Robin sequence (RS) is a congenital condition characterized by micrognathia, glossoptosis and upper airway obstruction [1, 2]. It is highly variable in phenotype ranging from mild mandibular micrognathia with only occasional obstructive apnea during sleep and undisturbed breathing while awake to life-threatening upper airway obstruction necessitating immediate postnatal intervention to secure the airway and avoid life-threatening hypoxemia. Untreated airway obstruction can lead to intermittent hypoxemia with growth failure, cognitive deficits, and cor pulmonale [3, 4]. The prevalence of RS is estimated at 1:8,500 to 1:14,000 [5–7]. There is evidence suggesting an increased familial risk of the disease. About 80% present with a cleft palate, and half the patients have an isolated diagnosis of RS, while it is associated with other, primarily syndromic diseases in the remaining [8, 9].
There are both non-surgical and surgical treatment options. The former include prone positioning, continuous positive airway pressure (CPAP), use of a nasopharyngeal airway, and orthodontic treatment procedures like special palatal plates and logopedic functional therapy [10–12]. Surgical treatment options include releasing the floor of the mouth, tongue-lip adhesion, mandibular wire traction, mandibular distraction osteogenesis (MDO), or tracheostomy [13–15].
Utilization Of Disease Registries
As often the case with rare diseases, comparing effectiveness of different treatments using the gold standard, i.e. a randomized controlled trial (RCT) design, is not feasible. Therefore, cohort studies are the only realistic design, and here, registers collecting data from patients treated with different approaches may be helpful, even though the data thus obtained will only be hypothesis-generating. In other rare conditions, registry data have even sufficed instead of RCT to grant market authorization for drugs used to treat them [16, 17].
Need For A Multinational, Multicenter Clinical Registry For Rs
Regarding RS, there are very few diseases utilizing such diverse therapeutic approaches. Studies on the outcome of children with RS yet only included one or two of these approaches. Mostly, the parameters and timing of the outcome measures also differed, making it almost impossible to compare study results.
The individual choice of therapy depends on numerous factors and is often determined by the availability of resources, location, as well as experience and expertise of the local interdisciplinary team. Unfortunately, to date, there is no data gathered in a uniform manner enabling a comparison of patients with different therapies and allowing to weigh advantages and disadvantages in a fair and comparable way. In addition, there are hardly any long-term follow-up data on patients with RS. Therefore, little is known about the development and long-term outcome independent of the treatment applied.
Goals Of The Registry
We established this registry for patients with RS to systematically gather data in a uniform manner on diagnostics, treatment, adverse events and complications, and to increase the knowledge about neurocognition, growth, speech development, and hearing outcome. The multicenter design enables the collection of data on patients receiving different treatments in a uniform way.
As stated above, clinical evidence should primarily be based on randomized clinical trials, and comparing treatment approaches based on registry data has limitations [18]. Nonetheless, important evidence can also be obtained using appropriate statistical methods. Without systematically collected data in a registry, specific research questions in rare diseases such as RS cannot be investigated at all.
We will prospectively collect detailed baseline, diagnostic, treatment, and outcome data from several clinical centers specialized in the treatment of RS. The registry aims to describe different diagnostic techniques and the associated measurements under real-life conditions, as well as the impact of different phenotypic varieties on symptoms and treatment. Furthermore, the systematic collection of longitudinal data on characteristics and outcomes enables the detection of factors affecting outcomes. For example, we are interested in weight gain, method of feeding in affected infants (i.e., age < 1 year), or inpatient days in the first year of life.
A positive impact of the registry beyond the scientific work is the strengthening of international cooperation between RS experts and the facilitation of exchanging information on complex cases.
Effectiveness and safety of different treatment approaches
Another benefit is that a registry not only makes it possible to compare different treatment approaches but can also be used for research into relevant issues related to the respective therapies. Identifying risk factors and determining rates of complications and adverse events for each treatment approach and the different diagnostic procedures is important to increase the understanding of disease characteristics. In addition to the outlined a priori research questions, it is expected and intended that the availability of registry data will lead to further research questions, unknown at this stage, and provide the opportunity for scientific evaluation.
Since the registry design provides hospitals with a comprehensive database for their own center, researchers will be further motivated to conduct multiple research in this field. Centers with smaller numbers of cases can also participate, which ultimately increases knowledge about the disease and can improve the quality of care in the long term. Last but not least, information gained from the registry may be helpful in disseminating certain therapeutic and diagnostic procedures in healthcare systems with different jurisdictions and may assist the respective health policymakers in allocating resources.
Design Of The Registry
The RS registry is a prospective, observational, noninterventional, multicenter, multinational study. Data are recorded in an online accessible, secure database using Castor Electronic Data Capture System (Castor EDC, Ciwit BV, Amsterdam, The Netherlands) under license from the university medical center of Amsterdam (Amsterdam UMC). This user-friendly database enables data entry from every web-connected device (Fig. 1). A user account is required for access, protected by individual passwords and two-factor authentication. Castor applications run on fully managed virtual private servers with providers in the Netherlands. The Castor EDC database complies with the General Data Protection Regulation and is ISO 27001 certified (Standards for Information Security Assurance). Data is encrypted at rest and in transit.
The database allows the definition of individual user rights and data exporting functions, as well as at least partly extracting data directly from clinical data management systems. Data will be entered pseudonymized directly by physicians and academic staff. The principal investigators of the respective study centers will be required to maintain a secure participation list linking the registry ID number with the personal identifying data. The registry ID is a sequential number that is automatically generated by the system and allows identification of the reporting center but not the reported patient.
The registry will be conducted under routine clinical conditions, according to the treating physicians. Registry participation does not influence the patients' management or the relationship of the patients with their treating physicians. No clinical, instrumental, or laboratory assessments will be performed other than those required for disease management according to each site's best practice. Follow-up visits will be scheduled according to the standard practice of each center and the treating physician's best judgment. In addition to clinical data collection, it is planned to assess topics such as quality of life or neurodevelopment (e.g., developmental milestones) with parental questionnaires.
The idea and design of the register are based on the cooperation of four European centers: Great Ormond Street Hospital for Children NHS in London, the Necker–Enfants Malades Hospital in Paris, the Emma Children's Hospital in Amsterdam, and the Center for Cleft Palate and Craniofacial Malformations at the University Children's Hospital in Tübingen. Each of these four initial centers applies a different treatment modality. All participating research centers were involved in the item development process to accommodate the diversity of treatment options through item selection. Any hospital treating children with RS can join the registry and participate in the recruitment of patients (readers interested in joining the registry can do so via [email protected]).
Case Definition And Eligibility Criteria
All patients diagnosed with RS are eligible for participation in the registry. The diagnosis can be an isolated condition or be part of a syndrome or multiple-anomaly disorder. Patients are eligible irrespective of their treatment. Inclusion is conditional on an informed consent form signed by the child's legal guardians.
For a long time, definitions for RS differed between studies and centers. However, at an international consensus meeting in Utrecht in 2014, experts agreed on a valid definition also forming the basis for inclusion in the registry. Micrognathia, glossoptosis, and airway obstruction are mandatory diagnostic characteristics [1]. Cleft palate is common in children with RS but not a necessary characteristic of the diagnosis. These three main criteria are queried in the first part of the registry. Generally, borderline cases (cases where the three diagnostic criteria are not clearly identifiable) can also be entered into the registry aiming to facilitate the diagnostic process in unclear cases and to discuss these cases within the expert community.
Since the registry is designed as prospective, patients will be recruited for participation at the earliest possible stage. However, as the time for patients to be admitted to a Robin Sequence center varies, we defined the maximum age at registry enrolment as 12 months.
Data Collection Procedure And Data Management
Medical records and data documented in routine care are the primary data sources of this registry, which is designed in two parts. There is a core or minimum data set that must be entered entirely for each participant. The registry is structured into different modules (details of RS phenotype, demographics, pre- and postnatal data, parental data and family history, admission, clinical signs, diagnostics, therapy, adverse events, nutrition, short-term outcome at discharge, and follow-up visits). For each module, there is a second part for which the entry of data is optional. This approach provides flexibility in the volume of data entry for the principal investigators and addresses limited data entry resources. The data entry screen is designed with the aim that data entry should not take longer than 15 minutes per patient. Each center regularly can only access its own center-specific data. From the other centers, only the number of participating patients is visible. The pooling of center-specific data only takes place within the framework of a research hypothesis and with the consent of all parties involved. This blinding approach is also intended to minimize possible bias in data entry by preventing comparisons being made only at the time of data entry.
The design of the modules will be evaluated regularly. In particular, potential biases in the registry data will be considered. We will reevaluate the modules with regard to generalizability, selection bias, user bias, confounding, and loss to follow-up. Prior to each data analysis, it is up to the principal investigator to check the correctness and plausibility of the data.
Evaluation and adaptation of the data recording are planned at regular intervals, especially in the initial period of the registry, taking into account the suggestions of participating physicians and scientists. This is a longterm, open-ended registry that is intended to evolve and change with the emerging research questions that the registry can help clarify.
Dataset
The data set was developed and refined over several years in collaboration with a panel of RS experts. The current data set focuses on the first weeks of primary therapy (see Appendix 1). In particular, an attempt was made to include and standardize routine data already documented for clinical purposes. Nevertheless, it may be necessary for participating centers to extend their previous data collection to include the elements of this dataset, making it imperative to adapt internal clinical processes accordingly.
Statistical Analyses
Appropriate descriptive statistics will be used to describe patient and disease characteristics. Depending on the investigated outcome, characteristics will be presented by the treatment approach. Statistical means such as regression/logistic models will be used in the analysis to evaluate specific effects, taking into account relevant covariables. Provided that a sufficient number of patients per treatment approach will be enrolled, we plan to conduct a comparison of outcome parameters between the groups using propensity score analysis.
Ethics And Agreements
The ethics boards of the four initial study centers independently approved the registry protocol. The registry complies with all applicable laws and regulations, including Good Clinical Practice and General Data Protection Regulations. Each newly participating center must submit a positive ethics approval from its local ethics committee for participation. The Steering Group provides study materials, but the responsibility lies with the local principal investigators. Local implementation and administration of local data collection are also the responsibility of the respective study partner. The steering committee is, of course, available to provide support. Participation in the registry also requires the informed consent of the parents/guardians. There are templates provided for the process, but they can and should be adapted to the different policies and regulations in the institutions and countries. However, the general concept, particularly not to collect person-identifying data at any time, remains unaffected. As only anonymized data is available, linking the data with other sources at the registry level is impossible. The central independent data management is located at the study site of the University Hospital in Tübingen and is responsible for implementing and maintaining the database.
The study centers must disclose the annual number of cases actually treated and the number of children included in the registry to minimize bias by not including all relevant patients. Due to the low expected annual number of cases, it is reasonable to inform all potential study participants and record refusals to participate or reasons for nonenrolment in writing.
The Registry Steering Committee is made up of representatives from the four study centers that launched the registry. The steering group is open to members from any other actively participating center. In case the number of participating centers exceeds the capacity of the steering committee in the future, centers with a larger number of participants will have priority for a seat on the committee. The steering committee plans to meet virtually at least twice a year. All centers participating in the registry are invited to these committee meetings. Centre-specific data are permitted to be used for research purposes independent of the other participating centers. Researchers interested in pooling data from the different participating centers to answer a research question are to submit proposals for specific analysis plans for individual research requests to the Steering Committee for approval before the data are released. In addition to the approval by the Steering Committee, the principal investigator of each center whose data are to be included in the analysis must also approve the pooling of data and the analysis plan. The steering committee also considers data use requests of researchers not participating in the registry.