A continuous-time Markov model approach for modeling myelodysplastic syndromes progression from cross-sectional data.

The integration of both genomics and clinical data to model disease progression is now possible, thanks to the increasing availability of molecular patients' profiles. This may lead to the definition of novel decision support tools, able to tailor therapeutic interventions on the basis of a "precise" patients' risk stratification, given their health status evolution. However, longitudinal analysis requires long-term data collection and curation, which can be time demanding, expensive and sometimes unfeasible. Here we present a clinical decision support framework that combines the simulation of disease progression from cross-sectional data with a Markov model that exploits continuous-time transition probabilities derived from Cox regression. Trajectories between patients at different disease stages are stochastically built according to a measure of patient similarity, computed with a matrix tri-factorization technique. Such trajectories are seen as realizations drawn from the stochastic process driving the transitions between the disease stages. Eventually, Markov models applied to the resulting longitudinal dataset highlight potentially relevant clinical information. We applied our method to cross-sectional genomic and clinical data from a cohort of Myelodysplastic syndromes (MDS) patients. MDS are heterogeneous clonal hematopoietic disorders whose patients are characterized by different risks of Acute Myeloid Leukemia (AML) development, defined by an international score. We computed patients' trajectories across increasing and subsequent levels of risk of developing AML, and we applied a Cox model to the simulated longitudinal dataset to assess whether genomic characteristics could be associated with a higher or lower probability of disease progression. We then used the learned parameters of such Cox model to calculate the transition probabilities of a continuous-time Markov model that describes the patients' evolution across stages. Our results are in most cases confirmed by previous studies, thus demonstrating that simulated longitudinal data represent a valuable resource to investigate disease progression of MDS patients.

Trusting telemedicine: A discussion on risks, safety, legal implications and liability of involved stakeholders.

OBJECTIVES: The main purpose of the article is to raise awareness among all the involved stakeholders about the risks and legal implications connected to the development and use of modern telemedicine systems. Particular focus is given to the class of "active" telemedicine systems, that imply a real-world, non-mediated, interaction with the final user. A secondary objective is to give an overview of the European legal framework that applies to these systems, in the effort to avoid defensive medicine practices and fears, which might be a barrier to their broader adoption. METHODS: We leverage on the experience gained during two international telemedicine projects, namely MobiGuide (pilot studies conducted in Spain and Italy) and AP@home (clinical trials enrolled patients in Italy, France, the Netherlands, United Kingdom, Austria and Germany), whose development our group has significantly contributed to in the last 4 years, to create a map of the potential criticalities of active telemedicine systems and comment upon the legal framework that applies to them. Two workshops have been organized in December 2015 and March 2016 where the topic has been discussed in round tables with system developers, researchers, physicians, nurses, legal experts, healthcare economists and administrators. RESULTS: We identified 8 features that generate relevant risks from our example use cases. These features generalize to a broad set of telemedicine applications, and suggest insights on possible risk mitigation strategies. We also discuss the relevant European legal framework that regulate this class of systems, providing pointers to specific norms and highlighting possible liability profiles for involved stakeholders. CONCLUSIONS: Patients are more and more willing to adopt telemedicine systems to improve home care and day-by-day self-management. An essential step towards a broader adoption of these systems consists in increasing their compliance with existing regulations and better defining responsibilities for all the involved stakeholders.

UceWeb: a web-based collaborative tool for collecting and sharing quality of life data.

OBJECTIVES: This work aims at building a platform where quality-of-life data, namely utility coefficients, can be elicited not only for immediate use, but also systematically stored together with patient profiles to build a public repository to be further exploited in studies on specific target populations (e.g. cost/utility analyses). METHODS: We capitalized on utility theory and previous experience to define a set of desirable features such a tool should show to facilitate sound elicitation of quality of life. A set of visualization tools and algorithms has been developed to this purpose. To make it easily accessible for potential users, the software has been designed as a web application. A pilot validation study has been performed on 20 atrial fibrillation patients. RESULTS: A collaborative platform, UceWeb, has been developed and tested. It implements the standard gamble, time trade-off and rating-scale utility elicitation methods. It allows doctors and patients to choose the mode of interaction to maximize patients' comfort in answering difficult questions. Every utility elicitation may contribute to the growth of the repository. CONCLUSION: UceWeb can become a unique source of data allowing researchers both to perform more reliable comparisons among healthcare interventions and build statistical models to gain deeper insight into quality of life data.

Improving thrombolysis for acute ischemic stroke in Lombardia stroke centers.

The purpose of this study is to identify which factors are able to limit or hamper the access to systemic thrombolysis (evTPA) in Lombardia to define corrective interventions. We analyzed 1,015 patients with ischemic stroke admitted to emergency departments (ED) participating to the Lombardia Stroke Unit Registry and eligible for evTPA; 303 (29.9%) patients were treated with evTPA (evTPA+ group) and 712 (70.1%) were not (evTPA- group). We collected case-mix and stroke care process variables.The evTPA+ group was characterized by a shorter ED arrival time, a greater neurological impairment, a more chance to be admitted to ED linked to comprehensive stroke center (CSC) and a shorter waiting time to access to diagnostic procedures. The chance to be treated with evTPA was greater if neurological evaluation anticipated neuroimaging (p = 0.0003). The multivariate analysis confirmed that the admission to ED linked to CSC (OR: 2.50, 95% CI: 1.39-4.48, p < 0.0001) and neurological evaluation performed before neuroimaging (OR: 2.34, 95% CI: 1.35-4.04, p = 0.002) increased the probability to receive rtPA. The evTPA treatment is strictly dependent on pre-hospital and ED care process phases and strongly influenced by the degree of stroke severity. Door-to-needle time is shorter in patients with a greater stroke severity and a shorter ED arrival time. A 24-h/week availability of the neurologist in ED can increase the percentage of thrombolysis optimizing the selection of patients and the timing of the diagnostic procedures.

Adding docetaxel to cisplatin and fluorouracil in patients with unresectable head and neck cancer: a cost-utility analysis.

BACKGROUND: Adding docetaxel (Taxotere, T) to induction chemotherapy with platinum/infusional 5-FU (PF) has been shown to improve overall survival of patients with head and neck cancer. The aim of the study was to analyze the cost-utility of TPF in patients with unresectable disease. DESIGN: We developed a Markov model to represent patient's weekly transitions among different health states, related to treatment or disease status. Transition probabilities were obtained from the TAX 324 clinical trial report and from the European Organization for Research and Treatment of Cancer (EORTC) 24971/TAX 323 raw data. Costs were estimated in Italy from a Regional Healthcare System perspective. A 5-year temporal horizon was adopted and a 3.5% yearly discount rate was applied. RESULTS: When compared with PF, TPF treatment increases life expectancy by 0.33 quality-adjusted life-years (QALYs) in TAX 323 and 0.41 QALYs in TAX 324. The benefit was achieved at a cost of €11,822/QALY for TAX 323 and €6757/QALY for TAX 324. Monte Carlo sensitivity analysis showed that 69% (TAX 323) and 99% (TAX 324) of the results lie below the threshold of €50,000/QALY saved. CONCLUSIONS: In our analysis, TPF induction chemotherapy proved to be cost-effective when compared with PF, having a cost-utility ratio comparable to other widely accepted healthcare interventions.

Assessment of the bronchodilation test by visual analog scale in the selection of patients with rhinitis for screening spirometry.

BACKGROUND: The nose and bronchi are closely linked, and rhinitis often precedes the onset of asthma. Bronchial obstruction is a characteristic of asthma, and demonstration of its reversibility is a key element in diagnosis. However, reversibility testing requires a spirometer, which is rarely available in the doctor's office. Visual analog scales (VAS) are frequently used in daily practice. OBJECTIVE: This study evaluated the suitability of a VAS for assessing bronchodilation in patients with persistent allergic rhinitis as a means of selecting candidates for screening spirometry. METHODS: We evaluated 120 patients with moderate to severe persistent allergic rhinitis. All patients underwent a clinical examination, skin prick test, spirometry, bronchodilation test, and VAS. RESULTS: Patients with rhinitis showed significantly increased forced expiratory volume in the first second (FEV1) after the bronchodilation test (median, 11.5%). Positive results were observed in 60%, and VAS values increased (>30%) after the test. There was a significant relationship between deltaVAS and deltaFEV1 (P<.0001; r=0.482). CONCLUSION: This preliminary study shows that patients with moderate to severe persistent allergic rhinitis often experience an increase in FEV1 after the bronchodilation test. VAS assessment of the test might be useful when selecting candidates for spirometry for possible bronchial involvement.

Assessment of sensorized garments as a flexible support to self-administered post-stroke physical rehabilitation.

The aim of this study was to provide a description of a newly-developed remote rehabilitation system that can be employed both at home and in the hospital, supporting motor rehabilitation for post-stroke patients with upper-limb impairment. A garment, which embeds kinesthetic sensors made of a piezoresitive polymer, is provided with a wireless connection to a computer (the patient station). The station detects in real time whether the patient is performing the exercises correctly or not, and provides feedback through an easy visual representation on the screen. Movement recognition is performed using a template matching approach, which allows exercises to be defined during each session as required without additional configuration. In this study an healthy volunteer used the garment to record 840 exercises, mimicking both correct and incorrect compensatory movements under expert supervision. The sensitivity and specificity of the recognition system were measured through its ability to correctly identify the pre-labelled exercises. A pilot set of 13 post-stroke subjects (mean age of 50) was then offered to use the rehabilitation system while in the neuro-rehabilitation ward; the acceptability was assessed through a 10-question subjective evaluation questionnaire. The wearable system tested provided a raw recognition performance (correct-versus-incorrect exercise detection) above 90%. The majority of the patients were satisfied with the system, considered it useful, and would use it at home. In conclusion, computer-based interventions can support widespread, earlier and more intense physical therapy after a neurological event, provided they are easy to use and blend well with the existing rehabilitation workflow. Wearable sensors are promising candidates to realize unobtrusive devices to support the rehabilitation process and its continuity after discharge from the Rehabilitation Unit.

Evidence-based careflow management systems: the case of post-stroke rehabilitation.

The activities of a care providers' team need to be coordinated within a process properly designed on the basis of available best practice medical knowledge. It requires a rethinking of the management of care processes within health care organizations. The current workflow technology seems to offer the most convenient solution to build such cooperative systems. However, some of its present weaknesses still require an intense research effort to find solutions allowing its exploitation in real medical practice. This paper presents an approach to design and build evidence-based careflow management systems, which can be viewed as components of a knowledge management infrastructure each health care organization should be provided with to increase its performance in delivering high quality care by efficiently exploiting the available knowledge resources. The post-stroke rehabilitation process has been taken as a challenging care problem to assess our methodology for designing and developing careflow management systems. Then a system was co-developed with a team of rehabilitation professionals who will be committed to use it in their daily work. The system's main goal is to deliver a full array of rehabilitation services provided by an interdisciplinary team. They are related to identify which patients are most likely to benefit from rehabilitation, manage a rehabilitation treatment plan, and monitor progress both during rehabilitation and after return to a community residence. A model of the rehabilitation process was derived from an international guideline and adapted to the local organization of work. It involves different organizational units, such as wards, rehabilitation units, clinical laboratories, and imaging services. Several organizational agents work within them and play one or more roles. Each role is defined by the goals' set that she/he must fulfill. Special effort has been given to the design and development of a knowledge-based system for managing exceptions, which may occur in daily medical work as any deviation from the normal flow of activities. It allows either avoiding or recovering automatically from expected exceptions. When they are not expected, organizational agents, with enough power to do that, are allowed to modify the scheduled flow of activities for an individual patient under the only constraint of justifying their decision. After an intensive testing in a research laboratory, the system is now in the process of being transferred in a real working setting with the full support of its future users.

Cost-effectiveness of screening and extended anticoagulation for carriers of both factor V Leiden and prothrombin G20210A.

Carriers of a double thrombophilic mutation (factor V Leiden and prothrombin G20210A) are at high risk of a recurrent venous thromboembolism (VTE), and may benefit from a longer course of secondary prophylaxis. We examined the costs and health benefits of screening for both the mutations, provided that double heterozygotes undergo 2 years of anticoagulation as compared to the standard 6 months. We thus pooled the available evidence and calculated that the OR for recurrence in double heterozygotes was 5.9 (95% CI 2.65-13.20). A Markov model tracked patients' health lifelong, and calculated that prolonged prophylaxis saved 26 quality-adjusted days of life and $410 per double heterozygote treated. Screening all the patients with venous thromboembolism thus provided one additional day of life at the cost of 13624 $/QALY (95% CI 12 965-22 889). Screening was not cost-effective in those cohorts with a low prevalence of the mutations, a high bleeding risk or in those where prophylaxis prevented <65% of recurrences. Screening for factor V Leiden and prothrombin G20210A, with prolonged prophylaxis of double carriers, is cost-effective in most patients with VTE.

Deciding when to intervene: a Markov decision process approach.

The aim of this paper is to point out the difference between static and dynamic approaches to choosing the optimal time for intervention. The paper demonstrates that classical approaches, such as decision trees and influence diagrams, hardly cope with dynamic problems: they cannot simulate all the real-world strategies and consequently can only calculate suboptimal solutions. A dynamic formalism based on Markov decision processes (MPPs) is then proposed and applied to a medical problem: the prophylactic surgery in mild hereditary spherocytosis. The paper compares the proposed approach with a static approach on the same medical problem. The policy provided by the dynamic approach achieved significant gain over the static policy by delaying the intervention time in some categories of patients. The calculations are carried out with DT-Planner, a graphical decision aid specifically built for dealing with dynamic decision processes.

Decision support systems in health economics.

This article describes a system addressed to different health care professionals for building, using, and sharing decision support systems for resource allocation. The system deals with selected areas, namely the choice of diagnostic tests, the therapy planning, and the instrumentation purchase. Decision support is based on decision-analytic models, incorporating an explicit knowledge representation of both the medical domain knowledge and the economic evaluation theory. Application models are built on top of meta-models, that are used as guidelines for making explicit both the cost and effectiveness components. This approach improves the transparency and soundness of the collaborative decision-making process and facilitates the result interpretation.

Cost-effectiveness of interferon alfa in chronic myelogenous leukemia.

PURPOSE: To evaluate the cost-effectiveness of interferon alfa (IFN alpha) treatment of patients with chronic myelogenous leukemia relative to conventional chemotherapy. MATERIALS AND METHODS: A decision-analysis model that involved a multistate Markov process was designed to estimate the expected cost and quality-adjusted life expectancies for two cohorts of patients to be administered conventional chemotherapy or IFN alpha. Two IFN alpha strategies were modeled: prolonged treatment for patients who achieved a hematologic response (scenario A) or only for patients who achieved a cytogenetic remission in a 2-year period (scenario B). Data on response and transition probabilities between health states were obtained from the literature by a MEDLINE search and pooled with a meta-analytic method. Costs were based on local charges. Expected survival was adjusted for quality of life on the basis of an expert panel judgment. RESULTS: Baseline analysis showed IFN alpha treatment to increase the quality-adjusted life expectancy by 15.5 and 12.5 months relative to conventional chemotherapy, in scenarios A and B, respectively. Marginal cost-effectiveness was $89,500 and $63,500 per quality-adjusted life-year (QALY) gained. Sensitivity analysis confirmed IFN alpha as the most effective approach. Cost-effectiveness results were sensitive to the cost of IFN alpha therapy and to the assumptions about the rate of cytogenetic remission. Reducing the drug dose, as suggested by a recent report, would decrease the marginal cost-effectiveness to less than $20,000. CONCLUSION: IFN alpha is substantially superior to conventional chemotherapy in terms of quality-adjusted survival, but, at the current doses, marginal cost-effectiveness ranges from $50,000 to $100,000 per QALY gained under most of our assumptions.

Testing for occult cancer in patients with idiopathic deep vein thrombosis--a decision analysis.

OBJECTIVE: To determine the effectiveness and cost-effectiveness of testing for occult cancer in idiopathic deep vein thrombosis (IDVT). DESIGN: Threshold analysis was performed on the risk-adjusted cancer prevalence in a cost-effectiveness model of ideal testing for selecting cancers with potentially desirable utility (candidate cancers). Decision analysis was employed to compare different testing programs for candidate cancers with that of no testing. Life expectancy (LE) of early- and late-detected cancers and costs of testing were the dimensions of utility. Cost-effectiveness was expressed as marginal cost per year of life saved. The perspective of the third payer was adopted, and a discount rate of 3% was applied to both costs and benefits. DATA SOURCES: Risk of cancer in IDVT, testing policies, test characteristics, and LE were gathered from literature. Costs were provided from our hospital rate book and accounting service. RESULTS: Ideal testing would support a gain of LE of 40 days or more for prostate, colon and bladder cancer in males and for colon, breast and endometrium cancer in females aged from 60 to 69 years. Testing females with colonoscopy and mammography in any sequence provides 70 days of life gained. Testing males with colonoscopy provides 27 days of life gained. Lower and older ages reduce testing effectiveness. The qualitative results are stable over plausible ranges of test characteristics, while variations in the value of benefit for early cancer diagnosis may modify the strategy. Incremental cost-effectiveness ranges from $1,789 to $ 6,979 per year of life gained. CONCLUSIONS: According to the effectiveness criterion adopted, the only worthwhile investigation strategy includes colon and breast cancer in females. Testing for colon cancer in males is desirable at a lower criterion of effectiveness. All the strategies are cost effective.

Use of recombinant human erythropoietin after bone marrow transplantation in pediatric patients with acute leukemia: effect on erythroid repopulation in autologous versus allogeneic transplants.

We carried out a pilot study on the use of recombinant human erythropoietin (rHuEPO) in children undergoing allogeneic or mafosfamide-purged autologous BMT for ALL or AML. rHuEPO was administered intravenously at a dose of 75 U/kg/day for 30 days after transplant. Ten rHuEPO-treated patients receiving allogeneic BMT and 10 given autologous BMT were compared with 15 allogeneic and 10 autologous historical controls. Endogenous EPO production was appropriate for the degree of anemia after autologous BMT. In these patients, rHuEPO did not accelerate erythroid repopulation and did not modify transfusion requirements. With allogeneic BMT, erythroid marrow activity increased faster in patients given rHuEPO than in controls and resulted in higher red cell production, the mean reticulocyte count on day +30 being 187 +/- 51 x 10(9)/l in treated patients versus 107 +/- 63 x 10(9)/l in controls (p < 0.01). The total number of RBC units administered was 1.7 +/- 1.3 in the rHuEPO group versus 5.1 +/- 3.0 in the control group (p < 0.001). The total number of platelet transfusions was 4.0 +/- 2.3 for patients given allogeneic BMT and receiving rHuEPO versus 8.4 +/- 6.8 for historical controls (p < 0.05) whereas it was similar in rHuEPO-treated and control autologous BMT patients.(ABSTRACT TRUNCATED AT 250 WORDS)