A statistical approach to latent dynamic modeling with differential equations

Ordinary differential equations (ODEs) can provide mechanistic models of temporally local changes of processes, where parameters are often informed by external knowledge. While ODEs are popular in systems modeling, they are less established for statistical modeling of longitudinal cohort data, e.g., in a clinical setting. Yet, modeling of local changes could also be attractive for assessing the trajectory of an individual in a cohort in the immediate future given its current status, where ODE parameters could be informed by further characteristics of the individual. However, several hurdles so far limit such use of ODEs, as compared to regression-based function fitting approaches. The potentially higher level of noise in cohort data might be detrimental to ODEs, as the shape of the ODE solution heavily depends on the initial value. In addition, larger numbers of variables multiply such problems and might be difficult to handle for ODEs. To address this, we propose to use each observation in the course of time as the initial value to obtain multiple local ODE solutions and build a combined estimator of the underlying dynamics. Neural networks are used for obtaining a low-dimensional latent space for dynamic modeling from a potentially large number of variables, and for obtaining patient-specific ODE parameters from baseline variables. Simultaneous identification of dynamic models and of a latent space is enabled by recently developed differentiable programming techniques. We illustrate the proposed approach in an application with spinal muscular atrophy patients and a corresponding simulation study. In particular, modeling of local changes in health status at any point in time is contrasted to the interpretation of functions obtained from a global regression. This more generally highlights how different application settings might demand different modeling strategies.Comment: 29 pages, 6 figure

High-sensitive cardiac troponin I (hs-cTnI) concentrations in newborns diagnosed with spinal muscular atrophy

BackgroundSpinal muscular atrophy (SMA) is a genetic neurodegenerative disease leading to muscular weakness and premature death. Three therapeutic options are currently available including gene replacement therapy (GRT), which is potentially cardiotoxic. High-sensitive cardiac troponin I (hs-cTnI) is widely used to monitor potential cardiac contraindications or side effects of GRT, but reference data in healthy newborns are limited and lacking in neonates with SMA. The aim of this study is to determine the range of pre-therapeutic hs-cTnI concentrations in neonates with SMA and to provide guidance for the assessment of these values.MethodsHs-cTnI levels, genetic and clinical data of 30 newborns (age range 2–26 days) with SMA were retrospectively collected from 6 German neuromuscular centers. In addition, hs-cTnI levels were measured in 16 neonates without SMA.ResultsThe median hs-cTnI concentration in neonates with SMA was 39.5 ng/L (range: 4–1205). In 16 newborns with SMA, hs-cTnI levels were above the test-specific upper reference limit (URL). Exploratory statistical analysis revealed no relevant correlation between hs-cTnI levels and gender, gestational age, mode of delivery, SMN2 copy number, symptoms of SMA or abnormal cardiac findings.DiscussionOur results suggest higher hs-cTnI plasma levels in newborns with and without SMA compared to assay-specific reference values generated in adults. Given the wide range of hs-cTnI values in neonates with SMA, hs-cTnI levels must be determined before treatment in each patient and post-treatment elevations should be interpreted in the context of the course rather than as individual values

Evaluating case management for caregivers of children with spinal muscular atrophy type I and II—an exploratory, controlled, mixed-methods trial

IntroductionSpinal muscular atrophy (SMA) is a rare neuromuscular disease requiring various clinical specialists and therapists to provide care. Due to the disease's dynamic nature and the long distances between specialized centers and local providers, integrating care between disciplines can be challenging. Care that is inadequately integrated can compromise the quality of care and become a burden for patients and families. This trial aimed to improve the care of patients through a case management (CM) intervention.MethodsWe conducted an exploratory, controlled, two-arm trial with pre-, post-, and follow-up measures (process and outcome evaluation). Proof of efficacy based on statistical significance was not our primary study objective since we were investigating a rare disease. Primary outcomes were caregivers' HRQoL and caregiver-rated quality of care integration. Our secondary outcome was the children's HRQoL.ResultsQuestionnaires and semi-structured interviews yielded heterogeneous results depending on caregivers' level of experience and desire (or possibility) to delegate care tasks.DiscussionDespite differing perceptions, all participants supported the establishment of a care coordination model. We recommend CM immediately after diagnosis to provide the greatest benefit to families. We hope that our trial will support the further development of CM interventions that can be customized for specific diseases

Congenital myasthenic syndrome with mild intellectual disability caused by a recurrent SLC25A1 variant

Abstract: Congenital myasthenic syndromes (CMS) are a clinically and genetically heterogeneous group of disorders caused by mutations which lead to impaired neuromuscular transmission. SLC25A1 encodes a mitochondrial citrate carrier, associated mainly with the severe neurometabolic disease combined D-2- and L-2-hydroxyglutaric aciduria (D/L-2-HGA). We previously reported a single family with a homozygous missense variant in SLC25A1 with a phenotype restricted to relatively mild CMS with intellectual disability, but to date no additional cases of this CMS subtype had been reported. Here, we performed whole exome sequencing (WES) in three additional and unrelated families presenting with CMS and mild intellectual disability to identify the underlying causative gene. The WES analysis revealed the presence of a homozygous c.740G>A; p.(Arg247Gln) missense SLC25A1 variant, the same SLC25A1 variant as identified in the original family with this phenotype. Electron microscopy of muscle from two cases revealed enlarged and accumulated mitochondria. Haplotype analysis performed in two unrelated families suggested that this variant is a result of recurrent mutation and not a founder effect. This suggests that p.(Arg247Gln) is associated with a relatively mild CMS phenotype with subtle mitochondrial abnormalities, while other variants in this gene cause more severe neurometabolic disease. In conclusion, the p.(Arg247Gln) SLC25A1 variant should be considered in patients presenting with a presynaptic CMS phenotype, particularly with accompanying intellectual disability

Identification of Novel Functional Inhibitors of Acid Sphingomyelinase

We describe a hitherto unknown feature for 27 small drug-like molecules, namely functional inhibition of acid sphingomyelinase (ASM). These entities named FIASMAs (Functional Inhibitors of Acid SphingoMyelinAse), therefore, can be potentially used to treat diseases associated with enhanced activity of ASM, such as Alzheimer's disease, major depression, radiation- and chemotherapy-induced apoptosis and endotoxic shock syndrome. Residual activity of ASM measured in the presence of 10 µM drug concentration shows a bimodal distribution; thus the tested drugs can be classified into two groups with lower and higher inhibitory activity. All FIASMAs share distinct physicochemical properties in showing lipophilic and weakly basic properties. Hierarchical clustering of Tanimoto coefficients revealed that FIASMAs occur among drugs of various chemical scaffolds. Moreover, FIASMAs more frequently violate Lipinski's Rule-of-Five than compounds without effect on ASM. Inhibition of ASM appears to be associated with good permeability across the blood-brain barrier. In the present investigation, we developed a novel structure-property-activity relationship by using a random forest-based binary classification learner. Virtual screening revealed that only six out of 768 (0.78%) compounds of natural products functionally inhibit ASM, whereas this inhibitory activity occurs in 135 out of 2028 (6.66%) drugs licensed for medical use in humans

Increased von Willebrand factor parameters in children with febrile seizures.

IntroductionPrimary blood coagulation and wound sealing are orchestrated by von Willebrand factor (VWF), a large multimeric glycoprotein. Upon release of arginine vasopressin (AVP), VWF containing high molecular weight multimers is secreted. By measuring copeptin, the C-terminal part of the AVP prohormone, we recently found strongly increased AVP levels in children with febrile seizures (FS) as compared to children with fever but without seizures. It is unknown if increased AVP levels in FS are of any biological function. Therefore, our a priori hypothesis was that children with FS have increased VWF parameters in parallel with higher AVP levels.MethodsWe conducted a prospective, cross-sectional study of children aged between 6 months and 5 years. Children that presented at our emergency department with fever or a recent FS (within four hours) were evaluated to be included to the study. We measured serum copeptin and VWF parameters, including analyses of VWF:Antigen (WVF:Ag), VWF:collagen binding activity (VWF:CB) and VWF multimers in children with FS, febrile infections without seizures and additionally, in a non-febrile control group.ResultsWe included 54 children in our study, 30 with FS, 10 in the febrile control group, and 14 in the non-febrile control group. Serum copeptin levels were significantly higher in children with FS (median [IQR] 24.73 pmol/l [13.65-68.65]) compared to the febrile control group (5.66 pmol/l [4.15-8.07], p = 0.002) and the non-febrile control group (4.78 pmol/l [3.33-5.3], pConclusionsOur results suggest that increased secretion of AVP in children with FS is associated with higher plasma levels of VWF parameters. Especially VWF:CB may serve as additional biomarker in the diagnosis of FS