Preferences for Injection Device Settings and the Association with Adherence to Growth Hormone Treatment in Patient with Growth Disorders.

Adherence to recombinant human growth hormone (r-hGH; somatropin, [Saizen®], Merck Healthcare KGaA, Darmstadt, Germany) treatment is important to achieve positive growth and other outcomes in children with growth disorders. Automated injection devices can facilitate the delivery of r-hGH, injections of which are required daily for a number of years. The ability to adjust injection device settings may improve patient comfort and needle anxiety, influencing adoption and acceptance of such devices, thereby improving treatment adherence. Here, we present the results of a retrospective observational study which investigated the association between injection device settings and adherence in the first 3 months of treatment in patients with growth disorders. Patients aged ≥2 and <18.75 years of age at treatment start, with ≥3 months of adherence data from start of treatment with the third generation of the easypod® device (EP3; Merck Healthcare KGaA, Darmstadt, Germany) were selected (N=832). The two most chosen combinations of device settings at treatment start were the default settings for injection speed, depth and time, or a slow injection speed and default depth and time. These combinations also demonstrated the highest adherence rates (94% and 95%, respectively) compared to other device settings (89%). A higher proportion of patients with intermediate/low adherence in the first month of treatment (31%, n=18/59) changed the device settings during treatment compared with those with high adherence (16%, n=128/803) (p=0.005). The ability to adjust injection device settings offers a valuable opportunity for personalizing treatment, improving patient comfort and treatment adherence.

The growzen™ buddy smartphone app to improve adherence in patients receiving recombinant human growth hormone therapy: a retrospective observational study in Argentina.

Introduction: This study in Argentina evaluated the impact of the growzen™ buddy smartphone app on adherence to recombinant human growth hormone (r-hGH) treatment. Methods: The adherence data, invitation dates with a link to the app, app activation dates, and height measurements entered were extracted from the growzen™ digital health ecosystem. Patients with 12 months of adherence data, aged ≥2 years at treatment start, and aged <19 years were selected both before and after app implementation. Mean adherence was classified as optimal (≥85%) versus suboptimal (<85%). Adherence before and after implementation and the pre-post effect on adherence were assessed. Results: Data for 830 patients were available. Prior to app implementation, the proportion of patients with optimal adherence was 68% (n = 348/515). Following the app implementation, out of 315 patients, 302 (96%) received an invitation with a link to the app, 225 (71%) activated their account, and 127 (40%) entered height data in the first year. There was a significant early increase in the proportion of patients with optimal adherence following implementation: 82% (n = 258/315), p < 0.001. After implementation, the proportion of patients with optimal adherence included 80% (n = 78/98) of those with an active account who did not enter height measurements and 89% (n = 113/127) of those who did. There was a significant and positive pre-post app effect on adherence (p < 0.01) in patients with an active account. Discussion: Our results show that using the growzen™ buddy app has a rapid and positive impact on adherence to r-hGH treatment, and patients who were more engaged with the app demonstrated better adherence.

Short developmental milestone risk assessment tool to identify Duchenne muscular dystrophy in primary care.

BACKGROUND: In patients without a family history, Duchenne muscular dystrophy (DMD) is typically diagnosed at around 4-5 years of age. It is important to diagnose DMD during infancy or toddler stage in order to have timely access to treatment, opportunities for reproductive options, prevention of potential fatal reactions to inhaled anesthetics, awareness of a child's abilities needed for good parenting, and opportunities for enrolment in clinical trials. METHOD: We aimed to develop a short risk assessment tool based on developmental milestones that may contribute to the early detection of boys with DMD in primary care. As part of the case-control 4D-DMD study (Detection by Developmental Delay in Dutch boys with DMD), data on developmental milestones, symptoms and therapies for 76 boys with DMD and 12,414 boys from a control group were extracted from the health records of youth health care services and questionnaires. Multiple imputation, diagnostic validity and pooled backward logistic regression analyses with DMD (yes/no) as the dependent variable and attainment of 26 milestones until 36 months of age (yes/no) as the independent variable were performed. Descriptive statistics on symptoms and therapies were provided. RESULTS: A tool with seven milestones assessed at specific ages between 12 and 36 months resulted in a sensitivity of 79% (95CI:67-88%), a specificity of 95.8% (95%CI:95.3-96.2), and a positive predictive value of 1:268 boys. Boys with DMD often had symptoms (e.g. 43% had calf muscle pseudohypertrophy) and were referred to therapy (e.g. 59% for physical therapy) before diagnosis. DISCUSSION: This tool followed by the examination of other DMD-related symptoms could be used by youth health care professionals during day-to-day health assessments in the general population to flag children who require further action. CONCLUSIONS: The majority of boys (79%) with DMD can be identified between 12 and 36 months of age with this tool. It increases the initial a priori risk of DMD from 1 in 5,000 to approximately 1 in 268 boys. We expect that other neuromuscular disorders and disabilities can also be found with this tool.

New Hyperacusis Therapy Combines Psychoeducation, Sound Exposure, and Counseling.

PURPOSE: The aim of this study was to investigate the short- and long-term effects of a new cognitive sound exposure therapy (CSET) in patients with hyperacusis. METHOD: A new therapy was developed to reduce hyperacusis using sound exposure combined with breathing and relaxation strategies from both acceptance and commitment therapy and cognitive behavioral therapy. Patients who were referred to the Speech and Hearing Centers located in Hengelo and Zwolle in the Netherlands and aged ≥ 18 years with hyperacusis as main complaint and no or mild hearing loss were included in this study. Patients were seen for CSET between June 2020 and August 2022. The sessions took place biweekly. Sessions ended when exposure reached a level with a maximum of 70-80 dB SPL. Short-term effects between the start and the end of therapy were based on tolerable level of sound exposure (dB SPL), subjective-level hinderance of hyperacusis, and sensitivity to sound using the Hyperacusis Questionnaire (HQ). The long-term effect was based on HQ 6 months after the end of therapy. Linear mixed-effects and regression models were applied to study outcomes over time. RESULTS: In total, 30 patients, 15 men and 15 women, aged between 24 and 76 years were included in this study. The mean number of sessions during therapy was 6 and ranged between 4 and 8. Results showed an increase of exposure level (mean change was +23.7 dB with an SD of 7.9, p < .001), a decrease in sensitivity to daily sounds (mean [SD] change was -1.6 [2.1], p < .001), and a decrease in HQ (mean [SD] change was -9.8 [4.9], p < .001), between the start and the end of therapy. There was no significant change in HQ after the end of therapy and 6 months later; mean (SD) change was 0.2 (4.3), p = .81. CONCLUSIONS: The evaluation of CSET indicated a decrease in short- and long-term sensitivity to sound in patients with hyperacusis. Additionally, CSET has shown a positive impact, not only for the sounds used in the therapy sessions but also in transferring benefits to everyday sounds. The results of combining psychoeducation, sound exposure, and counseling are promising and warrant further evaluation.

Health status and public health needs in a Togolese child health care centre modelled after the Dutch system.

BACKGROUND: The charity foundation Association Soutien Enfants Togo started a child health care (CHC) centre in Togo that was modelled after the Dutch high-quality CHC system to improve child health. AIM: To describe health care data of children who visited the centre. SUBJECTS AND METHODS: Data were routinely collected between October 2010-July 2017. Outcomes were completed vaccinations, growth, development, lifestyle, physical examination, and laboratory testing results. RESULTS: In total, 8,809 children aged 0-24 years were available. Half (47.5%) of children aged 0-4 years did not receive all eligible free vaccinations from the government. The proportions of stunted children (all) or with a developmental delay (0-4 years) were 10.1% and 9.5%, respectively. In total, 40-50% of all children did not wash their hands with soap after toilet or before eating, or did not use clean drinking water. Furthermore, 5.1-6.6% had insufficient vision, high eye pressure or hearing loss. Sickle cell disease was detected in 5.3%. CONCLUSION: A large group of children in need of prevention and early treatment were detected, informed and treated by the centre. Further research is needed to confirm if this strategy can improve children's health in Sub-Saharan Africa. Our data are available for further research.

An eight-year follow-up on auditory outcomes after neonatal hearing screening.

OBJECTIVE: The aim of this study is to assess the neonatal click Auditory Brainstem Response (ABR) results in relation to the subsequently determined mean hearing loss (HL) over 1, 2 and 4 kHz, as well as over 2 and 4 kHz. METHODS: Between 2004-2009, follow-up data were collected from Visual Reinforcement Audiometry (VRA) at 1 and 2 years and playaudiometry at 4 and 8 years of newborns who had failed neonatal hearing screening in the well-baby clinics and who had been referred to a single Speech and Hearing center. Hearing Level data were compared with ABR threshold-levels established during the first months of life. The Two One-Sided Tests equivalence procedure for paired means was applied, using a region of similarity equal to 10 dB. RESULTS: Initially, in 135 out of 172 children referred for diagnostic procedures hearing loss was confirmed in the neonatal period. In 106/135 of the HL children the eight-year follow-up was completed. Permanent conductive HL was established in 5/106 cases; the hearing thresholds were predominantly stable over time. Temporary conductive HL was found in 48/106 cases and the loss disappeared by 4 years of age at the latest. Sensorineural hearing loss (SNHL) was found in 53/106 cases, of which 13 were unilateral and 40 bilateral. ABR levels were equivalent (within a 10 dB range) to VRA levels at age 1 and 2 and play audiometry levels at age 4 and 8, both when VRA and play audiometry were averaged over both frequency ranges. CONCLUSION: Long term follow-up data of children with SNHL suggest that the initial click ABR level established in the first months of life, are equivalent to the hearing threshold measured at the age of 1, 2, 4 and 8 years for both mean frequency ranges. Click ABR can reliably be used as starting point for long-term hearing rehabilitation.

The association between serum vitamin D status and dental caries or molar incisor hypomineralisation in 7-9-year-old Norwegian children: a cross-sectional study.

BACKGROUND: Research focusing on the association between serum vitamin D and oral health outcomes in children, such as dental caries and molar incisor hypomineralisation (MIH), shows inconsistent results. Previous studies have predominantly investigated dental caries and MIH as dichotomized outcomes, which limits the information on their distribution. In addition, the methods used for analysing serum vitamin D have varied. The present study aimed to investigate potential associations between serum vitamin D status measured by Liquid Chromatography with Tandem Mass Spectrometry (LC-MS/MS) and the prevalence, as well as the number of teeth, affected by dental caries or MIH among 7-9-year-old Norwegian children. METHODS: The study had a cross-sectional design and included 101 children aged 7-9 years. Serum 25-hydroxyvitamin D (25(OH)D) was measured and included as continuous (per 25 nmol/l) and categorised (insufficient (< 50 nmol/l) and sufficient (≥50 nmol/l)) exposure variables. Adjusted negative binomial hurdle models were used to investigate the potential associations between serum vitamin D and the oral health outcomes (dental caries and MIH) adjusted for sex, age, body mass index, season of blood draw, and mother's educational level. RESULTS: Of the 101 children in the total sample, 27% had insufficient vitamin D levels (< 50 nmol/l). The descriptive analysis indicated that the children with insufficient vitamin D levels had a higher prevalence (33.3%) and a higher number of teeth affected by dental caries (mean (SD) = 0.7 (1.4)), compared to children with sufficient levels of vitamin D (21.6% and mean (SD) = 0.4 (0.8), respectively). The same holds for MIH, with a higher prevalence (38.5%) and a higher number of teeth affected (mean (SD) = 1.2 (2.3)), compared to children with sufficient levels of vitamin D (30.1% and mean (SD) = 0.8 (1.6), respectively). However, in the adjusted hurdle model analysis, neither the prevalence or number of teeth affected by caries or MIH showed statistically significant associations with having insufficient or lower vitamin D levels. CONCLUSIONS: Vitamin D status was not significantly associated with the prevalence and number of teeth affected by caries and MIH among the participating children. Large prospective studies with multiple serum vitamin D measurements and oral examinations throughout childhood are warranted to elucidate the relationship.

Birth weight discordance in very and extremely preterm twins and the risk of neonatal hearing loss.

OBJECTIVE: Birth weight (BW) discordant twins have an increased risk of mortality and morbidity. We aimed to study the effect of BW discordance on the risk of neonatal hearing loss (NHL) in very and extremely preterm twins. STUDY DESIGN: Results of the nationwide newborn hearing screening program in Dutch Neonatal Intensive Care Units and diagnostic examination were centrally registered between 2003 and 2021 and included in this study. We selected twins and singletons with a gestational age (GA) 24- < 32 weeks. Logistic regression analyses were applied to study the effect of BW discordance on the risk of NHL adjusted for BW, GA and sex. Singletons and concordant twins, defined as a BW discordance of ≤20 %, were used as two reference groups. BW discordance was further categorized as medium (>20-30 %) and high (>30 %). RESULTS: In total, 3430 twins (2694 concordant, 428 medium and 308 high BW discordant), and 23,114 singletons were available. Smaller newborns of high BW discordant twins showed an increased risk of NHL compared to singletons (adjusted odds ratio with 95 % confidence interval was 3.56 (2.26-5.60)). Also, smaller newborns of medium and high BW discordant twins showed an increased risk of NHL compared to concordant twins (adjusted odds ratio with 95 % confidence interval were 1.97 (1.13-3.44) and 4.17 (2.56-6.82), respectively). No other statistically significant differences were found. CONCLUSION: BW discordance increased the risk of NHL in the smaller of the twin born very or extremely preterm. This risk increased as the weight difference increased.

Key developmental milestones helped to identify children with special educational needs and disabilities at an early stage.

AIM: Responding to developmental delay promptly is important, as it helps children to reach their full potential. This study investigated how developmental milestones predicted primary school children with special educational needs and disabilities (SEND) at an early stage. METHODS: We obtained data about 36 milestones between 12 and 45 months using the Dutch Development Instrument. Development, primary school classification and background characteristics were collected from the Dutch Preventive Child Healthcare system in Utrecht from 2008 to 2016. We investigated SEND classifications and the primary schools that the children attended at 4-12 years of age. The findings include area under the curve (AUC) data. RESULTS: Data on 30 579 children in mainstream schools and 1055 children with SEND were available. Different milestones predicted SEND classifications. Fourteen milestones and parental education predicted attendance at special needs schools with smaller classes (AUC 0.913). Nine milestones, sex, migration background and parental education predicted attendance at schools for severe communication problems (AUC 0.963). Ten milestones and parental education predicted attendance at schools for severe learning difficulties (AUC 0.995). Milestones did not accurately predict attendance at schools for severe behavioural or psychiatric problems. CONCLUSION: Milestones at 12-45 months predicted most SEND classifications at primary school age, except severe behavioural or psychiatric problems.

Curve matching to predict growth in patients receiving growth hormone therapy: An interpretable & explainable method.

Curve matching may be used to predict growth outcomes using data of patients whose growth curves resemble those of a new patient with growth hormone deficiency (GHD) and those born small for gestational age (SGA). We aimed to investigate the validity of curve matching to predict growth in patients with GHD and those born SGA receiving recombinant human growth hormone (r-hGH). Height data collected between 0-48 months of treatment were extracted from the easypod™ connect ecosystem and the easypod™ connect observational study. Selected patients with height standard deviation scores (HSDS) [-4, <-1] and age [3, <16y] at start were included. The 'Matching Database' consisted of patients' monthly HSDS obtained by the broken stick method and imputation. Standard deviation (SD) was obtained from the observed minus the predicted HSDS (error) based on matched patients within the 'Matching Database'. Data were available for 3,213 patients in the 'Matching Database', and 2,472 patients with 16,624 HSDS measurements in the observed database. When ≥2 HSDS measurements were available, the error SD for a one-year prediction was approximately 0.2, which corresponds to 1.1 cm, 1.3 cm, and 1.5 cm at 7, 11, and 15 years of age, respectively. Indication and age at treatment start (<11 vs ≥11 years) had a small impact on the error SD, with patients born SGA and patients aged <11 years at treatment start generally having slightly lower values. We conclude that curve matching is a simple and valid technique for predicting growth in patients with GHD and those born SGA.

Integrated Digital Health Solutions in the Management of Growth Disorders in Pediatric Patients Receiving Growth Hormone Therapy: A Retrospective Analysis.

Digital health has seen rapid advancements over the last few years in helping patients and their healthcare professionals better manage treatment for a variety of illnesses, including growth hormone (GH) therapy for growth disorders in children and adolescents. For children and adolescents requiring such therapy, as well as for their parents, the treatment is longitudinal and often involves daily injections plus close progress monitoring; a sometimes daunting task when young children are involved. Here, we describe our experience in offering devices and digital health tools to support GH therapy across some 40 countries. We also discuss how this ecosystem of care has evolved over the years based on learnings and advances in technology. Finally, we offer a glimpse of future planned enhancements and directions for digital health to play a bigger role in better managing conditions treated with GH therapy, as well as model development for adherence prediction. The continued aim of these technologies is to improve clinical decision making and support for GH-treated patients, leading to better outcomes.

Adherence to r-hGH Therapy in Pediatric Growth Hormone Deficiency: Current Perspectives on How Patient-Generated Data Will Transform r-hGH Treatment Towards Integrated Care.

Pediatric growth hormone (GH) deficiency is a licensed indication for replacement therapy with recombinant human growth hormone (r-hGH). Treatment, consisting of daily subcutaneous injections, extends from the time of diagnosis until cessation of linear growth at completion of puberty. Suboptimal adherence to r-hGH therapy is common and has been well documented to substantially impair the growth response and achievement of the optimal goal which is attainment of adult height within the genetic target range. The causes of poor adherence are complex and include disease-, patient-, doctor-, and treatment-related factors. Interventions for suboptimal adherence are important for a long-term successful outcome and can include both face-to-face and digital strategies. Face-to-face interventions include behavioral change approaches such as motivational interviewing and non-judgmental assessment. Medical and nursing staff require training in these techniques. Digital solutions are rapidly advancing as evidenced by the electronic digital auto-injector device, easypod® (Merck Healthcare KGaA, Darmstadt, Germany), which uses the web-based easypod® connect platform allowing adherence data to be transmitted electronically to healthcare professionals (HCPs), who can then access GH treatment history, enhancing clinical decisions. Over the past 10 years, the multi-national Easypod® Connect Observational Study has reported high levels of adherence (>85%) from up to 40 countries. The easypod® connect system can be supported by a smartphone app, growlink™, which facilitates the interactions between the patients, their care team, and patient support services. HCPs are empowered by new digital techniques, however, the human-digital partnership remains essential for optimal growth management. The pediatric patient on r-hGH therapy will benefit from these innovations to enhance adherence and optimize long-term response.

Rates of spectacle wear in early childhood in the Netherlands.

BACKGROUND: Refractive errors are relatively common all around the world. In particular, early onset myopia is associated with a significant burden in later life. Little is known about refractive errors in preschool children. The aim of this study was to assess the prevalence of spectacle wear, visual acuity and refractive errors in young Dutch children. METHODS: We analyzed data of three prospective population-based studies: 99,660 3- to 5-year-olds undergoing vision screening at preventive child healthcare organizations, 6934 6-year-olds from the Generation R study, and 2974 7-year-olds from the RAMSES study. Visual acuity was measured with Landolt-C or LEA charts, spectacle wear was assessed, and refractive errors at age 6 and 7 were measured with cycloplegic refraction. RESULTS: The prevalence of spectacle wear ranged from 1.5 to 11.8% between 3 to 7 years with no significant gender differences. Among children with spectacle wear at 6 years (N = 583) and 7 years (N = 350) 29.8 and 34.6% had myopia respectively, of which 21.1 and 21.6% combined with astigmatism; 19.6 and 6.8% had hyperopia, 37.2 and 11.1% hyperopia and astigmatism, and 12.5 and 32.7% astigmatism only. CONCLUSIONS: Spectacle wear in European children starts early in preschool and increases to a relatively frequent visual aid at school age. Advocating early detection and monitoring of refraction errors is warranted in order to prevent visual morbidities later in life.

Use of machine learning to identify patients at risk of sub-optimal adherence: study based on real-world data from 10,929 children using a connected auto-injector device.

BACKGROUND: Our aim was to develop a machine learning model, using real-world data captured from a connected auto-injector device and from early indicators from the first 3 months of treatment, to predict sub-optimal adherence to recombinant human growth hormone (r-hGH) in patients with growth disorders. METHODS: Adherence to r-hGH treatment was assessed in children (aged < 18 years) who started using a connected auto-injector device (easypod™), and transmitted injection data for ≥ 12 months. Adherence in the following 3, 6, or 9 months after treatment start was categorized as optimal (≥ 85%) versus sub-optimal (< 85%). Logistic regression and tree-based models were applied. RESULTS: Data from 10,929 children showed that a random forest model with mean and standard deviation of adherence over the first 3 months, infrequent transmission of data, not changing certain comfort settings, and starting treatment at an older age was important in predicting the risk of sub-optimal adherence in the following 3, 6, or 9 months. Sensitivities ranged between 0.72 and 0.77, and specificities between 0.80 and 0.81. CONCLUSIONS: To the authors' knowledge, this is the first attempt to integrate a machine learning model into a digital health ecosystem to help healthcare providers to identify patients at risk of sub-optimal adherence to r-hGH in the following 3, 6, or 9 months. This information, together with patient-specific indicators of sub-optimal adherence, can be used to provide support to at-risk patients and their caregivers to achieve optimal adherence and, subsequently, improve clinical outcomes.

Observed High Adherence to Recombinant Human Growth Hormone Treatment Using a Multi-Component Approach to Improve Adherence in Individuals with Growth Disorders.

We explored whether a multi-component approach - using a digital health device, the easypod™ auto-injector, the 'MySupport' patient support programme (PSP) and a Patient Activation Measure® (PAM®) - could improve adherence in patients receiving recombinant human growth hormone (r-hGH). A 13-item PAM was used to assess caregiver self-reported knowledge, resulting in two PAM scores for 88 patients at four UK hospitals after an average of 5.6 months. Most patients improved their PAM score by ≥1 level (43%) or maintained it (>-1 and <1; 21%). In parallel, 74% of patients maintained (-5 to +5%) or improved (≥5%) their adherence. Further studies are required to evaluate a multi-component approach to adherence in a larger population and for a longer duration.

Validity of data collection methods for time spent, professional involvement and treatment volume for the purpose of cost-effectiveness studies in dentistry.

OBJECTIVES: Economic evaluations can support provision of adequate and affordable oral care, requiring valid information on costs. The aim was to assess the validity of (a) patients' self-report (PS) and routine electronic patient records (EPR) regarding time spent per visit and (b) PS regarding types of treatment and type of dental professionals involved. METHODS: Data were collected in four dental clinics regarding time spent using PS and EPR, on types of treatment and dental professionals involved using PS. As reference standard for time spent, independent research assistants (RA) collected data on time per visit using stopwatches. As reference standard for types of treatment and of dental professionals involved, we used the dental clinic's Electronic Patient Files (DEPF). The two one-sided tests (TOST) equivalence procedure for the difference between paired means for time and kappa statistics for treatment and professional were used to assess agreement of data collection methods with the reference standards. RESULTS: Equivalence and agreement was good between (a) PS and RA registration concerning waiting time, appointment time and total time spent and (b) EPR and DEPF concerning appointment time. Agreement between PS and DEPF concerning types of treatment was moderate to fair (kappa values between 0.49 and 0.56 for preventive consultation, restoration, radiographs and extractions and between 0.15 and 0.26 for fluoride applications and sealants). Agreement between PS and DEPF for dental professional involved was fair (kappa = 0.41). CONCLUSIONS: Data collection regarding time using PS and EPR was valid. Data collection via PS on treatment and professionals involved were not sufficiently valid and should occur via DEPF.

Adherence to Growth Hormone Treatment Using a Connected Device in Latin America: Real-World Exploratory Descriptive Analysis Study.

BACKGROUND: Recombinant human growth hormone (rhGH) therapy is an effective treatment for children with growth disorders. However, poor outcomes are often associated with suboptimal adherence to treatment. OBJECTIVE: The easypod connected injection device records and transmits injection settings and dose data from patients receiving rhGH. In this study, we evaluated adherence to rhGH treatment, and associated growth outcomes, in Latin American patients. METHODS: Adherence and growth data from patients aged 2-18 years from 12 Latin American countries were analyzed. Adherence data were available for 6207 patients with 2,449,879 injections, and growth data were available for 497 patients with 2232 measurements. Adherence was categorized, based on milligrams of rhGH injected versus milligrams of rhGH prescribed, as high (≥85%), intermediate (>56%-<85%), or low (≤56%). Transmission frequency was categorized as high (≥1 per 3 months) or low (<1 per 3 months). Chi-square tests were applied to study the effect of pubertal status at treatment start and sex on high adherence, and to test differences in frequency transmission between the three adherence levels. Multilevel linear regression techniques were applied to study the effect of adherence on observed change in height standard deviation score (∆HSDS). RESULTS: Overall, 68% (4213/6207), 25% (n=1574), and 7% (n=420) of patients had high, intermediate, and low adherence, respectively. Pubertal status at treatment start and sex did not have a significant effect on high adherence. Significant differences were found in the proportion of patients with high transmission frequency between high (2018/3404, 59%), intermediate (608/1331, 46%), and low (123/351, 35%) adherence groups (P<.001). Adherence level had a significant effect on ∆HSDS (P=.006). Mean catch-up growth between 0-24 months was +0.65 SD overall (+0.52 SD in patients with low/intermediate monthly adherence and +0.69 SD in patients with high monthly adherence). This difference translated into 1.1 cm greater catch-up growth with high adherence. CONCLUSIONS: The data extracted from the easypod Connect ecosystem showed high adherence to rhGH treatment in Latin American patients, with positive growth outcomes, indicating the importance of connected device solutions for rhGH treatment in patients with growth disorders.

A Data-Driven Intervention Framework for Improving Adherence to Growth Hormone Therapy Based on Clustering Analysis and Traffic Light Alerting Systems.

Recombinant human growth hormone (r-hGH) is an established therapy for growth hormone deficiency (GHD); yet, some patients fail to achieve their full height potential, with poor adherence and persistence with the prescribed regimen often a contributing factor. A data-driven clinical decision support system based on "traffic light" visualizations for adherence risk management of patients receiving r-hGH treatment was developed. This research was feasible thanks to data-sharing agreements that allowed the creation of these models using real-world data of r-hGH adherence from easypod™ connect; data was retrieved for 11,015 children receiving r-hGH therapy for ≥180 days. Patients' adherence to therapy was represented using four values (mean and standard deviation [SD] of daily adherence and hours to next injection). Cluster analysis was used to categorize adherence patterns using a Gaussian mixture model. Following a traffic lights-inspired visualization approach, the algorithm was set to generate three clusters: green, yellow, or red status, corresponding to high, medium, and low adherence, respectively. The area under the receiver operating characteristic curve (AUC-ROC) was used to find optimum thresholds for independent traffic lights according to each metric. The most appropriate traffic light used the SD of the hours to the next injection, with an AUC-ROC value of 0.85 when compared to the complex clustering algorithm. For the daily adherence-based traffic lights, optimum thresholds were >0.82 (SD, <0.37), 0.53-0.82 (SD, 0.37-0.61), and <0.53 (SD, >0.61) for high, medium, and low adherence, respectively. For hours to next injection, the corresponding optimum thresholds were <27.18 (SD, <10.06), 27.18-34.01 (SD, 10.06-29.63), and >34.01 (SD, >29.63). Our research indicates that implementation of a practical data-driven alert system based on recognised traffic-light coding would enable healthcare practitioners to monitor sub-optimally-adherent patients to r-hGH treatment for early intervention to improve treatment outcomes.

Exploring the Effects of Environmental Factors on the Development of 0-4-Year Old Children in The Netherlands.

Air pollution, noise, and green space are important environmental exposures, having been linked to a variety of specific health outcomes. However, there are few studies addressing overall early life development. To assess their effects, associations between developmental milestones for a large population of 0-4-year old children in The Netherlands and environmental exposures were explored. Developmental milestones and background characteristics were provided by Preventive Child Health Care (PCHC) and supplemented with data from Statistics Netherlands. Milestones were summarized and standardized into an aggregate score measuring global development. Four age groups were selected. Environmental exposures were assigned to geocoded addresses using publicly available maps for PM2.5, PM10, PMcoarse, NO2, EC, road traffic noise, and green space. Associations were investigated using single and multiple-exposure logistic regression models. 43,916 PCHC visits by 29,524 children were available. No consistent associations were found for air pollution and road traffic noise. Green space was positively associated in single and multiple-exposure models although it was not significant in all age groups (OR 1.01 (0.95; 1.08) (1 year) to 1.07 (1.01; 1.14) (2 years)). No consistent associations were found between air pollution, road traffic noise, and global child development. A positive association of green space was indicated.

Using Deep Learning for Individual-Level Predictions of Adherence with Growth Hormone Therapy.

The problem of consistent therapy adherence is a current challenge for health informatics, and its solution can increase the success rate of treatments. Here we show a methodology to predict, at individual-level, future therapy adherence for patients receiving daily injections of growth hormone (GH) therapy for GH deficiency. Our proposed model is able to generate predictions of future adherence using a recurrent neural network with adherence data recorded by easypodTM, a connected autoinjection device. The model was trained with a multi-year long dataset with 2500 patients, from January 2007 to June 2019. When testing, the model reached an average sensitivity of 0.70 and a specificity of 0.88 per patient when predicting non-adherence (<85%) periods. When evaluated with thousands of therapy segments extracted from a test set, our model reached an AUC-PR score of 0.79 and AUC-ROC of 0.90; both metrics were consistently better than traditional approaches, such as simple average model. Using this model, we can perform precise early identification of patients who are likely to become non-adherent patients. This opens a path for healthcare practitioners to personalize GH therapy at any stage of the patients' journey and improve shared decision making with patients and caregivers to achieve optimal outcomes.