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.

Economic evaluation of supplemental breast cancer screening modalities to mammography or digital breast tomosynthesis in women with heterogeneously and extremely dense breasts and average or intermediate breast cancer risk in US healthcare.

OBJECTIVE: To evaluate the cost-effectiveness of supplemental breast imaging modalities for women with heterogeneously and extremely dense breasts and average or intermediate risk of breast cancer (BC) in the USA, and analyze capacity requirements for supplemental magnetic resonance imaging (MRI) and contrast-enhanced mammography (CEM). METHODS: Clinical and economic outcomes for supplemental imaging modalities including full- and abbreviated-protocol MRI (Fp-MRI, Ab-MRI), CEM, and ultrasound (U/S) as add-on to x-ray mammography (XM) or digital breast tomosynthesis (DBT), were compared to XM or DBT alone, in a decision tree linked to a Markov chain validated by comparison with a microsimulation analysis. A Delphi panel supplemented model input parameters from the literature. A capacity model evaluated the number of additional daily scans and scanners required for Fp-MRI and CEM. RESULTS: Compared to XM or DBT alone, all supplemental imaging protocols were cost-effective. Both Fp- and Ab-MRI, and to a lesser extent CEM and U/S, yielded superior clinical outcomes to XM or DBT. Compared to XM alone, U/S and Ab-MRI had the lowest incremental cost-effectiveness ratios (ICER). For U/S, the ICER was $23,394 for the average-risk population and $13,241 for the intermediate-risk population. For CEM, the ICER was $38,423 and $23,772, respectively. For the extremely dense subpopulation with intermediate risk, supplemental screening requirements could be accommodated by conducting one Fp-MRI scan per day per existing general scanner. CONCLUSIONS: While ultrasound had the lowest ICER, MRI and CEM demonstrated the best clinical outcomes, compared to XM or DBT alone for women with dense breasts and intermediate and high risk. Existing MRI scanner capacity has the potential to meet most of the supplemental screening needs of this population.

Impact of non-adherence to direct oral anticoagulants amongst Swedish patients with non-valvular atrial fibrillation: results from a real-world cost-utility analysis.

AIMS: A third of non-valvular atrial fibrillation (NVAF) patients are non-adherent to direct oral anticoagulants (DOACs). Estimates of the economic value of full adherence and the cost of two types of adherence improving interventions are important to healthcare planners and decision-makers. METHODS: A cost-utility analysis estimated the impact of non-adherence over a 20-year horizon, for a patient cohort with a mean age of 77 years, based on data from the Stockholm Healthcare database of NVAF patients with incident stroke between 2011 and 2018. Adherence was defined using a medication possession ratio (MPR) cut-off of 90%; primary outcomes were the number of ischemic strokes and associated incremental cost-utility ratio. RESULTS: Hypothetical comparisons between cohorts of 1,000 patients with varying non-adherence levels and full adherence (MPR >90%) predicted an additional number of strokes ranging from 117 (MPR = 81-90%) to 866 (MPR <60%), and years of life lost ranging from 177 (MPR = 81- 90%) to 1,318 (MPR < 60%; discounted at 3%). Chronic disease co-management intervention occurring during each DOAC prescription renewal and patient education intervention at DOAC initiation will be cost-saving to the health system if its cost is below SEK 143 and SEK 4,655, and cost-effective if below SEK 858 and SEK 28,665, respectively. CONCLUSION: Adherence improving interventions for NVAF patients on DOACs such as chronic disease co-management and patient education can be cost-saving and cost-effective, within a range of costs that appear reasonable to the Swedish healthcare system.

Atrial fibrillation (AF) is the most common type of chronic cardiac arrhythmia and a major risk factor for ischemic stroke (IS). The objective of this study was to compare the costs and health outcomes associated with adherence to direct oral anticoagulant (DOAC) therapy in Sweden. The study also aimed to demonstrate the potential benefits of developing interventions to improve DOAC adherence. DOAC therapy (DOACs; apixaban, dabigatran, edoxaban, and rivaroxaban) has been approved in Europe for the prevention of stroke in adult patients with AF. It has been demonstrated to provide warfarin-similar reductions in stroke risk in NVAF patients, with reductions in mortality and intracranial hemorrhage. However, non-adherence to DOAC medication prevents patients and healthcare systems from fully benefiting from DOAC therapy, resulting in a lower benefit than those seen in randomized controlled trials. DOAC non-adherence is where AF patients deviate from the DOAC treatment regimen as prescribed by health providers. This study suggested that non-adherence to DOAC therapy has a substantial impact on ischemic stroke risk and significant additional healthcare system costs. Patient education and chronic disease co-management (two types of DOAC adherence improving intervention) can be cost-saving and cost-effective within a range of costs that appear reasonable to the Swedish healthcare system. Healthcare policy-makers should prioritize initiatives aimed at improving DOAC adherence in order to improve outcomes in AF.

Modelling the impact of 4CMenB and MenACWY meningococcal combined vaccination strategies including potential 4CMenB cross-protection: An application to England.

Invasive meningococcal disease (IMD), an uncommon but severe disease, affects mainly infants, young children and adolescents. Meningococcal B (4CMenB) and ACWY (MenACWY) vaccines targeting IMD-causing serogroups B and A, C, W and Y, respectively are available for these mostly-affected age-groups. The objective was to assess the impact of 4CMenB and/or MenACWY vaccination strategies on IMD in England, considering MenACWY carriage protection and potential cross-protection of 4CMenB against non-B serogroups. A novel dynamic transmission model was developed, accounting for vaccine characteristics, with separate variables for meningococcal carriage and IMD for three groups: B; ACWY; and 'Other' mostly non-pathogenic serogroups. A dynamic force of infection is assumed for each group. The model analysis uses data from England before 2015 (when 4CMenB and MenACWY were introduced), and accounts for existing MenC vaccination impact. Compared with no vaccination, the smallest decrease in IMD cases is observed for MenACWY strategies (toddler and/or adolescent). 4CMenB (infant or infant/adolescent), alone or with MenACWY, always results in the most rapid and steep decline in IMD cases. Combined strategies with adolescent 4CMenB result in the largest decrease in IMD cases, whereas adding MenACWY for toddlers has a minor impact. With potential 4CMenB cross-protection, 4CMenB infant strategy has a notable impact on reduction of MenW and MenY IMD cases in strategies where MenACWY toddler and/or adolescent vaccination is absent. This novel model allows for analysis of combined 4CMenB and MenACWY strategies including potential 4CMenB cross-protection. In settings comparable to England, a comprehensive meningococcal vaccination programme should include infant 4CMenB as essential building block. Decisions to include MenACWY toddler programmes should consider herd effects of MenACWY adolescent programmes and 4CMenB potential cross-protection effects. Extending 4CMenB infant and MenACWY adolescent programmes with a 4CMenB adolescent programme allows for the largest overall reduction in IMD cases.

Cost-Effectiveness Analysis of Sequential Biologic Therapy with Ixekizumab Versus Secukinumab in the Treatment of Active Psoriatic Arthritis with Concomitant Moderate-to-Severe Psoriasis in the UK.

BACKGROUND: Interleukin-17A (IL-17A) antagonists are a recent innovation for treating psoriatic arthritis (PsA). There are currently no cost-effectiveness analyses (CEAs) comparing the IL-17A antagonists ixekizumab and secukinumab in PsA from a UK perspective. OBJECTIVE: We conducted a CEA from the UK National Health Service perspective to compare ixekizumab versus secukinumab in patients with PsA and concomitant moderate-to-severe plaque psoriasis. METHODS: A Markov model was developed based on the widely accepted York model. In biologic disease-modifying antirheumatic drug (bDMARD)-naïve patients, ixekizumab → ustekinumab → best supportive care (BSC) was compared with secukinumab → ustekinumab → BSC. For bDMARD-experienced patients, ixekizumab → BSC was compared with secukinumab → BSC. At the end of the bDMARD trial period, Psoriatic Arthritis Response Criteria (PsARC) responders continued to receive the bDMARD in the continuous treatment period. PsARC nonresponders and patients who ceased continuous treatment transitioned to the trial period of the next treatment. RESULTS: Ixekizumab was less costly and provided more quality-adjusted life-years (QALYs) than secukinumab in bDMARD-naïve and -experienced patients based on list prices, although cost savings and QALY gains were small to modest. In bDMARD-naïve patients, total costs were £155,455 compared with £155,530 for secukinumab (year 2017 values). Total QALYs were 8.127 versus 7.989. In bDMARD-experienced patients, the corresponding values were £140,051 versus £140,264 for total costs and 3.996 versus 3.875 for total QALYs. CONCLUSION: Ixekizumab provided more QALYs at a marginally lower cost than secukinumab, and the results were most sensitive to changes in drug costs. Other factors, such as patient preferences for the number of injections and confidential price discounts, may be important considerations in clinical decision-making.

Real-world cost-effectiveness of targeted therapy in metastatic renal cell carcinoma in Sweden: a population-based retrospective analysis.

OBJECTIVE: To explore cost-effectiveness of targeted therapies (TTs) in the treatment of metastatic renal cell carcinoma (mRCC) in a real-world context using a nationwide population-based approach. METHODS: Data on patients diagnosed with mRCC between 2002 and 2012 were extracted from Swedish national health data registers. To facilitate comparisons of patients diagnosed before and after TT introduction to the market, three cohorts were derived: pre-TT introduction (preTT), patients diagnosed 2002-2005; early TT introduction (TTi), patients diagnosed 2006-2008; and late TT introduction (TTii), which was limited to patients diagnosed 2009-2010 to ensure availability of total health care resource utilization (HCRU) data. Patients were followed until end of 2012. The value of TTs across cohorts was estimated using mean HCRU costs per life-year (LY) gained. Data on HCRU were obtained through national health registers for dispensed medication and inpatient and outpatient care, and the associated costs were estimated using the Lin method to account for censoring. LYs gained were defined as the difference in mean survival over the study period. RESULTS: The preTT, TTi, and TTii cohorts consisted of 1,366, 1,158, and 806 patients, respectively. Mean survival in years from mRCC diagnosis was 1.45 in the preTT cohort, 1.62 in the TTi cohort, and 1.83 in the TTii cohort. The respective mean total HCRU cost per patient over the study period was US$16,894, US$29,922, and US$30,037. The cost per LY gained per cohort was US$78,656 for TTi vs preTT, US$34,132 for TTii vs preTT, and US$523 for TTii vs TTi. CONCLUSION: Given common willingness-to-pay per LY gained thresholds, this study in a real-world population suggests the use of TTs in the Swedish mRCC population is increasingly cost-effective over time.

High-Resolution Regulatory Maps Connect Vascular Risk Variants to Disease-Related Pathways.

BACKGROUND: Genetic variant landscape of coronary artery disease is dominated by noncoding variants among which many occur within putative enhancers regulating the expression levels of relevant genes. It is crucial to assign the genetic variants to their correct genes both to gain insights into perturbed functions and better assess the risk of disease. METHODS: In this study, we generated high-resolution genomic interaction maps (≈750 bases) in aortic endothelial, smooth muscle cells and THP-1 (human leukemia monocytic cell line) macrophages stimulated with lipopolysaccharide using Hi-C coupled with sequence capture targeting 25 429 features, including variants associated with coronary artery disease. We also sequenced their transcriptomes and mapped putative enhancers using chromatin immunoprecipitation with an antibody against H3K27Ac. RESULTS: The regions interacting with promoters showed strong enrichment for enhancer elements and validated several previously known interactions and enhancers. We detected interactions for 727 risk variants obtained by genome-wide association studies and identified novel, as well as established genes and functions associated with cardiovascular diseases. We were able to assign potential target genes for additional 398 genome-wide association studies variants using haplotype information, thereby identifying additional relevant genes and functions. Importantly, we discovered that a subset of risk variants interact with multiple promoters and their expression levels were strongly correlated. CONCLUSIONS: In summary, we present a catalog of candidate genes regulated by coronary artery disease-related variants and think that it will be an invaluable resource to further the investigation of cardiovascular pathologies and disease.

HiCapTools: a software suite for probe design and proximity detection for targeted chromosome conformation capture applications.

Summary: Folding of eukaryotic genomes within nuclear space enables physical and functional contacts between regions that are otherwise kilobases away in sequence space. Targeted chromosome conformation capture methods (T2C, chi-C and HiCap) are capable of informing genomic contacts for a subset of regions targeted by probes. We here present HiCapTools, a software package that can design sequence capture probes for targeted chromosome capture applications and analyse sequencing output to detect proximities involving targeted fragments. Two probes are designed for each feature while avoiding repeat elements and non-unique regions. The data analysis suite processes alignment files to report genomic proximities for each feature at restriction fragment level and is isoform-aware for gene features. Statistical significance of contact frequencies is evaluated using an empirically derived background distribution. Targeted chromosome conformation capture applications are invaluable for locating target genes of disease-associated variants found by genome-wide association studies. Hence, we believe our software suite will prove to be useful for a wider user base within clinical and functional applications. Availability: https://github.com/sahlenlab/HiCapTools. Contact: pelinak@kth.se. Supplementary information: Supplementary data are available at Bioinformatics online.

Cost of Dementia and Its Correlation With Dependence.

OBJECTIVE: To estimate the cost of dementia care and its relation to dependence. METHOD: Disease severity and health care resource utilization was retrieved from the Swedish National Study on Aging and Care. Informal care was assessed with the Resource Utilization in Dementia instrument. A path model investigates the relationship between annual cost of care and dependence, cognitive ability, functioning, neuropsychiatric symptoms, and comorbidities. RESULTS: Average annual cost among patients diagnosed with dementia was €43,259, primarily incurred by accommodation. Resource use, that is, institutional care, community care, and accommodation, and corresponding costs increased significantly by increasing dependency. Path analysis showed that cognitive ability, functioning, and neuropsychiatric symptoms were significantly correlated with dependence, which in turn had a strong impact on annual cost. DISCUSSION: This study confirms that cost of dementia care increases with dependence and that the impact of other disease indicators is mainly mediated by dependence.

Interpreting overall survival results when progression-free survival benefits exist in today's oncology landscape: a metastatic renal cell carcinoma case study.

BACKGROUND: The debate surrounding the acceptance of progression-free survival (PFS) as an intermediate endpoint to overall survival (OS) has grown in recent years, due to the challenges in demonstrating an OS benefit within clinical trials today. PFS is generally a good predictor of OS for cases where survival post-progression (SPP) is short, and less so when SPP is long. SPP depends on multiple factors, including residual effect from experimental treatment and effect from crossover or other subsequent therapies, posing unique challenges into the translation of PFS benefit into OS. METHODS: The objective of this analysis was to conduct simulations investigating how increasing SPP impacts PFS translation to OS, utilizing data from the AXIS (axitinib versus sorafenib in advanced metastatic renal cell carcinoma) trial. The underlying assumption was a treatment benefit in PFS (the PFS distribution parameters were chosen to be equal to median PFS in the AXIS trial) but no treatment effect on SPP, implying that PFS improvement is directly reflected in OS improvement. RESULTS: The probability of a statistically significant difference between arms for OS decreased from 54.7% to 6.1% when median SPP was increased from one to 20 months. The probability of the hazard ratio of OS being ≥0.9 was similarly increased from 24.3% to 72.6%, even though the hazard ratio for PFS was 0.69. CONCLUSION: The present study shows that when simulated SPP is added to trial PFS data, the existing PFS benefit is diluted. Knowing that the AXIS treatment arms are well balanced with respect to post-trial treatments, we conclude that the PFS to OS benefit translation is primarily obscured by random variability largely unrelated to the true outcomes. The implications for drug development are not insignificant, as there would be a need to include more patients in studies or utilize a longer follow-up time to overcome the SPP variability issue.

Economic evaluation of posaconazole versus fluconazole or itraconazole in the prevention of invasive fungal infection in high-risk neutropenic patients in Sweden.

BACKGROUND: In patients undergoing induction chemotherapy for acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS), posaconazole has been proven more effective in the prevention of invasive fungal infection (IFI) than fluconazole or itraconazole (standard azoles) The current analysis seeks to estimate the cost effectiveness of prophylactic posaconazole compared with standard azoles in AML or MDS patients with severe chemotherapy-induced neutropenia in Sweden. METHODS: A decision-analytic model was used to estimate life expectancy, costs, and quality-adjusted life-years (QALYs). Efficacy data were derived from a phase III clinical trial. Life expectancy and quality of life data were collected from the literature. A modified Delphi method was used to gather expert opinion on resource use for an IFI. Unit costs were captured from hospital and pharmacy pricelists. A probabilistic sensitivity analysis (PSA) was used to investigate the impact of uncertainty in the model parameters on the cost-effectiveness results. RESULTS: The estimated mean direct cost per patient with posaconazole prophylaxis was 46,893 Swedish kronor (SEK) (€5,387) and SEK50,017 (€5,746) with standard azoles. Prophylaxis with posaconazole resulted in 0.075 QALYs gained compared with standard azoles. At a cost-effectiveness threshold of SEK500,000/QALY the PSA demonstrated a more than 95 % probability that posaconazole is cost effective versus standard azoles for the prevention of IFI in high-risk neutropenic patients in Sweden. CONCLUSION: Given the assumptions, methods, and data used, posaconazole is expected to be cost effective compared with standard azoles when used as antifungal prophylaxis in AML or MDS patients with chemotherapy-induced prolonged neutropenia in Sweden.

Cost-effectiveness of dronedarone and standard of care compared with standard of care alone: US results of an ATHENA lifetime model.

BACKGROUND: The first antiarrhythmic drug to demonstrate a reduced rate of cardiovascular hospitalization in atrial fibrillation/flutter (AF/AFL) patients was dronedarone in a placebo-controlled, double-blind, parallel arm Trial to assess the efficacy of dronedarone 400 mg bid for the prevention of cardiovascular Hospitalization or death from any cause in patiENts with Atrial fibrillation/atrial flutter (ATHENA trial). The potential cost-effectiveness of dronedarone in this patient population has not been reported in a US context. This study assesses the cost-effectiveness of dronedarone from a US health care payers' perspective. METHODS AND RESULTS: ATHENA patient data were applied to a patient-level health state transition model. Probabilities of health state transitions were derived from ATHENA and published data. Associated costs used in the model (2010 values) were obtained from published sources when trial data were not available. The base-case model assumed that patients were treated with dronedarone for the duration of ATHENA (mean 21 months) and were followed over a lifetime. Cost-effectiveness, from the payers' perspective, was determined using a Monte Carlo microsimulation (1 million fictitious patients). Dronedarone plus standard care provided 0.13 life years gained (LYG), and 0.11 quality-adjusted life years (QALYs), over standard care alone; cost/QALY was $19,520 and cost/LYG was $16,930. Compared to lower risk patients, patients at higher risk of stroke (Congestive heart failure, history of Hypertension, Age ≥ 75 years, Diabetes mellitus, and past history of Stroke or transient ischemic attack (CHADS(2)) scores 3-6 versus 0) had a lower cost/QALY ($9580-$16,000 versus $26,450). Cost/QALY was highest in scenarios assuming lifetime dronedarone therapy, no cardiovascular mortality benefit, no cost associated with AF/AFL recurrence on standard care, and when discounting of 5% was compared with 0%. CONCLUSIONS: By extrapolating the results of a large, multicenter, randomized clinical trial (ATHENA), this model suggests that dronedarone is a cost-effective treatment option for approved indications (paroxysmal/persistent AF/AFL) in the US.

Cost-effectiveness analysis of dronedarone versus other anti-arrhythmic drugs for the treatment of atrial fibrillation--results for Canada, Italy, Sweden and Switzerland.

The ATHENA clinical trial enrolled 4,628 patients in 37 countries and evaluated the efficacy of dronedarone 400 mg twice daily versus placebo for the prevention of cardiovascular hospitalisation or death from any cause in patients with paroxysmal or persistent atrial fibrillation or atrial flutter. The trial showed a statistically significant 24% reduction in the primary endpoint cardiovascular hospitalisations or all-cause death. In the current paper, parameters that drive the cost-effectiveness of dronedarone on top of standard therapy versus likely comparators, i.e. amiodarone, sotalol and flecainide, were investigated by means of a health economic model based on the ATHENA clinical trial. Dronedarone is cost-effective, and ICERs are low versus amiodarone with €5,340; €4,620; €3,850 and €5,630 per QALY gained for Canada, Italy, Sweden and Switzerland, respectively. The most significant driving factor for the cost-effectiveness of dronedarone is the increased survival rate for patients on dronedarone.

Cost-effectiveness of dronedarone in atrial fibrillation: results for Canada, Italy, Sweden, and Switzerland.

BACKGROUND: Dronedarone is a therapy for the treatment of patients with paroxysmal and persistent atrial fibrillation or atrial flutter. According to results in the ATHENA trial, dronedarone on top of standard of care (SOC) decreases the risk of cardiovascular hospitalizations or death by 24% compared with SOC alone. OBJECTIVES: A patient-level health economic model was developed to evaluate the cost-effectiveness of dronedarone on top of SOC versus SOC alone. METHODS: The risk of experiencing stroke, congestive heart failure, acute coronary syndromes, treatment discontinuation, and death was modeled by separate health states, whereas adverse events were included as 1-time cost and utility decrements. State transition probabilities were primarily deduced from the patient-level data from ATHENA using survival analysis. Four sets of analyses were performed to reflect costs and treatment effects in Canada, Italy, Sweden, and Switzerland. Cost-effectiveness analysis was also conducted in a newly defined patient population identified by the European Medicines Agency (EMA) to avoid the use of dronedarone in permanent AF patients resembling those in the PALLAS study. RESULTS: The predicted survival time was, for the Canadian cohort, extended from 10.11 to 10.24 years when dronedarone was added to SOC. Similar results were found for the other countries, resulting in incremental cost-effectiveness ratios (ICERs) of €5828, €5873, €14,970, and €8554 per QALYs for Canada, Italy, Sweden, and, Switzerland, respectively. These results are all well below current established cost-effectiveness thresholds. In the EMA-restricted population, all patients were predicted to live longer, and the ICER increased but remained within established thresholds, with an average cost per QALY gained of €15,900. CONCLUSIONS: Dronedarone on top of SOC appears to be a cost-effective treatment for atrial fibrillation compared with SOC alone. Despite the differences in the local settings considered, the results were consistent among all the countries included in the study. ClinicalTrials.gov identifier: NCT00174785.

A computational screen for site selective A-to-I editing detects novel sites in neuron specific Hu proteins.

BACKGROUND: Several bioinformatic approaches have previously been used to find novel sites of ADAR mediated A-to-I RNA editing in human. These studies have discovered thousands of genes that are hyper-edited in their non-coding intronic regions, especially in alu retrotransposable elements, but very few substrates that are site-selectively edited in coding regions. Known RNA edited substrates suggest, however, that site selective A-to-I editing is particularly important for normal brain development in mammals. RESULTS: We have compiled a screen that enables the identification of new sites of site-selective editing, primarily in coding sequences. To avoid hyper-edited repeat regions, we applied our screen to the alu-free mouse genome. Focusing on the mouse also facilitated better experimental verification. To identify candidate sites of RNA editing, we first performed an explorative screen based on RNA structure and genomic sequence conservation. We further evaluated the results of the explorative screen by determining which transcripts were enriched for A-G mismatches between the genomic template and the expressed sequence since the editing product, inosine (I), is read as guanosine (G) by the translational machinery. For expressed sequences, we only considered coding regions to focus entirely on re-coding events. Lastly, we refined the results from the explorative screen using a novel scoring scheme based on characteristics for known A-to-I edited sites. The extent of editing in the final candidate genes was verified using total RNA from mouse brain and 454 sequencing. CONCLUSIONS: Using this method, we identified and confirmed efficient editing at one site in the Gabra3 gene. Editing was also verified at several other novel sites within candidates predicted to be edited. Five of these sites are situated in genes coding for the neuron-specific RNA binding proteins HuB and HuD.

Simultaneous Bayesian gene tree reconstruction and reconciliation analysis.

We present GSR, a probabilistic model integrating gene duplication, sequence evolution, and a relaxed molecular clock for substitution rates, that enables genomewide analysis of gene families. The gene duplication and loss process is a major cause for incongruence between gene and species tree, and deterministic methods have been developed to explain such differences through tree reconciliations. Although probabilistic methods for phylogenetic inference have been around for decades, probabilistic reconciliation methods are far less established. Based on our model, we have implemented a Bayesian analysis tool, PrIME-GSR, for gene tree inference that takes a known species tree into account. Our implementation is sound and we demonstrate its utility for genomewide gene-family analysis by applying it to recently presented yeast data. We validate PrIME-GSR by comparing with previous analyses of these data that take advantage of gene order information. In a case study we apply our method to the ADH gene family and are able to draw biologically relevant conclusions concerning gene duplications creating key yeast phenotypes. On a higher level this shows the biological relevance of our method. The obtained results demonstrate the value of a relaxed molecular clock. Our good performance will extend to species where gene order conservation is insufficient.

Birth-death prior on phylogeny and speed dating.

BACKGROUND: 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 iid 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. RESULTS: We demonstrate that a hill-climbing maximum a posteriori (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 rbcL 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. CONCLUSION: 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.