Topological data analysis reveals genotype-phenotype relationships in primary ciliary dyskinesia.

BACKGROUND: Primary ciliary dyskinesia (PCD) is a heterogeneous inherited disorder caused by mutations in approximately 50 cilia-related genes. PCD genotype-phenotype relationships have mostly arisen from small case series because existing statistical approaches to investigating relationships have been unsuitable for rare diseases. METHODS: We applied a topological data analysis (TDA) approach to investigate genotype-phenotype relationships in PCD. Data from separate training and validation cohorts included 396 genetically defined individuals carrying pathogenic variants in PCD genes. To develop the TDA models, 12 clinical and diagnostic variables were included. TDA-driven hypotheses were subsequently tested using traditional statistics. RESULTS: Disease severity at diagnosis, measured by forced expiratory volume in 1 s (FEV1) z-score, was significantly worse in individuals with CCDC39 mutations (compared to other gene mutations) and better in those with DNAH11 mutations; the latter also reported less neonatal respiratory distress. Patients without neonatal respiratory distress had better preserved FEV1 at diagnosis. Individuals with DNAH5 mutations were phenotypically diverse. Cilia ultrastructure and beat pattern defects correlated closely to specific causative gene groups, confirming these tests can be used to support a genetic diagnosis. CONCLUSIONS: This large scale, multi-national study presents PCD as a syndrome with overlapping symptoms and variations in phenotype according to genotype. TDA modelling confirmed genotype-phenotype relationships reported by smaller studies (e.g. FEV1 worse with CCDC39 mutation) and identified new relationships, including FEV1 preservation with DNAH11 mutations and diversity of severity with DNAH5 mutations.

The child's perspective on discomfort during medical research procedures: a descriptive study.

OBJECTIVE: The evaluation of discomfort in paediatric research is scarcely evidence-based. In this study, we make a start in describing children's self-reported discomfort during common medical research procedures and compare this with discomfort during dental check-ups which can be considered as a reference level of a 'minimal discomfort' medical procedure. We exploratory study whether there are associations between age, anxiety-proneness, gender, medical condition, previous experiences and discomfort. We also describe children's suggestions for reducing discomfort. DESIGN: Cross-sectional descriptive study. SETTING: Paediatric research at three academic hospitals. PATIENTS: 357 children with and without illnesses (8-18 years, mean=10.6 years) were enrolled: 307 from paediatric research studies and 50 from dental care. MAIN OUTCOME MEASURES: We measured various generic forms of discomfort (nervousness, annoyance, pain, fright, boredom, tiredness) due to six common research procedures: buccal swabs, MRI scans, pulmonary function tests, skin prick tests, ultrasound imaging and venepunctures. RESULTS: Most children reported limited discomfort during the research procedures (means: 1-2.6 on a scale from 1 to 5). Compared with dental check-ups, buccal swab tests, skin prick tests and ultrasound imaging were less discomforting, while MRI scans, venepunctures and pulmonary function tests caused a similar degree of discomfort. 60.3% of the children suggested providing distraction by showing movies to reduce discomfort. The exploratory analyses suggested a positive association between anxiety-proneness and discomfort. CONCLUSIONS: The findings of this study support the acceptability of participation of children in the studied research procedures, which stimulates evidence-based research practice. Furthermore, the present study can be considered as a first step in providing benchmarks for discomfort of procedures in paediatric research.