynamics of the focus group and semi-structured interviews, ensuring that all relevant topics are discussed (Table 1). Similarly, this script may be expanded or modified in response to the issues raised by the participants. The focus group data may be used to modify the topics to be discussed in the semi-structured interviews that will follow, if it is determined that relevant topics have emerged that were not previously included in the interview script (Fig 1). The focus group and each interview will last approximately an hour and a half to two hours.

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Fig 1. Study flow chart.

https://doi.org/10.1371/journal.pone.0281573.g001

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Table 1. Topic guide for focus group and semi-structured interviews.

https://doi.org/10.1371/journal.pone.0281573.t001

Discussion

In general, patients living with a disease can help clinicians and scientists understand the morbidities associated with the disease, and provide a context for the development of potential interventions [25]. This becomes even more necessary and specific in the case of rare diseases, where experiences with the healthcare process are different from those of common conditions [26]. Hence the need to know their perspectives and preferences when developing clinical decision support documents such as CPGs.

Focus on NKX2-1- related disorders, and as far as we are aware, this is the first study to investigate the values, preferences, and information needs of patients with NKX2-1-related disorders. The proposed study’s findings will contribute to the generation of useful knowledge that will be used to develop the ongoing Clinical Practice Guideline and accompanying patient information booklet, likewise, it will be published in international peer-reviewed journals and presented in conferences. It is further expected that given the focus on patient preference of this study, the results deriving from this study may have a positive impact on the implementation of CPG-derived recommendations and their acceptance by patients and caregivers, and also, improve the care they receive and their satisfaction with same and better informed shared clinical decision-making.

The major anticipated limitation of this study is that, while it will provide valuable insights into the perspectives of patients with NKX2-1-related disorders, the findings are unlikely to be generalizable to patients with other conditions. However, conducting this study and disseminating it may serve as a wake-up call of the need to integrate the patient perspective into CPGs, especially those addressing rare diseases.

Acknowledgments

Participating investigators who are members of the NKX2-1-related disorders Guideline Working Group:

➢ Beatriz Carmona-Hidalgo. Health Technology Assessment Area-AETSA, Andalusian Public Foundation for Progress and Health (“Fundación Progreso y Salud”–“FPS”), Seville, Spain. Lead author: beatriz.carmona.hidalgo@juntadeandalucia.es

➢ Jose C Moreno. Thyroid Molecular Laboratory, Institute for Medical and Molecular Genetics (INGEMM), La Paz University Hospital, Autonomous University of Madrid, Madrid, Spain.

➢ Matthias Griese. Department of Pediatrics, Dr. von Hauner Children’s Hospital, University Hospital, Ludwig-Maximilians-University Munich, Munich, Germany.

➢ Katarzyna Michael. Department of Pediatrics, Dr. von Hauner Children’s Hospital, University Hospital, Ludwig-Maximilians-University Munich, Munich, Germany.

➢ Giovanna Zorzi. U.O. Neuropsichiatria Infantile Fondazione IRCCS, 9328 Istituto Neurologico Carlo Besta, Milan, Italy.

➢ Alessandro Capuano. Movement Disorder Clinic -Dept. of Neuroscience. Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy.

➢ Thomas O F Wagner. Frankfurt Reference Center for Rare Diseases, University Hospital Frankfurt, Frankfurt, Germany.

➢ Beate Bartes, patient advocate. Vivre sans Thyroide, France.

➢ Steve Winter. ERN-RND patient advocate.

➢ Rebeca Isabel-Gómez. Health Technology Assessment Area-AETSA, Andalusian Public Foundation for Progress and Health (“Fundación Progreso y Salud”–“FPS”), Seville, Spain.

➢ Luz López-Samaniego. Health Technology Assessment Area-AETSA, Andalusian Public Foundation for Progress and Health (“Fundación Progreso y Salud”–“FPS”), Seville, Spain.