A flexible ancestral genome reconstruction method based on gapped adjacencies.

BACKGROUND: The "small phylogeny" problem consists in inferring ancestral genomes associated with each internal node of a phylogenetic tree of a set of extant species. Existing methods can be grouped into two main categories: the distance-based methods aiming at minimizing a total branch length, and the synteny-based (or mapping) methods that first predict a collection of relations between ancestral markers in term of "synteny", and then assemble this collection into a set of Contiguous Ancestral Regions (CARs). The predicted CARs are likely to be more reliable as they are more directly deduced from observed conservations in extant species. However the challenge is to end up with a completely assembled genome. RESULTS: We develop a new synteny-based method that is flexible enough to handle a model of evolution involving whole genome duplication events, in addition to rearrangements, gene insertions, and losses. Ancestral relationships between markers are defined in term of Gapped Adjacencies, i.e. pairs of markers separated by up to a given number of markers. It improves on a previous restricted to direct adjacencies, which revealed a high accuracy for adjacency prediction, but with the drawback of being overly conservative, i.e. of generating a large number of CARs. Applying our algorithm on various simulated data sets reveals good performance as we usually end up with a completely assembled genome, while keeping a low error rate. AVAILABILITY: All source code is available at http://www.iro.umontreal.ca/~mabrouk.

Validation of the Rockall scoring system for outcomes from non-variceal upper gastrointestinal bleeding in a Canadian setting.

AIM: To validate the Rockall scoring system for predicting outcomes of rebleeding, and the need for a surgical procedure and death. METHODS: We used data extracted from the Registry of Upper Gastrointestinal Bleeding and Endoscopy including information of 1869 patients with non-variceal upper gastrointestinal bleeding treated in Canadian hospitals. Risk scores were calculated and used to classify patients based on outcomes. For each outcome, we used chi2 goodness-of-fit tests to assess the degree of calibration, and built receiver operating characteristic curves and calculated the area under the curve (AUC) to evaluate the discriminative ability of the scoring system. RESULTS: For rebleeding, the chi2 goodness-of-fit test indicated an acceptable fit for the model [chi2 (8) = 12.83, P = 0.12]. For surgical procedures [chi2 (8) = 5.3, P = 0.73] and death [chi2 (8) = 3.78, P = 0.88], the tests showed solid correspondence between observed proportions and predicted probabilities. The AUC was 0.59 (95% CI: 0.55-0.62) for the outcome of rebleeding and 0.60 (95% CI: 0.54-0.67) for surgical procedures, representing a poor discriminative ability of the scoring system. For the outcome of death, the AUC was 0.73 (95% CI: 0.69-0.78), indicating an acceptable discriminative ability. CONCLUSION: The Rockall scoring system provides an acceptable tool to predict death, but performs poorly for endpoints of rebleeding and surgical procedures.

Economic evaluation of treating chronic obstructive pulmonary disease with inhaled corticosteroids and long-acting beta2-agonists in a health maintenance organization.

OBJECTIVES: In light of recent results from observational studies showing prolonged survival in subjects taking long-acting beta2-agonists (LABA) and/or inhaled corticosteroids (ICS) for chronic obstructive pulmonary disease (COPD), we investigated their cost-effectiveness (CE). METHODS: Costs and survival data were collected for a sample of members enrolled in a large Health Maintenance Organization in the United States. An observational study design was used to evaluate cumulative costs and health benefits of LABA, ICS, ICS+LABA, or comparison drugs. Survival was estimated using a parametric regression model. Costs were adjusted for censoring and prognostic factors. CE was evaluated over a time horizon of 36 months and the remaining lifetime of subjects. RESULTS: Over 36 months, life expectancy and costs were: 2.4 years (95% confidence interval (CI): 2.3; 2.5) and $28,030 (CI: $23,400; $33,570) for not receiving ICS or LABA; 2.6 years (CI: 2.6; 2.7) and $35,170 (CI: $29,970; $40,620) for ICS alone; 2.6 years (CI: 2.5; 2.7) and $27,380 (CI: $21,780; $32,510) for LABA alone; and, 2.7 years (CI: 2.6; 2.8) and $33,780 (CI: $28,700; $39,440) for subjects treated with ICS+LABA. The lifetime analysis showed similar trends. CONCLUSIONS: There is an acute need to find effective, life-extending treatments for persons with COPD. ICS, LABA or their combination represent promising treatment options and are currently being tested in randomized trials. If the impact on survival seen in these trials compares to that seen in observational studies, LABA and the combination treatment are likely to be cost-effective in the United States.

Getting the cat back in the bag: reforming the way provinces manage drug expenditures to make them manageable.

The fiscal "cat" of healthcare spending - drug expenditures - is out of the bag: drug costs are now the fastest rising component of healthcare expenditures in Canada. Laupacis, Anderson and O'Brien describe the current process of listing drugs on the provincial drug formulary in Ontario, identify factors that may contribute to the rapid growth in drug expenditures, and make a number of recommendations for controlling drug expenditures, including (1) improving the evidence on cost-effectiveness; (2) disseminating the evidence to prescribers; (3) re-evaluating the evidence; and (4) increasing the transparency about the acquisition costs of drugs. These are recommendations that, if implemented, would theoretically help decision-makers make more rational decisions about which drugs to list on provincial formularies. The question of how to implement the recommendations remains to be elucidated, as does an evaluation of the trade-offs between costs and benefits of obtaining better information on cost-effectiveness.

Genome halving and double distance with losses.

Given a phylogenetic tree involving whole genome duplication events, we contribute to solving the problem of computing the rearrangement and double cut-and-join (DCJ) distances on a branch of the tree linking a duplication node d to a speciation node or a leaf s. In the case of a genome G at s containing exactly two copies of each gene, the genome halving problem is to find a perfectly duplicated genome D at d minimizing the rearrangement distance with G. We generalize the existing exact linear-time algorithm for genome halving to the case of a genome G with missing gene copies. In the case of a known ancestral duplicated genome D, we develop a greedy approach for computing the distance between G and D, called the double distance. Two algorithms are developed in both cases of a genome G containing exactly two copies of each gene, or at most two copies of each gene (with missing gene copies). These algorithms are shown time-efficient and very accurate for both the rearrangement and DCJ distances.

Treatment costs in Canada of health conditions resulting from chronic hepatitis B infection.

GOALS: To estimate resource use and expected annual cost of care for subjects with chronic hepatitis B and resulting complications in Canada. BACKGROUND: Patients chronically infected with hepatitis B virus are at an increased risk of progressing to complications from deteriorating liver function. STUDY: The direct medical costs for six disease states associated with chronic hepatitis B virus infection were estimated for the year 2001. METHODS: Information on resource utilization patterns was obtained from: 1) a questionnaire administered to eight specialists with experience treating hepatitis B patients, and 2) a data set on hospitalizations in nine Canadian provinces for specific diagnostic codes. Unit costs were collected from published literature and provincial physician payment schedules and lists of reimbursed medications. All sources of information were combined to calculate expected annual costs. Uncertainty analysis was performed using Monte Carlo simulations. Costs are reported in 2001 Canadian dollars. RESULTS: The expected annual per-person costs of care and their 95% confidence intervals (CIs) were: 2191 dollars (CI, 1997 dollars-2556 dollars) for chronic hepatitis B, 2987 dollars (CI, 2389 dollars-4462 dollars) for compensated cirrhosis, 11,228 dollars (CI, 8309 dollars-16,388 dollars) for decompensated cirrhosis, 13,350 dollars (CI, 10,608 dollars-17,187 dollars) for hepatocellular carcinoma, 99,066 dollars (CI, 94,328 dollars-106,833 dollars) for liver transplant, and 38,242 dollars (CI, 33,443 dollars-46,087 dollars) for transplant care after the first year. Main cost drivers were hospitalizations and medications. CONCLUSION: The cost of treating Canadian subjects with hepatitis B-related conditions increases substantially with deteriorating liver function. Any new therapy that proves to be more effective at slowing or preventing the course of liver disease progression would be cost-effective.

Aggravation of respiratory disturbances by the use of an occlusal splint in apneic patients: a pilot study.

PURPOSE: This pilot study was designed to test the hypothesis that the use of a single oral splint may aggravate respiratory disturbance in sleep apneic patients. MATERIALS AND METHODS: A group of 10 patients with a history of snoring and a recording night confirming a diagnosis of sleep apnea were included. Patients were then invited to spend 2 nights in the sleep laboratory: night 2 to establish baseline data (baseline night) and night 3, 1 week later, to assess the influence of an occlusal maxillary splint on sleep (splint night). The following variables were analyzed under blind conditions: total sleep time, sleep efficiency and number of awakenings, microarousals, apnea-hypopnea index per hour of sleep (AHI), respiratory disturbances index per hour of sleep (RDI), and percentage of sleeping time with snoring. RESULTS: No statistically significant difference in AHI was noted between baseline and splint nights. However, four patients experienced an aggravation in apnea diagnosis category on the night they used the splint. The AHI was increased by more than 50% in 5 of the 10 patients. The RDI showed a 30% increase from baseline to splint nights. The percentage of sleeping time with snoring also increased by 40% with the splint. CONCLUSION: This open study suggested that the use of an occlusal splint is associated with a risk of aggravation of respiratory disturbances. It may therefore be relevant for clinicians to question patients about snoring and sleep apnea when recommending an occlusal splint.

Cost implications of administering intravenous proton pump inhibitors to all patients presenting to the emergency department with peptic ulcer bleeding.

OBJECTIVES: Administering proton pump inhibitors (PPI) intravenously (iv) after endoscopic treatment of bleeding peptic ulcers reduces the incidence of rebleeding, the need for operative procedures, and hospitalizations. We assessed the cost implications of iv PPI initiated in all patients presenting to the emergency department (ED) with signs of upper gastrointestinal (UGI) bleeding. METHODS: From a third-party payer perspective with a time horizon of 60 days, we built a decision analytic model comparing standard endoscopic therapy to a strategy in which all patients presenting to the ED with UGI bleeding would start iv PPI before endoscopy. After endoscopy, only those with peptic ulcers would be kept on iv PPI added to standard therapy. Probabilities of health events were extracted from published literature. Resource utilization profiles and costs (iv PPI, hospital stay for medical and operative procedures, and professional fees) were based on Medicare reimbursement data from a large hospital in Alabama. All costs were expressed in 2000 US dollars. Uncertainty was investigated through one-way sensitivity analyses and probabilistic analyses using Monte Carlo simulations. RESULTS: In a hypothetical group of 1000 individuals, routine use of iv PPI prevented 40 rebleeds, 9 surgical procedures, and 223 hospital days, and led to incremental savings of dollars 920 per subject. Probabilistic sensitivity analyses indicated that the strategy of using iv PPI was likely to be dominant even when accounting for uncertainty. CONCLUSIONS: Based on available evidence, routine administration of iv PPI to all persons presenting with UGI bleeding represents good value for money and merits consideration as standard hospital policy.