Cost-effectiveness of low-molecular-weight heparin for treatment of pulmonary embolism.

BACKGROUND: Low-molecular-weight heparin (LMWH) appears to be safe and effective for treating pulmonary embolism (PE), but its cost-effectiveness has not been assessed. METHODS: We built a Markov state-transition model to evaluate the medical and economic outcomes of a 6-day course with fixed-dose LMWH or adjusted-dose unfractionated heparin (UFH) in a hypothetical cohort of 60-year-old patients with acute submassive PE. Probabilities for clinical outcomes were obtained from a meta-analysis of clinical trials. Cost estimates were derived from Medicare reimbursement data and other sources. The base-case analysis used an inpatient setting, whereas secondary analyses examined early discharge and outpatient treatment with LMWH. Using a societal perspective, strategies were compared based on lifetime costs, quality-adjusted life-years (QALYs), and the incremental cost-effectiveness ratio. RESULTS: Inpatient treatment costs were higher for LMWH treatment than for UFH (dollar 13,001 vs dollar 12,780), but LMWH yielded a greater number of QALYs than did UFH (7.677 QALYs vs 7.493 QALYs). The incremental costs of dollar 221 and the corresponding incremental effectiveness of 0.184 QALYs resulted in an incremental cost-effectiveness ratio of dollar 1,209/QALY. Our results were highly robust in sensitivity analyses. LMWH became cost-saving if the daily pharmacy costs for LMWH were < dollar 51, if > or = 8% of patients were eligible for early discharge, or if > or = 5% of patients could be treated entirely as outpatients. CONCLUSION: For inpatient treatment of PE, the use of LMWH is cost-effective compared to UFH. Early discharge or outpatient treatment in suitable patients with PE would lead to substantial cost savings.

Testing Spatial Autocorrelation in Weighted Networks : the Modes Permutation Test

In a weighted spatial network, as specified by an exchange matrix, the variances of the spatial values are inversely proportional to the size of the regions. Spatial values are no more exchangeable under independence, thus weakening the rationale for ordinary permutation and bootstrap tests of spatial autocorrelation. We propose an alternative permutation test for spatial autocorrelation, based upon exchangeable spatial modes, constructed as linear orthogonal combinations of spatial values. The coefficients obtain as eigenvectors of the standardised exchange matrix appearing in spectral clustering, and generalise to the weighted case the concept of spatial filtering for connectivity matrices. Also, two proposals aimed at transforming an acessibility matrix into a exchange matrix with with a priori fixed margins are presented. Two examples (inter-regional migratory flows and binary adjacency networks) illustrate the formalism, rooted in the theory of spectral decomposition for reversible Markov chains.

Cost effectiveness and cost utility of risedronate for osteoporosis treatment and fracture prevention in women: a Swiss perspective.

OBJECTIVES: To assess the incremental cost-effectiveness ratio (ICER) and incremental cost-utility ratio (ICUR) of risedronate compared to no intervention in postmenopausal osteoporotic women in a Swiss perspective. METHODS: A previously validated Markov model was populated with epidemiological and cost data specific to Switzerland and published utility values, and run on a population of 1,000 women of 70 years with established osteoporosis and previous vertebral fracture, treated over 5 years with risedronate 35 mg weekly or no intervention (base case), and five cohorts (according to age at therapy start) with eight risk factor distributions and three lengths of residual effects. RESULTS: In the base case population, the ICER of averting a hip fracture and the ICUR per quality-adjusted life year gained were both dominant. In the presence of a previous vertebral fracture, the ICUR was below euro45,000 (pound30,000) in all the scenarios. For all osteoporotic women>or=70 years of age with at least one risk factor, the ICUR was below euro45,000 or the intervention may even be cost saving. Age at the start of therapy and the fracture risk profile had a significant impact on results. CONCLUSION: Assuming a 2-year residual effect, that ICUR of risedronate in women with postmenopausal osteoporosis is below accepted thresholds from the age of 65 and even cost saving above the age of 70 with at least one risk factor.

Cost-effectiveness analysis of a European primary-care physician training in smoking cessation counseling.

BACKGROUND: Physician training in smoking cessation counseling has been shown to be effective as a means to increase quit success. We assessed the cost-effectiveness ratio of a smoking cessation counseling training programme. Its effectiveness was previously demonstrated in a cluster randomized, control trial performed in two Swiss university outpatients clinics, in which residents were randomized to receive training in smoking interventions or a control educational intervention. DESIGN AND METHODS: We used a Markov simulation model for effectiveness analysis. This model incorporates the intervention efficacy, the natural quit rate, and the lifetime probability of relapse after 1-year abstinence. We used previously published results in addition to hospital service and outpatient clinic cost data. The time horizon was 1 year, and we opted for a third-party payer perspective. RESULTS: The incremental cost of the intervention amounted to US$2.58 per consultation by a smoker, translating into a cost per life-year saved of US$25.4 for men and 35.2 for women. One-way sensitivity analyses yielded a range of US$4.0-107.1 in men and US$9.7-148.6 in women. Variations in the quit rate of the control intervention, the length of training effectiveness, and the discount rate yielded moderately large effects on the outcome. Variations in the natural cessation rate, the lifetime probability of relapse, the cost of physician training, the counseling time, the cost per hour of physician time, and the cost of the booklets had little effect on the cost-effectiveness ratio. CONCLUSIONS: Training residents in smoking cessation counseling is a very cost-effective intervention and may be more efficient than currently accepted tobacco control interventions.

Stochastic models and numerical algorithms for a class of regulatory gene networks.

Regulatory gene networks contain generic modules, like those involving feedback loops, which are essential for the regulation of many biological functions (Guido et al. in Nature 439:856-860, 2006). We consider a class of self-regulated genes which are the building blocks of many regulatory gene networks, and study the steady-state distribution of the associated Gillespie algorithm by providing efficient numerical algorithms. We also study a regulatory gene network of interest in gene therapy, using mean-field models with time delays. Convergence of the related time-nonhomogeneous Markov chain is established for a class of linear catalytic networks with feedback loops.

The cost effectiveness of pharmacological smoking cessation therapies in developing countries: a case study in the Seychelles

OBJECTIVE: To examine the incremental cost effectiveness of the five first line pharmacological smoking cessation therapies in the Seychelles and other developing countries. DESIGN: A Markov chain cohort simulation. SUBJECTS: Two simulated cohorts of smokers: (1) a reference cohort given physician counselling only; (2) a treatment cohort given counselling plus cessation therapy. INTERVENTION: Addition of each of the five pharmacological cessation therapies to physician provided smoking cessation counselling. MAIN OUTCOME MEASURES: Cost per life-year saved (LYS) associated with the five pharmacotherapies. Effectiveness expressed as odds ratios for quitting associated with pharmacotherapies. Costs based on the additional physician time required and retail prices of the medications. RESULTS: Based on prices for currently available generic medications on the global market, the incremental cost per LYS for a 45 year old in the Seychelles was 599 US dollars for gum and 227 dollars for bupropion. Assuming US treatment prices as a conservative estimate, the incremental cost per LYS was significantly higher, though still favourable in comparison to other common medical interventions: 3712 dollars for nicotine gum, 1982 dollars for nicotine patch, 4597 dollars for nicotine spray, 4291 dollars for nicotine inhaler, and 1324 dollars for bupropion. Cost per LYS increased significantly upon application of higher discount rates, which may be used to reflect relatively high opportunity costs for health expenditures in developing countries with highly constrained resources and high overall mortality. CONCLUSION: Pharmacological cessation therapy can be highly cost effective as compared to other common medical interventions in low mortality, middle income countries, particularly if medications can be procured at low prices.

Missed appointments in an outpatient clinic for adolescents, an approach to predict the risk of missing.

PURPOSE: To predict the risk of an adolescent patient to miss an appointment, based on the previous appointments and on the characteristics of the patient and the appointment. METHODS: Two thousand one hundred ninety-three (1873 females) patients aged 12 to 20 years having scheduled at least four appointments were included. We assessed the rate of missed nonexcused appointments of each patient. Second, a Markovian multilevel model was used to predict the risk of defaulting. RESULTS: Forty-five percent of the patients have not missed even once, and 14% of females and 17% of males have missed &gt;25% of their appointments. Females show two types of behaviors (an abstract concept that groups individuals based on a combination of their appointment-keeping and their recorded type of healthcare need) depending on the diagnosis. Somatic, gynecology, violence, and counseling diagnoses are mostly grouped together. In this group, having already missed and having an appointment with a paramedical provider increases the risk of missing. In the second group (eating disorders and psychiatric diagnoses) having already missed and a longer delay between appointments influence the risk of missing, although the risk is lower for this latter group. Males only show one type of behavior regarding missed appointments. Having missed a previous appointment, being older, having cancelled the next to last appointment and the type of diagnosis explain the risk of missing. CONCLUSIONS: Patients who have already defaulted have a higher risk of defaulting again. Means of control regarding missed appointments should consequently focus on defaulters, to decrease the associated workload. Reminders could be a solution for the follow-up appointments scheduled with a long delay.

RDM1, a novel RNA recognition motif (RRM)-containing protein involved in the cell response to cisplatin in vertebrates.

A variety of cellular proteins has the ability to recognize DNA lesions induced by the anti-cancer drug cisplatin, with diverse consequences on their repair and on the therapeutic effectiveness of this drug. We report a novel gene involved in the cell response to cisplatin in vertebrates. The RDM1 gene (for RAD52 Motif 1) was identified while searching databases for sequences showing similarities to RAD52, a protein involved in homologous recombination and DNA double-strand break repair. Ablation of RDM1 in the chicken B cell line DT40 led to a more than 3-fold increase in sensitivity to cisplatin. However, RDM1-/- cells were not hypersensitive to DNA damages caused by ionizing radiation, UV irradiation, or the alkylating agent methylmethane sulfonate. The RDM1 protein displays a nucleic acid binding domain of the RNA recognition motif (RRM) type. By using gel-shift assays and electron microscopy, we show that purified, recombinant chicken RDM1 protein interacts with single-stranded DNA as well as double-stranded DNA, on which it assembles filament-like structures. Notably, RDM1 recognizes DNA distortions induced by cisplatin-DNA adducts in vitro. Finally, human RDM1 transcripts are abundant in the testis, suggesting a possible role during spermatogenesis.

Effects of colonization asymmetries on metapopulation persistence.

Ocean currents, prevailing winds, and the hierarchical structures of river networks are known to create asymmetries in re-colonization between habitat patches. The impacts of such asymmetries on metapopulation persistence are seldom considered, especially rarely in theoretical studies. Considering three classical models (the island, the stepping stone and the distance-dependent model), we explore how metapopulation persistence is affected by (i) asymmetry in dispersal strength, in which the colonization rate between two patches differs in direction, and (ii) asymmetry in connectivity, in which the overall colonization pattern displays asymmetry (circulating or dendritic networks). Viability can be drastically reduced when directional bias in dispersal strength is higher than 25%. Re-colonization patterns that allow for strong local connectivity provide the highest persistence compared to systems that allow circulation. Finally, asymmetry has relatively weak effects when metapopulations maintain strong general connectivity.

Monte Carlo Methods in Parameter Estimation of Nonlinear Models

Yksi keskeisimmistä tehtävistä matemaattisten mallien tilastollisessa analyysissä on mallien tuntemattomien parametrien estimointi. Tässä diplomityössä ollaan kiinnostuneita tuntemattomien parametrien jakaumista ja niiden muodostamiseen sopivista numeerisista menetelmistä, etenkin tapauksissa, joissa malli on epälineaarinen parametrien suhteen. Erilaisten numeeristen menetelmien osalta pääpaino on Markovin ketju Monte Carlo -menetelmissä (MCMC). Nämä laskentaintensiiviset menetelmät ovat viime aikoina kasvattaneet suosiotaan lähinnä kasvaneen laskentatehon vuoksi. Sekä Markovin ketjujen että Monte Carlo -simuloinnin teoriaa on esitelty työssä siinä määrin, että menetelmien toimivuus saadaan perusteltua. Viime aikoina kehitetyistä menetelmistä tarkastellaan etenkin adaptiivisia MCMC menetelmiä. Työn lähestymistapa on käytännönläheinen ja erilaisia MCMC -menetelmien toteutukseen liittyviä asioita korostetaan. Työn empiirisessä osuudessa tarkastellaan viiden esimerkkimallin tuntemattomien parametrien jakaumaa käyttäen hyväksi teoriaosassa esitettyjä menetelmiä. Mallit kuvaavat kemiallisia reaktioita ja kuvataan tavallisina differentiaaliyhtälöryhminä. Mallit on kerätty kemisteiltä Lappeenrannan teknillisestä yliopistosta ja Åbo Akademista, Turusta.

El desarrollo humano: perfiles y perspectivas futuras

El PNUD calcula todos los años el Índice de Desarrollo Humano (IDH). El objetivo de este trabajo es analizar los antecedentes y las perspectivas futuras del desarrollo humano a partir de los datos de este índice durante el periodo 1970-2000. Esto es, comprobar, a partir de los datos pasados, si las diferencias entre el IDH de los países del mundo están aumentando y valorar la tendencia del IDH esperada para los próximos años. En definitiva, se trata de buscar respuesta a la siguiente pregunta ¿cómo se modificarán los niveles de desarrollo humano en el futuro? Para ello, se utiliza la metodología estadística del análisis dinámico de distribución mediante las cadenas de Markov.

Computational methods for tactical simulations

Tämä taktiikan tutkimus keskittyy tietokoneavusteisen simuloinnin laskennallisiin menetelmiin, joita voidaan käyttää taktisen tason sotapeleissä. Työn tärkeimmät tuotokset ovat laskennalliset mallit todennäköisyyspohjaisen analyysin mahdollistaviin taktisen tason taistelusimulaattoreihin, joita voidaan käyttää vertailevaan analyysiin joukkue-prikaatitason tarkastelutilanteissa. Laskentamallit keskittyvät vaikuttamiseen. Mallit liittyvät vahingoittavan osuman todennäköisyyteen, jonka perusteella vaikutus joukossa on mallinnettu tilakoneina ja Markovin ketjuina. Edelleen näiden tulokset siirretään tapahtumapuuanalyysiin operaation onnistumisen todennäköisyyden osalta. Pienimmän laskentayksikön mallinnustaso on joukkue- tai ryhmätasolla, jotta laskenta-aika prikaatitason sotapelitarkasteluissa pysyisi riittävän lyhyenä samalla, kun tulokset ovat riittävän tarkkoja suomalaiseen maastoon. Joukkueiden mies- ja asejärjestelmävahvuudet ovat jakaumamuodossa, eivätkä yksittäisiä lukuja. Simuloinnin integroinnissa voidaan käyttää asejärjestelmäkohtaisia predictor corrector –parametreja, mikä mahdollistaa aika-askelta lyhytaikaisempien taistelukentän ilmiöiden mallintamisen. Asemallien pohjana ovat aiemmat tutkimukset ja kenttäkokeet, joista osa kuuluu tähän väitöstutkimukseen. Laskentamallien ohjelmoitavuus ja käytettävyys osana simulointityökalua on osoitettu tekijän johtaman tutkijaryhmän ohjelmoiman ”Sandis”- taistelusimulointiohjelmiston avulla, jota on kehitetty ja käytetty Puolustusvoimien Teknillisessä Tutkimuslaitoksessa. Sandikseen on ohjelmoitu karttakäyttöliittymä ja taistelun kulkua simuloivia laskennallisia malleja. Käyttäjä tai käyttäjäryhmä tekee taktiset päätökset ja syöttää nämä karttakäyttöliittymän avulla simulointiin, jonka tuloksena saadaan kunkin joukkuetason peliyksikön tappioiden jakauma, keskimääräisten tappioiden osalta kunkin asejärjestelmän aiheuttamat tappiot kuhunkin maaliin, ammuskulutus ja radioyhteydet ja niiden tila sekä haavoittuneiden evakuointi-tilanne joukkuetasolta evakuointisairaalaan asti. Tutkimuksen keskeisiä tuloksia (kontribuutio) ovat 1) uusi prikaatitason sotapelitilanteiden laskentamalli, jonka pienin yksikkö on joukkue tai ryhmä; 2) joukon murtumispisteen määritys tappioiden ja haavoittuneiden evakuointiin sitoutuvien taistelijoiden avulla; 3) todennäköisyyspohjaisen riskianalyysin käyttömahdollisuus vertailevassa tutkimuksessa sekä 4) kokeellisesti testatut tulen vaikutusmallit ja 5) toimivat integrointiratkaisut. Työ rajataan maavoimien taistelun joukkuetason todennäköisyysjakaumat luovaan laskentamalliin, kenttälääkinnän malliin ja epäsuoran tulen malliin integrointimenetelmineen sekä niiden antamien tulosten sovellettavuuteen. Ilmasta ja mereltä maahan -asevaikutusta voidaan tarkastella, mutta ei ilma- ja meritaistelua. Menetelmiä soveltavan Sandis -ohjelmiston malleja, käyttötapaa ja ohjelmistotekniikkaa kehitetään edelleen. Merkittäviä jatkotutkimuskohteita mallinnukseen osalta ovat muun muassa kaupunkitaistelu, vaunujen kaksintaistelu ja maaston vaikutus tykistön tuleen sekä materiaalikulutuksen arviointi.

Stochastic variability of output levels in a pulp mill

Quite often, in the construction of a pulp mill involves establishing the size of tanks which will accommodate the material from the various processes in which case estimating the right tank size a priori would be vital. Hence, simulation of the whole production process would be worthwhile. Therefore, there is need to develop mathematical models that would mimic the behavior of the output from the various production units of the pulp mill to work as simulators. Markov chain models, Autoregressive moving average (ARMA) model, Mean reversion models with ensemble interaction together with Markov regime switching models are proposed for that purpose.

Risk Aversion, Intertemporal Substitution, and Option Pricing

This paper develops a general stochastic framework and an equilibrium asset pricing model that make clear how attitudes towards intertemporal substitution and risk matter for option pricing. In particular, we show under which statistical conditions option pricing formulas are not preference-free, in other words, when preferences are not hidden in the stock and bond prices as they are in the standard Black and Scholes (BS) or Hull and White (HW) pricing formulas. The dependence of option prices on preference parameters comes from several instantaneous causality effects such as the so-called leverage effect. We also emphasize that the most standard asset pricing models (CAPM for the stock and BS or HW preference-free option pricing) are valid under the same stochastic setting (typically the absence of leverage effect), regardless of preference parameter values. Even though we propose a general non-preference-free option pricing formula, we always keep in mind that the BS formula is dominant both as a theoretical reference model and as a tool for practitioners. Another contribution of the paper is to characterize why the BS formula is such a benchmark. We show that, as soon as we are ready to accept a basic property of option prices, namely their homogeneity of degree one with respect to the pair formed by the underlying stock price and the strike price, the necessary statistical hypotheses for homogeneity provide BS-shaped option prices in equilibrium. This BS-shaped option-pricing formula allows us to derive interesting characterizations of the volatility smile, that is, the pattern of BS implicit volatilities as a function of the option moneyness. First, the asymmetry of the smile is shown to be equivalent to a particular form of asymmetry of the equivalent martingale measure. Second, this asymmetry appears precisely when there is either a premium on an instantaneous interest rate risk or on a generalized leverage effect or both, in other words, whenever the option pricing formula is not preference-free. Therefore, the main conclusion of our analysis for practitioners should be that an asymmetric smile is indicative of the relevance of preference parameters to price options.

Explaining the Transition Between Exchange Rate Regimes

This paper studies the transition between exchange rate regimes using a Markov chain model with time-varying transition probabilities. The probabilities are parameterized as nonlinear functions of variables suggested by the currency crisis and optimal currency area literature. Results using annual data indicate that inflation, and to a lesser extent, output growth and trade openness help explain the exchange rate regime transition dynamics.