Birth-death prior on phylogeny and speed dating

<p>Abstract</p> <p>Background</p> <p>In recent years there has been a trend of leaving the strict molecular clock in order to infer dating of speciations and other evolutionary events. Explicit modeling of substitution rates and divergence times makes formulation of informative prior distributions for branch lengths possible. Models with birth-death priors on tree branching and auto-correlated or <it>iid </it>substitution rates among lineages have been proposed, enabling simultaneous inference of substitution rates and divergence times. This problem has, however, mainly been analysed in the Markov chain Monte Carlo (MCMC) framework, an approach requiring computation times of hours or days when applied to large phylogenies.</p> <p>Results</p> <p>We demonstrate that a hill-climbing maximum <it>a posteriori </it>(MAP) adaptation of the MCMC scheme results in considerable gain in computational efficiency. We demonstrate also that a novel dynamic programming (DP) algorithm for branch length factorization, useful both in the hill-climbing and in the MCMC setting, further reduces computation time. For the problem of inferring rates and times parameters on a fixed tree, we perform simulations, comparisons between hill-climbing and MCMC on a plant <it>rbcL </it>gene dataset, and dating analysis on an animal mtDNA dataset, showing that our methodology enables efficient, highly accurate analysis of very large trees. Datasets requiring a computation time of several days with MCMC can with our MAP algorithm be accurately analysed in less than a minute. From the results of our example analyses, we conclude that our methodology generally avoids getting trapped early in local optima. For the cases where this nevertheless can be a problem, for instance when we in addition to the parameters also infer the tree topology, we show that the problem can be evaded by using a simulated-annealing like (SAL) method in which we favour tree swaps early in the inference while biasing our focus towards rate and time parameter changes later on.</p> <p>Conclusion</p> <p>Our contribution leaves the field open for fast and accurate dating analysis of nucleotide sequence data. Modeling branch substitutions rates and divergence times separately allows us to include birth-death priors on the times without the assumption of a molecular clock. The methodology is easily adapted to take data from fossil records into account and it can be used together with a broad range of rate and substitution models.</p

Estimated health economic impact of conducting urine albumin-to-creatinine ratio testing alongside estimated glomerular filtration rate testing in the early stages of chronic kidney disease in patients with type 2 diabetes

Aim: To estimate the health economic impact of undertaking urine albumin-to-creatinine ratio (UACR) testing versus no UACR testing in early stages of chronic kidney disease (CKD) progression in patients with type 2 diabetes (T2D). Methods: An economic model, taking a UK healthcare system perspective, estimated the impact of UACR testing on additional costs, clinical benefits measured as prevented dialyses and cardiovascular-related deaths, life years gained (LYg), LYg before kidney failure, and incremental cost-effectiveness ratio (ICER). Sixteen of the 18 Kidney Disease: Improving Global Outcomes (KDIGO) heatmap categories were considered separately, and grouped in health states according to CKD risk. Results were derived for current standard-of-care and emerging CKD therapies. Results: The cohort that adhered to both UACR and estimated glomerular filtration rate (eGFR) testing guidelines in early stages of CKD (n = 1000) was associated with approximately 500 LYg before kidney failure onset; costing approximately £2.5 M. ICERs across the KDIGO heatmap categories were approximately £5,000. Limitations: This model used data from a comprehensive meta-analysis that was initiated more than 10 years ago (2009). While this was the most comprehensive source identified, recent changes in the treatment landscape, patient population and social determinants of CKD will not be captured. Furthermore, a narrow approach was taken, aligning included costs with UK NHS reference materials. This means that some direct and indirect drivers of costs in late-stage disease have been excluded. Conclusions: UACR testing in the early stages of CKD is cost effective in T2D patients. Emerging therapies with the potential to slow CKD progression, mean that optimal monitoring through UACR/eGFR testing will become increasingly important for accurate identification and timely treatment initiation, particularly for the highest-risk A3 category

Improved gene tree error correction in the presence of horizontal gene transfer

Motivation: The accurate inference of gene trees is a necessary step in many evolutionary studies. Although the problem of accurate gene tree inference has received considerable attention, most existing methods are only applicable to gene families unaffected by horizontal gene transfer. As a result, the accurate inference of gene trees affected by horizontal gene transfer remains a largely unaddressed problem. Results: In this study, we introduce a new and highly effective method for gene tree error correction in the presence of horizontal gene transfer. Our method efficiently models horizontal gene transfers, gene duplications and losses, and uses a statistical hypothesis testing framework [Shimodaira–Hasegawa (SH) test] to balance sequence likelihood with topological information from a known species tree. Using a thorough simulation study, we show that existing phylogenetic methods yield inaccurate gene trees when applied to horizontally transferred gene families and that our method dramatically improves gene tree accuracy. We apply our method to a dataset of 11 cyanobacterial species and demonstrate the large impact of gene tree accuracy on downstream evolutionary analyses. Availability and implementation: An implementation of our method is available at http://compbio.mit.edu/treefix-dtl/National Science Foundation (U.S.) (CAREER Award 0644282)National Institutes of Health (U.S.) (RC2 HG005639)National Science Foundation (U.S.). Assembling the Tree of Life (Program) (0936234)University of Connecticu

Taking advantage of phylogenetic trees in comparative genomics

Phylogenomics can be regarded as evolution and genomics in co-operation. Various kinds of evolutionary studies, gene family analysis among them, demand access to genome-scale datasets. But it is also clear that many genomics studies, such as assignment of gene function, are much improved by evolutionary analysis. The work leading to this thesis is a contribution to the phylogenomics field. We have used phylogenetic relationships between species in genome-scale searches for two intriguing genomic features, namely and A-to-I RNA editing. In the first case we used pairwise species comparisons, specifically human-mouse and human-chimpanzee, to infer existence of functional mammalian pseudogenes. In the second case we profited upon later years' rapid growth of the number of sequenced genomes, and used 17-species multiple sequence alignments. In both these studies we have used non-genomic data, gene expression data and synteny relations among these, to verify predictions. In the A-to-I editing project we used 454 sequencing for experimental verification. We have further contributed a maximum a posteriori (MAP) method for fast and accurate dating analysis of speciations and other evolutionary events. This work follows recent years' trend of leaving the strict molecular clock when performing phylogenetic inference. We discretised the time interval from the leaves to the root in the tree, and used a dynamic programming (DP) algorithm to optimally factorise branch lengths into substitution rates and divergence times. We analysed two biological datasets and compared our results with recent MCMC-based methodologies. The dating point estimates that our method delivers were found to be of high quality while the gain in speed was dramatic. Finally we applied the DP strategy in a new setting. This time we used a grid laid out on a species tree instead of on an interval. The discretisation gives together with speciation times a common timeframe for a gene tree and the corresponding species tree. This is the key to integration of the sequence evolution process and the gene evolution process. Out of several potential application areas we chose gene tree reconstruction. We performed genome-wide analysis of yeast gene families and found that our methodology performs very well.QC 2010092

Priorities at group level within assistive technology activities : experiences from a development work in Region Halland

Uppdraget Hjälpmedelscentrum har är att förse Hallands invånare med hjälpmedel. För att skapa en röd tråd mellan hjälpmedel hos Hallands invånare till besluten i den politiska nämnd som har yttersta ansvaret för vilka hjälpmedel som förskrivs i Halland behövde Hjälpmedelscentrum en transparant modell kring prioriteringar och beslutsunderlag, en modell grundad i medicinska behov, hälso- och sjukvårdens etiska plattform samt inkluderande ett hälsoekonomiskt perspektiv. Det primära syftet med förstudien var att rent praktiskt arbeta med ett verkligt hjälpmedelsärende genom stöd av Nationell modell för öppna prioriteringar inom hälso- och sjukvård i syfte att skapa en djupare förståelse och kunskap om modellens tillämpning på gruppnivå utifrån Hjälpmedelscentrums egna tvärprofessionella förutsättningar. Ett andra syfte har handlat om att identifiera förutsättningar för en implementering av modellen inom Hjälpmedelscentrum. Förstudien har genomförts digitalt vilket ställt särskilda krav på upplägget och dokumentationen av arbetet. Hjälpmedelscentrums yrkesfunktioner har funnits representerade vid de 25 mötestillfällena som förstudien bestod av, möten som följde stegen i Nationell modell. Arbetssättet upplevdes som omständligt och tidskrävande jämfört med dagens arbetssätt och tankesättet kring gruppnivå istället för individnivå var ovant. Trots det ser arbetsgruppen vikten av att ta välgrundade beslut och förhoppningen är att tidsåtgången kommer att bli mer effektiv när arbetssättet etablerats i organisationen. Verksamhetsledningen har därför tagit beslut att implementera arbetssättet under 2021–2022 vilket resulterar i att ett implementeringsprojekt nu tar vid. Vid en planerad implementering krävs en utbildningsinsats för berörd personal. Det behövs även en arbetsgrupp som har en djupare kunskap om modellen och som kan fungera som ambassadörer för det arbetssätt som i sina byggstenar bör genomsyra det dagliga prioriteringsarbetet på Hjälpmedelscentrum. Verksamheten behöver också säkerhetsställa uppbyggnad av ett etiskt råd för reflektioner som rör ställningstaganden i samband med prioriteringar.The task of Hjälpmedelscentrum (Center for Assistive Technology) is to provide Halland's residents with assistive technology. In order to achieve a common thread running from the need of Halland's residents to the political committee, that has the ultimate responsibility for which assistive devices are prescribed in Halland, Hjälpmedelscentrum needed a transparent model for priority setting, based on medical needs, ethical principles and a health economic perspective. The primary aim of this project was to obtain a deeper understanding of how to applicate a National Model for Transparent Prioritisation in Swedish Health Care at group level, based on Hjälpmedelscentrums own interprofessional prerequisites, by testing the model practically on a real assistive technology case. The model includes assessment of severity level of ill health conditions, patient-benefit of interventions, evidence and cost-effectiveness. A second purpose has been to identify pre-conditions for an implementation of the model within Hjälpmedelscentrum. The pilot project and its 25 meetings has been carried out digitally, which places special demands on the structure and documentation of the work. A broad range of Hjälpmedelscentrum´s professional functions were represented at the meetings, meetings that followed the steps in the National Model. The method was perceived as cumbersome and time-consuming compared with the current decision processes, and the way of thinking about priority setting on group level instead of on individual level felt unfamiliar. However, the project group sees the importance of making informed decisions and the hope is that the time required will be more efficient when the model is established in the organization. The management group has therefore decided to implement the model during 2021-2022, which results in an implementation project now taking over. An implementation requires a broader training for the staff concerned, carried out by employees with a deeper knowledge of the model. The business also needs to ensure the establishment of an ethical council for reflections upon different standpoints in connection with priority setting