Cross-Validation of a Glucose-Insulin-Glucagon Pharmacodynamics Model for Simulation using Data from Patients with Type 1 Diabetes

Background: Currently, no consensus exists on a model describing endogenous glucose production (EGP) as a function of glucagon concentrations. Reliable simulations to determine the glucagon dose preventing or treating hypoglycemia or to tune a dual-hormone artificial pancreas control algorithm need a validated glucoregulatory model including the effect of glucagon. Methods: Eight type 1 diabetes (T1D) patients each received a subcutaneous (SC) bolus of insulin on four study days to induce mild hypoglycemia followed by a SC bolus of saline or 100, 200, or 300 µg of glucagon. Blood samples were analyzed for concentrations of glucagon, insulin, and glucose. We fitted pharmacokinetic (PK) models to insulin and glucagon data using maximum likelihood and maximum a posteriori estimation methods. Similarly, we fitted a pharmacodynamic (PD) model to glucose data. The PD model included multiplicative effects of insulin and glucagon on EGP. Bias and precision of PD model test fits were assessed by mean predictive error (MPE) and mean absolute predictive error (MAPE). Results: Assuming constant variables in a subject across nonoutlier visits and using thresholds of ±15% MPE and 20% MAPE, we accepted at least one and at most three PD model test fits in each of the seven subjects. Thus, we successfully validated the PD model by leave-one-out cross-validation in seven out of eight T1D patients. Conclusions: The PD model accurately simulates glucose excursions based on plasma insulin and glucagon concentrations. The reported PK/PD model including equations and fitted parameters allows for in silico experiments that may help improve diabetes treatment involving glucagon for prevention of hypoglycemia. </jats:sec

Practical considerations for omics experiments in biomedical sciences

Modern analytical techniques provide an unprecedented insight to biomedical samples, allowing an in depth characterization of cells or body fluids, to the level of genes, transcripts, peptides, proteins, metabolites, or metallic ions. The fine grained picture provided by such approaches holds the promise for a better understanding of complex pathologies, and consequently the personalization of diagnosis, prognosis and treatment procedures. In practice however, technical limitations restrict the resolution of the acquired data, and thus of downstream biomedical inference. As a result, the study of complex diseases like leukemia and other types of cancer is impaired by the high heterogeneity of pathologies as well as patient profiles. In this review, we propose an introduction to the general approach of characterizing samples and inferring biomedical results. We highlight the main limitations of the technique with regards to complex and heterogeneous pathologies, and provide ways to overcome these by improving the ability of experiments in discriminating samples.acceptedVersio

Towards the routine use of in silico screenings for drug discovery using metabolic modelling

Currently, the development of new effective drugs for cancer therapy is not only hindered by development costs, drug efficacy, and drug safety but also by the rapid occurrence of drug resistance in cancer. Hence, new tools are needed to study the underlying mechanisms in cancer. Here, we discuss the current use of metabolic modelling approaches to identify cancer-specific metabolism and find possible new drug targets and drugs for repurposing. Furthermore, we list valuable resources that are needed for the reconstruction of cancer-specific models by integrating various available datasets with genome-scale metabolic reconstructions using model-building algorithms. We also discuss how new drug targets can be determined by using gene essentiality analysis, an in silico method to predict essential genes in a given condition such as cancer and how synthetic lethality studies could greatly benefit cancer patients by suggesting drug combinations with reduced side effects

Targeted genomic analysis reveals widespread autoimmune disease association with regulatory variants in the TNF superfamily cytokine signalling network.

BACKGROUND: Tumour necrosis factor (TNF) superfamily cytokines and their receptors regulate diverse immune system functions through a common set of signalling pathways. Genetic variants in and expression of individual TNF superfamily cytokines, receptors and signalling proteins have been associated with autoimmune and inflammatory diseases, but their interconnected biology has been largely unexplored. METHODS: We took a hypothesis-driven approach using available genome-wide datasets to identify genetic variants regulating gene expression in the TNF superfamily cytokine signalling network and the association of these variants with autoimmune and autoinflammatory disease. Using paired gene expression and genetic data, we identified genetic variants associated with gene expression, expression quantitative trait loci (eQTLs), in four peripheral blood cell subsets. We then examined whether eQTLs were dependent on gene expression level or the presence of active enhancer chromatin marks. Using these eQTLs as genetic markers of the TNF superfamily signalling network, we performed targeted gene set association analysis in eight autoimmune and autoinflammatory disease genome-wide association studies. RESULTS: Comparison of TNF superfamily network gene expression and regulatory variants across four leucocyte subsets revealed patterns that differed between cell types. eQTLs for genes in this network were not dependent on absolute gene expression levels and were not enriched for chromatin marks of active enhancers. By examining autoimmune disease risk variants among our eQTLs, we found that risk alleles can be associated with either increased or decreased expression of co-stimulatory TNF superfamily cytokines, receptors or downstream signalling molecules. Gene set disease association analysis revealed that eQTLs for genes in the TNF superfamily pathway were associated with six of the eight autoimmune and autoinflammatory diseases examined, demonstrating associations beyond single genome-wide significant hits. CONCLUSIONS: This systematic analysis of the influence of regulatory genetic variants in the TNF superfamily network reveals widespread and diverse roles for these cytokines in susceptibility to a number of immune-mediated diseases.The Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the National Library of Medicine of the US National Institutes of Health (Intramural Research Program) , Wellcome Trust (080327/Z/06/Z, 087007/Z/08/Z, 094227/Z/10/Z, Clinical PhD Programme, 079895, 076113 and 085475) , Medical Research Council (G0400929) , National Institute for Health Research , National Institutes of Health (Oxford-Cambridge Scholars Program) , Istanbul University Research Fund and UK Behcet’s Syndrome Society.This is the final version of the article. It first appeared from BioMed Central via http://dx.doi.org/10.1186/s13073-016-0329-

Deep learning for health outcome prediction

Modern medical data contains rich information that allows us to make new types of inferences to predict health outcomes. However, the complexity of modern medical data has rendered many classical analysis approaches insufficient. Machine learning with deep neural networks enables computational models to process raw data and learn useful representations with multiple levels of abstraction. In this thesis, I present novel deep learning methods for health outcome prediction from brain MRI and genomic data. I show that a deep neural network can learn a biomarker from structural brain MRI and that this biomarker provides a useful measure for investigating brain and systemic health, can augment neuroradiological research and potentially serve as a decision-support tool in clinical environments. I also develop two tensor methods for deep neural networks: the first, tensor dropout, for improving the robustness of deep neural networks, and the second, Kronecker machines, for combining multiple sources of data to improve prediction accuracy. Finally, I present a novel deep learning method for predicting polygenic risk scores from genome sequences by leveraging both local and global interactions between genetic variants. These contributions demonstrate the benefits of using deep learning for health outcome prediction in both research and clinical settings.Open Acces

Trajectories of functioning and mental health: determinants in general population

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Psiquiatría. Fecha de lectura: 17-10-201

Data integration and simulation of population immunity at the beginning of a pandemic

Accurate knowledge of population exposure at the outset of a pandemic has critical ramifications for preparedness plans for future epidemic waves. In this thesis, I developed a mechanistically informed statistical model to integrate multiple epidemiological datasets in different settings and in different population and to estimate key epidemiological parameters as well as population exposure using Bayesian inference. First, I present a dynamic model to link together three key metrics for evaluating the progress of COVID-19 epidemic in England: seroprevalence, PR-PCR test positivity and death. While estimating the IgG antibody seroreversion rate and region-specific infection fatality ratios, I find that epidemic progression resulted in an increasing gap between measured serology prevalence levels and cumulative population exposure to the virus. Ultimately, this may mean that twice as many, or more, people have been exposed to the virus relative to the number of people who are seropositive by the end of 2020. Moreover, I demonstrate that the model could reconstruct the first, unobserved, epidemic wave of COVID-19 in England from March 2020 to June 2020 as long as two or three serological measurements are given as inputs, with the second wave during the winter of 2020 validated by the estimates from the ONS Coronavirus Infection Survey. Comparing with the inferred exposure, I find that the UK official COVID-9 online dashboard reported COVID-19 cases only accounted for less than ten percent by the end of October 2020. I then generalise the model to account for the undocumented COVID-19-related mortality and sparse measurements of seroprevalence. I apply this in the context of Afghanistan COVID- 19 epidemic and find the population exposure in nine regions of Afghanistan were all higher than the seroprevalence survey suggested by July 2020. Finally, I assess the impact of shielding among pregnant patients by comparing their exposure with the estimated exposure of the general population. To approach this, I develop a dynamic model to link RT-PCR and antibody testing results from patients who gave birth and then apply Bayesian inference to estimate transmission parameters and exposure among pregnant patients. I find that after considering the duration of each pregnancy pre-COVID onset and after, the impact of shielding on reducing the level of exposure among pregnant patients during early 2020 who gave birth in this New York City hospital were approximately 50%

Excitatory-inhibitory balance within EEG microstates and resting-state fMRI networks: assessed via simultaneous trimodal PET-MR-EEG imaging

The symbiosis of neuronal activities and glucose energy metabolism is reflected in the generation of functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) signals. However, their association with the balance between neuronal excitation and inhibition (E/I-B), which is closely related to the activities of glutamate and γ-aminobutyric acid (GABA) and the receptor availability (RA) of GABAA and mGluR5, remains unexplored. This research investigates these associations during the resting state (RS) condition using simultaneously recorded PET/MR/EEG (trimodal) data. The trimodal data were acquired from three studies using different radio-tracers such as, [11C]ABP688 (ABP) (N = 9), [11C]Flumazenil (FMZ) (N = 10) and 2-[18F]fluoro-2-deoxy-D-glucose (FDG) (N = 10) targeted to study the mGluR5, GABAA receptors and glucose metabolism respectively. Glucose metabolism and neuroreceptor binding availability (non-displaceable binding potential (BPND)) of GABAA and mGluR5 were found to be significantly higher and closely linked within core resting-state networks (RSNs). The neuronal generators of EEG microstates and the fMRI measures were most tightly associated with the BPND of GABAA relative to mGluR5 BPND and the glucose metabolism, emphasising a predominance of inhibitory processes within in the core RSNs at rest. Changes in the neuroreceptors leading to an altered coupling with glucose metabolism may render the RSNs vulnerable to psychiatric conditions. The paradigm employed here will likely help identify the precise neurobiological mechanisms behind these alterations in fMRI functional connectivity and EEG oscillations, potentially benefitting individualised healthcare treatment measures