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King, A.

Publications and source records attributed to King, A..

41 records · Page 3Linked to original sources

Comparison of alternative models of human movement and the spread of disease

Predictive models for the spatial spread of infectious diseases has received much attention in recent years as tools for the management of infectious diseas outbreaks. Prominently, various versions of the so-called gravity model, borrowed from transportation theory, have been used. However, the original literature suggests that the model has some potential misspecifications inasmuch as it fails to capture higher-order interactions among population centers. The fields of economics, geography and network sciences holds alternative formulations for the spatial coupling within and among conurbations. These includes Stouffers rank model, Fotheringhams competing destinations model and the radiation model of Simini et al. Since the spread of infectious disease reflects mobility through the filter of age-specific susceptibility and infectivity and since, moreover, disease may alter spatial behavior, it is essential to confront with epidemiological data on spread. To study their relative merit we, accordingly, fit variants of these models to the uniquely detailed dataset of prevaccination measles in the 954 cities and towns of England and Wales over the years 1944-65 and compare them using a consistent likelihood framework. We find that while the gravity model is a reasonable first approximation, both Stouffers rank model, an extended version of the radiation model and the Fotheringham competing destinations model provide significantly better fits, Stouffers model being the best. Through a new method of spatially disaggregated likelihoods we identify areas of relatively poorer fit, and show that it is indeed in densely-populated conurbations that higher order spatial interactions are most important. Our main conclusion is that it is premature to narrow in on a single class of models for predicting spatial spread of infectious disease. The supplemental materials contain all code for reproducing the results and applying the methods to other data sets. Author summaryThe ability to predict how infectious disease will spread is of great importance in the face of the numerous emergent and re-emergent pathogens that currently threatening human well-being. We identified a variety of alternative models that predict human mobility as as a function of population distribution across a landscape. These consider some models that account for pair-wise interactions between population centers, as well as some that allow for higher-order interactions. We trained the models using a uniquely rich spatiotemporal data set on pre-vaccination measles in England and wales (1944-65), which comprises more than a million records from 954 cities and towns. Likelihood rankings of the different models reveal strong evidence for higher-order interactions in the form of competition among cities as destinations for travelers and, thus, dilution of spatial transmission. The currently most commonly used so-called gravity models were far from the best in capturing spatial disease dynamics.

ecology↗

An integrated platform to systematically identify causal variants and genes for polygenic human traits.

Genome-wide association studies (GWAS) have identified over 150,000 links between common genetic variants and human traits or complex diseases. Over 80% of these associations map to polymorphisms in non-coding DNA. Therefore, the challenge is to identify disease-causing variants, the genes they affect, and the cells in which these effects occur. We have developed a platform using ATAC-seq, DNaseI footprints, NG Capture-C and machine learning to address this challenge. Applying this approach to red blood cell traits identifies a significant proportion of known causative variants and their effector genes, which we show can be validated by direct in vivo modelling.

genetics↗

Hippocampal subfield volumes are uniquely affected in PTSD and depression: International analysis of 31 cohorts from the PGC-ENIGMA PTSD Working Group

BackgroundPTSD and depression commonly co-occur and have been associated with smaller hippocampal volumes compared to healthy and trauma-exposed controls. However, the hippocampus is heterogeneous, with subregions that may be uniquely affected in individuals with PTSD and depression.\n\nMethodsWe used random effects regressions and a harmonized neuroimaging protocol based on FreeSurfer (v6.0) to identify sub-structural hippocampal markers of current PTSD (C-PTSD), depression, and the interaction of these conditions across 31 cohorts worldwide (N=3,115; Mage=38.9{+/-}13.9 years). Secondary analyses tested these associations by sex and after modeling the simultaneous effects of remitted PTSD, childhood trauma, mild traumatic brain injury, and alcohol use disorder.\n\nResultsA significant negative main effect of depression (n=800, vs. no depression, n=1456) was observed in the hippocampal tail ({beta}=-0.13) and CA1 ({beta}=-0.09) after adjusting for covariates and multiple testing (adjusted ps (q)=0.028). A main effect of C-PTSD (n=1042 vs. control, n=1359) was not significant, but an interaction between C-PTSD and depression was significant in the CA1 ({beta}=-0.24, q=0.044). Pairwise comparisons revealed significantly smaller CA1 volumes in individuals with C-PTSD+Depression than controls ({beta}=-0.12, q=0.012), C-PTSD-only ({beta}=-0.17, q=0.001), and Depression-only ({beta}=-0.18, q=0.023). Follow-up analyses revealed sex effects in the hippocampal tail of depressed females, and an interaction effect of C-PTSD and depression in the fimbria of males.\n\nConclusionsCollectively our results suggest that depression is a stronger predictor of hippocampal volumetry than PTSD, particularly in the CA1, and provide compelling evidence of more pronounced hippocampal phenotypes in comorbid PTSD and depression compared to either condition alone.

neuroscience↗

Stirred Suspension Bioreactor Culture of Porcine Induced Pluripotent Stem Cells

Induced pluripotent stem cells (iPSCs) are an attractive cell source for regenerative medicine and the development of therapies, as they can proliferate indefinitely under defined conditions and differentiate into any cell type in the body. Large scale expansion of cells is limited in adherent culture, making it difficult to obtain adequate cell numbers for research. It has been previously shown that stirred suspension bioreactors (SSBs) can be used to culture mouse and human stem cells. Pigs are important pre-clinical models for stem cell research. Therefore, this study investigated the use of SSBs as an alternative culture method for the expansion of iPSCs. Using an established porcine iPSC line as well as a new cell line derived and characterized in the current study, we report that porcine iPSCs (piPSCs) can grow in SSB while maintaining characteristics of pluripotency and karyotypic stability similar to cells grown in traditional two-dimensional static culture. This culture method provides a suitable platform for scale up of cell culture to provide adequate cell numbers for future research applications involving porcine induced pluripotent stem cells.

cell biology↗

A Pre-transplant Blood-based Lipid Signature for Prediction of Antibody-mediated Rejection in Kidney Transplant Patients

There is a lack of biomarkers for pre-kidney transplant immune risk stratification to avoid over- or under-immunosuppression, despite substantial advances in kidney transplant management. Since the circulating lipidome is integrally involved in various inflammatory process and pathophysiology of several immune response, we hypothesized that the lipidome may provide biomarkers that are helpful in the prediction of kidney rejection. Serial plasma samples collected over 1-year post-kidney transplant from a prospective, observational cohort of 45 adult Kidney Transplant [antibody-mediated rejection (AMR)=16; stable controls (SC) =29] patients, were assayed for 210 unique lipid metabolites by quantitative mass spectrometry. A stepwise regularized linear discriminant analysis (RLDA) was used to generate models of predictors of rejection and multivariate statistics was used to identify metabolic group differences. The RLDA models include lipids as well as of calculated panel reactive antibody (cPRA) and presence of significant donor-specific antibody (DSA) at the time of transplant. Analysis of lipids on day of transplant (T1) samples revealed a 7-lipid classifier (lysophosphatidylethanolamine and phosphatidylcholine species) which discriminated between AMR and SC with a misclassification rate of 8.9% [AUC = 0.95 (95% CI = 0.84-0.98), R2 = 0.63]. A clinical model using cPRA and DSA was inferior and produced a misclassification rate of 15.6% [AUC = 0.82 (95% CI = 0.69-0.93), R2 = 0.41]. A stepwise combined model using 4 lipid classifiers and DSA improved the AUC further to 0.98 (95% CI = 0.89-1.0, R2 = 0.83) with a misclassification of only 2.2%. Specific classes of lipids were lower in AMR compared with SC. Serial analysis of SC patients demonstrated metabolic changes between T1 and 6 months (T2) post-transplant, but not between 6 and 12 (T3) months post-transplant. There were no overtime changes in AMR patients. Analysis of SC T1 vs AMR T3 (that at time of AMR) showed sustained decreased levels of lipids in AMR at the time of rejection. These findings suggest that lack of anti-inflammatory polyunsaturated phospholipids differentiate SC from AMR pre-transplant and at the time of rejection, and a composite model using a 4-lipid classifier along with DSA could be used for prediction of antibody-mediated rejection before transplant. HighlightsO_LIDespite significant advancements in kidney transplant treatment and intensive clinical follow-up monitoring, all rejection events are unlikely to be recognized at the beginning. As a result, efforts have been made to identify new biomarkers for kidney rejection detection. C_LIO_LIWhile lipids are known to be potent mediators of inflammation, pro-resolving processes, and other cell signaling cascades, lipidomics can be applied to identify reliable biomarkers to monitor disease severity and may also allow prediction of kidney rejection. C_LIO_LIOur lipidomic study shows lipid profile changes between antibody-mediated rejection group and stable control group as a function of different time point, pre and post-kidney transplantation. Furthermore, our study demonstrates that combining lipid and clinical parameters allow prediction of rejection on the day of the transplant. C_LIO_LIThese findings have the potential to change the present paradigm of pre and post-transplant monitoring and management of these patients by implementing an evidence-based risk stratification technique, resulting in a substantial improvement in kidney transplant success. C_LI

biochemistry↗