Background Digital biomarkers are a promising novel method to capture clinical data in a home setting. However, clinical validation prior to implementation is of vital importance. The aim of this... Show moreBackground Digital biomarkers are a promising novel method to capture clinical data in a home setting. However, clinical validation prior to implementation is of vital importance. The aim of this study was to clinically validate physical activity, heart rate, sleep and forced expiratory volume in 1 s (FEV1) as digital biomarkers measured by a smartwatch and portable spirometer in children with asthma and cystic fibrosis (CF). Methods This was a prospective cohort study including 60 children with asthma and 30 children with CF (aged 6-16 years). Participants wore a smartwatch, performed daily spirometry at home and completed a daily symptom questionnaire for 28 days. Physical activity, heart rate, sleep and FEV1 were considered candidate digital end-points. Data from 128 healthy children were used for comparison. Reported outcomes were compliance, difference between patients and controls, correlation with disease activity, and potential to detect clinical events. Analysis was performed with linear mixed effects models. Results Median compliance was 88%. On average, patients exhibited lower physical activity and FEV1 compared with healthy children, whereas the heart rate of children with asthma was higher compared with healthy children. Days with a higher symptom score were associated with lower physical activity for children with uncontrolled asthma and CF. Furthermore, FEV1 was lower and (nocturnal) heart rate was higher for both patient groups on days with more symptoms. Candidate biomarkers appeared able to describe a pulmonary exacerbation. Conclusions Portable spirometer- and smartwatch-derived digital biomarkers show promise as candidate end-points for use in clinical trials or clinical care in paediatric lung disease. Show less
Peeters, D.; Pico-Knijnenburg, I.; Wieringa, D.; Rad, M.; Cuperus, R.; Ruige, M.; ... ; Driessen, G.J.A. 2022
Down syndrome (DS) is associated with increased susceptibility to infections, auto-immunity, immunodeficiency and haematological malignancies. The exact underlying immunological pathophysiology is... Show moreDown syndrome (DS) is associated with increased susceptibility to infections, auto-immunity, immunodeficiency and haematological malignancies. The exact underlying immunological pathophysiology is still unclear. The immunophenotype and clinical characteristics of DS resemble those of Activated PI3K Delta Syndrome (APDS), in which the PI3K/AKT/mTOR pathway is overactivated. We hypothesized that T cell exhaustion and the hyperactivation of the AKT signalling pathway is also present in immune cells of children with DS. In this observational non-interventional cohort study we collected blood samples of children with DS (n=22) and healthy age-matched controls (n=21) for flowcytometric immunophenotyping, phospho-flow AKT analysis and exhaustion analysis of T cells. The median age was 5 years (range 1-12y). Total T and NK cells were similar for both groups, but absolute values and transitional B cells, naive memory B cells and naive CD4+ and CD8+ T cells were lower in DS. pAKT and AKT were increased for CD3+ and CD4+ T cells and CD20+ B cells in children with DS. Total AKT was also increased in CD8+ T cells. Children with DS showed increased expression of inhibitory markers Programmed cell dealth-1 (PD-1), CD244 and CD160 on CD8+ T cells and increased PD-1 and CD244+ expression on CD4+ T cells, suggesting T cell exhaustion. Children with DS show increased pAKT and AKT and increased T cell exhaustion, which might contribute to their increased susceptibility to infections, auto immunity and haematological malignancies. Show less
IntroductionCoughing is a common symptom in pediatric lung disease and cough frequency has been shown to be correlated to disease activity in several conditions. Automated cough detection could... Show moreIntroductionCoughing is a common symptom in pediatric lung disease and cough frequency has been shown to be correlated to disease activity in several conditions. Automated cough detection could provide a noninvasive digital biomarker for pediatric clinical trials or care. The aim of this study was to develop a smartphone-based algorithm that objectively and automatically counts cough sounds of children.MethodsThe training set was composed of 3228 pediatric cough sounds and 480,780 noncough sounds from various publicly available sources and continuous sound recordings of 7 patients admitted due to respiratory disease. A Gradient Boost Classifier was fitted on the training data, which was subsequently validated on recordings from 14 additional patients aged 0–14 admitted to the pediatric ward due to respiratory disease. The robustness of the algorithm was investigated by repeatedly classifying a recording with the smartphone-based algorithm during various conditions.ResultsThe final algorithm obtained an accuracy of 99.7%, sensitivity of 47.6%, specificity of 99.96%, positive predictive value of 82.2% and negative predictive value 99.8% in the validation dataset. The correlation coefficient between manual- and automated cough counts in the validation dataset was 0.97 (p < .001). The intra- and interdevice reliability of the algorithm was adequate, and the algorithm performed best at an unobstructed distance of 0.5–1 m from the audio source.ConclusionThis novel smartphone-based pediatric cough detection application can be used for longitudinal follow-up in clinical care or as digital endpoint in clinical trials. Show less
Background: Pediatric patients admitted for acute lung disease are treated and monitored in the hospital, after which full recovery is achieved at home. Many studies report in-hospital recovery,... Show moreBackground: Pediatric patients admitted for acute lung disease are treated and monitored in the hospital, after which full recovery is achieved at home. Many studies report in-hospital recovery, but little is known regarding the time to full recovery after hospital discharge. Technological innovations have led to increased interest in home-monitoring and digital biomarkers. The aim of this study was to describe at-home recovery of 3 common pediatric respiratory diseases using a questionnaire and wearable device. Methods: In this study, patients admitted due to pneumonia (n = 30), preschool wheezing (n = 30), and asthma exacerbation (AE; n = 11) were included. Patients were monitored with a smartwatch and a questionnaire during admission, with a 14-day recovery period and a 10-day "healthy" period. Median compliance was calculated, and a mixed-effects model was fitted for physical activity and heart rate (HR) to describe the recovery period, and the physical activity recovery trajectory was correlated to respiratory symptom scores. Results: Median compliance was 47% (interquartile range [IQR] 33-81%) during the entire study period, 68% (IQR 54-91%) during the recovery period, and 28% (IQR 0-74%) during the healthy period. Patients with pneumonia reached normal physical activity 12 days postdischarge, while subjects with wheezing and AE reached this level after 5 and 6 days, respectively. Estimated mean physical activity was closely correlated with the estimated mean symptom score. HR measured by the smartwatch showed a similar recovery trajectory for subjects with wheezing and asthma, but not for subjects with pneumonia. Conclusions: The digital biomarkers, physical activity, and HR obtained via smartwatch show promise for quantifying postdischarge recovery in a noninvasive manner, which can be useful in pediatric clinical trials and clinical care. Show less
Kruizinga, M.D.; Heide, N. van der; Moll, A.; ZhuParris, A.; Yavuz, Y.; Kam, M.L. de; ... ; Driessen, G.J.A. 2021
Background: Digital devices and wearables allow for the measurement of a wide range of health-related parameters in a non-invasive manner, which may be particularly valuable in pediatrics.... Show moreBackground: Digital devices and wearables allow for the measurement of a wide range of health-related parameters in a non-invasive manner, which may be particularly valuable in pediatrics. Incorporation of such parameters in clinical trials or care as digital endpoint could reduce the burden for children and their parents but requires clinical validation in the target population. This study aims to determine the tolerability, repeatability, and reference values of novel digital endpoints in healthy children.MethodsApparently healthy children (n = 175, 46% male) aged 2-16 were included. Subjects were monitored for 21 days using a home-monitoring platform with several devices (smartwatch, spirometer, thermometer, blood pressure monitor, scales). Endpoints were analyzed with a mixed effects model, assessing variables that explained within- and between-subject variability. Endpoints based on physical activity, heart rate, and sleep-related parameters were included in the analysis. For physical-activity-related endpoints, a sample size needed to detect a 15% increase was calculated.FindingsMedian compliance was 94%. Variability in each physical activity-related candidate endpoint was explained by age, sex, watch wear time, rain duration per day, average ambient temperature, and population density of the city of residence. Estimated sample sizes for candidate endpoints ranged from 33-110 per group. Daytime heart rate, nocturnal heart rate and sleep duration decreased as a function of age and were comparable to reference values published in the literature.ConclusionsWearable- and portable devices are tolerable for pediatric subjects. The raw data, models and reference values presented here can be used to guide further validation and, in the future, clinical trial designs involving the included measures. Show less
Introduction Respiratory tract infections (RTIs) affect children all over the world and are associated with significant morbidity and mortality. In particular, recurrent RTIs cause a high burden of... Show moreIntroduction Respiratory tract infections (RTIs) affect children all over the world and are associated with significant morbidity and mortality. In particular, recurrent RTIs cause a high burden of disease and lead to frequent doctor visits. Children with recurrent RTIs generally have no significant alterations or deficits in systemic immunity. In an attempt to treat the assumed bacterial component involved, they are often treated with prolonged courses of prophylactic antibiotics taken on a daily basis. Despite its common use, there is no evidence that this is beneficial. Studies assessing the clinical effectiveness of antibiotic prophylaxis as well as potential adverse effects and antibiotic resistance development, are therefore urgently needed. Methods and analysis We present a protocol for a randomised double-blind placebo-controlled trial comparing co-trimoxazole with placebo treatment in children with recurrent RTIs. A total of 158 children (aged 6 months-10 years) with recurrent RTIs without significant comorbidity will be enrolled from a minimum of 10 Dutch hospitals. One group receives co-trimoxazole 18 mg/kg two times per day (36 mg/kg/day) and the other group receives a placebo two times per day for a period of 3 months. The main objective is to determine whether antibiotic prophylaxis is more effective than placebo to prevent/reduce respiratory symptoms in children with recurrent RTIs. Respiratory symptoms will be scored by parents on a daily basis in both study arms by the use of a mobile phone application. Our primary outcome will be the number of days with at least two respiratory symptoms during the treatment. Ethics and dissemination Ethics approval was obtained from the Medical Ethics Research Committee Zuidwest Holland/LDD. A manuscript with the study results will be submitted to a peer-reviewed journal. All participants will be informed about the study results. The results of the study will inform clinical guidelines regarding the prophylactic treatment of children with recurrent RTIs. Show less
Novel digital endpoints gathered via wearables, small devices, or algorithms hold great promise for clinical trials. However, implementation has been slow because of a lack of guidelines regarding... Show moreNovel digital endpoints gathered via wearables, small devices, or algorithms hold great promise for clinical trials. However, implementation has been slow because of a lack of guidelines regarding the validation process of these new measurements. In this paper, we propose a pragmatic approach toward selection and fit-for-purpose validation of digital endpoints. Measurements should be value-based, meaning the measurements should directly measure or be associated with meaningful outcomes for patients. Devices should be assessed regarding technological validity. Most importantly, a rigorous clinical validation process should appraise the tolerability, difference between patients and controls, repeatability, detection of clinical events, and correlation with traditional endpoints. When technically and clinically fit-for-purpose, case building in interventional clinical trials starts to generate evidence regarding the response to new or existing health-care interventions. This process may lead to the digital endpoint replacing traditional endpoints, such as clinical rating scales or questionnaires in clinical trials. We recommend initiating more data-sharing collaborations to prevent unnecessary duplication of research and integration of value-based measurements in clinical care to enhance acceptance by health-care professionals. Finally, we invite researchers and regulators to adopt this approach to ensure a timely implementation of digital measurements and value-based thinking in clinical trial design and health care.Significance Statement-Novel digital endpoints are often cited as promising for the clinical trial of the future. However, clear validation guidelines are lacking in the literature. This paper contains pragmatic criteria for the selection, technical validation, and clinical validation of novel digital endpoints and provides recommendations for future work and collaboration. Show less
Background Diagnosis and follow-up of respiratory diseases traditionally rely on pulmonary function tests (PFTs), which are currently performed in hospitals and require trained personnel.... Show moreBackground Diagnosis and follow-up of respiratory diseases traditionally rely on pulmonary function tests (PFTs), which are currently performed in hospitals and require trained personnel. Smartphone-connected spirometers, like the Air Next spirometer, have been developed to aid in the home monitoring of patients with pulmonary disease. The aim of this study was to investigate the technical validity and usability of the Air Next spirometer in pediatric patients. Methods Device variability was tested with a calibrated syringe. About 90 subjects, aged 6 to 16, were included in a prospective cohort study. Fifty-eight subjects performed conventional spirometry and subsequent Air Next spirometry. The bias and the limits of agreement between the measurements were calculated. Furthermore, subjects used the device for 28 days at home and completed a subject-satisfaction questionnaire at the end of the study period. Results Interdevice variability was 2.8% and intradevice variability was 0.9%. The average difference between the Air Next and conventional spirometry was 40 mL for forced expiratory volume in 1 second (FEV1) and 3 mL for forced vital capacity (FVC). The limits of agreement were -270 mL and +352 mL for FEV1 and -403 mL and +397 mL for FVC. About 45% of FEV1 measurements and 41% of FVC measurements at home were acceptable and reproducible according to American Thoracic Society/European Respiratory Society criteria. Parents scored difficulty, usefulness, and reliability of the device 1.9, 3.5, and 3.8 out of 5, respectively. Conclusion The Air Next device shows validity for the measurement of FEV1 and FVC in a pediatric patient population. Show less
Poelman, E.; Hoogeveen-Westerveld, M.; Hout, J.M.P. van den; Bredius, R.G.M.; Lankester, A.C.; Driessen, G.J.A.; ... ; Ploeg, A.T. van der 2019
Severe combined immunodeficiency (SCID) patients with an inactivating mutation in recombination activation gene 1 (RAG1) lack B and T cells due to the inability to rearrange immunoglobulin (Ig) and... Show moreSevere combined immunodeficiency (SCID) patients with an inactivating mutation in recombination activation gene 1 (RAG1) lack B and T cells due to the inability to rearrange immunoglobulin (Ig) and T-cell receptor (TCR) genes. Gene therapy is a valid treatment option for RAG-SCID patients, especially for patients lacking a suitable bone marrow donor, but developing such therapy has proven challenging. As a preclinical model for RAG-SCID, we used Rag1-/- mice and lentiviral self-inactivating (SIN) vectors harboring different internal elements to deliver native or codon-optimized human RAG1 sequences. Treatment resulted in the appearance of B and T cells in peripheral blood and developing B and T cells were detected in central lymphoid organs. Serum Ig levels and Ig and TCR V beta gene segment usage was comparable to wildtype (WT) controls, indicating that RAG-mediated rearrangement took place. Remarkably, relatively low frequencies of B cells produced WT levels of serum immunoglobulins. Upon stimulation of the TCR, corrected spleen cells proliferated and produced cytokines. In vivo challenge resulted in production of antigen-specific antibodies. No leukemia development as consequence of insertional mutagenesis was observed. The functional reconstitution of the B- as well as the T-cell compartment provides proof-of-principle for therapeutic RAG1 gene transfer in Rag1-/- mice using lentiviral SIN vectors. Leukemia (2011) 25, 1471-1483; doi: 10.1038/leu.2011.106; published online 27 May 2011 Show less
Severe combined immunodeficiency (SCID) patients with an inactivating mutation in recombination activation gene 1 (RAG1) lack B and T cells due to the inability to rearrange immunoglobulin (Ig) and... Show moreSevere combined immunodeficiency (SCID) patients with an inactivating mutation in recombination activation gene 1 (RAG1) lack B and T cells due to the inability to rearrange immunoglobulin (Ig) and T-cell receptor (TCR) genes. Gene therapy is a valid treatment option for RAG-SCID patients, especially for patients lacking a suitable bone marrow donor, but developing such therapy has proven challenging. As a preclinical model for RAG-SCID, we used Rag1-/- mice and lentiviral self-inactivating (SIN) vectors harboring different internal elements to deliver native or codon-optimized human RAG1 sequences. Treatment resulted in the appearance of B and T cells in peripheral blood and developing B and T cells were detected in central lymphoid organs. Serum Ig levels and Ig and TCR Vβ gene segment usage was comparable to wild-type (WT) controls, indicating that RAG-mediated rearrangement took place. Remarkably, relatively low frequencies of B cells produced WT levels of serum immunoglobulins. Upon stimulation of the TCR, corrected spleen cells proliferated and produced cytokines. In vivo challenge resulted in production of antigen-specific antibodies. No leukemia development as consequence of insertional mutagenesis was observed. The functional reconstitution of the B- as well as the T-cell compartment provides proof-of-principle for therapeutic RAG1 gene transfer in Rag1-/- mice using lentiviral SIN vectors. Show less
