Cost of exome analysis in patients with intellectual disability: a micro-costing study in a French setting.

BACKGROUND: With the development of next generation sequencing technologies in France, exome sequencing (ES) has recently emerged as an opportunity to improve the diagnosis rate of patients presenting an intellectual disability (ID). To help French policy makers determine an adequate tariff for ES, we aimed to assess the unit cost per ES diagnostic test for ID from the preparation of the pre-analytical step until the report writing step and to identify its main cost drivers. METHODS: A micro-costing bottom-up approach was conducted for the year 2018 in a French setting as part of the DISSEQ study, a cost-effectiveness study funded by the Ministry of Health and performed in collaboration with the GAD (Génétique des Anomalies du Développement), a genetic team from the Dijon University Hospital, and a public sequencing platform, the Centre National de Recherche en Génomique Humaine (CNRGH). The analysis was conducted from the point of view of these two ES stakeholders. All of the resources (labor, equipment, disposables and reagents, reusable material) required to analyze blood samples were identified, collected and valued. Several sensitivity analyses were performed. RESULTS: The unit nominal cost per ES diagnostic test for ID was estimated to be €2,019.39. Labor represented 50.7% of the total cost. The analytical step (from the preparation of libraries to the analysis of sequences) represented 88% of the total cost. Sensitivity analyses suggested that a simultaneous price decrease of 20% for the capture kit and 50% for the sequencing support kit led to an estimation of €1,769 per ES diagnostic test for ID. CONCLUSION: This is the first estimation of ES cost to be done in the French setting of ID diagnosis. The estimation is especially influenced by the price of equipment kits, but more generally by the organization of the centers involved in the different steps of the analysis and the time period in which the study was conducted. This information can now be used to define an adequate tariff and assess the efficiency of ES. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT03287206 on September 19, 2017.

Effectiveness, safety, and cost-utility of a knee brace in medial knee osteoarthritis: the ERGONOMIE randomized controlled trial.

OBJECTIVE: This pragmatic, multicenter, open-label, randomized controlled trial (RCT) aimed to compare the effectiveness, safety, and cost-utility of a custom-made knee brace versus usual care over 1 year in medial knee osteoarthritis (OA). DESIGN: 120 patients with medial knee OA (VAS pain at rest >40/100), classified as Kellgren-Lawrence grade II-IV, were randomized into two groups: ODRA plus usual care (ODRA group) and usual care alone (UCA group). The primary effectiveness outcome was the change in VAS pain between M0 and M12. Secondary outcomes included changes over 1 year in KOOS (function) and OAKHQOL (quality of life) scores. Drug consumption, compliance, safety of the knee brace, and cost-utility over 1 year were also assessed. RESULTS: The ODRA group was associated with a higher improvement in: VAS pain (adjusted mean difference of -11.8; 95% CI: -21.1 to -2.5); all KOOS subscales (pain: +8.8; 95% CI: 1.4-16.2); other symptoms (+10.4; 95% CI: 2.7-18); function in activities of daily living (+9.2; 95% CI: 1.1-17.2); function in sports and leisure (+12.3; 95% CI: 4.3-20.3); quality of life (+9.9; 95% CI: 0.9-15.9), OAKHQOL subscales (pain: +14.8; 95% CI: 5.0-24.6); and physical activities (+8.2; 95% CI: 0.6-15.8), and with a significant decrease in analgesics consumption at M12 compared with the UCA group. Despite localized side-effects, observance was good at M12 (median: 5.3 h/day). The ODRA group had a more than 85% chance of being cost-effective for a willingness-to-pay threshold of €45 000 per QALY. CONCLUSIONS: The ERGONOMIE RCT demonstrated significant clinical benefits of an unloader custom-made knee brace in terms of improvements in pain, function, and some aspects of quality of life over 1 year in medial knee OA, as well as its potential cost-utility from a societal perspective.

The Cognitive Assessment scale for Stroke Patients (CASP) vs. MMSE and MoCA in non-aphasic hemispheric stroke patients.

INTRODUCTION: CASP specifically assesses post-stroke cognitive impairments. Its items are visual and as such can be administered to patients with severe expressive aphasia. We have previously shown that the CASP was more suitable than the Mini Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) in aphasic patients. Our objective was to compare the above scales in non-aphasic stroke patients, and assess to what extent the solely visual items of the CASP were problematic in cases of neurovisual impairments. METHODS: Fifty non-aphasic patients admitted to Physical Medicine and Rehabilitation (PM&R) units after a recent left- or right-hemisphere stroke were evaluated with the CASP, MMSE and MoCA. We compared these three scales in terms of feasibility, concordance, and influence of neurovisual impairments on the total score. RESULTS: Twenty-nine men and 21 women were included (mean age 63 ± 14). For three patients, the MoCa was impossible to administer. It took significantly less time to administer the CASP (10 ± 5 min) than the MoCA (11 ± 5 min, P=0.02), yet it still took more time than MMSE administration (7 ± 3 min, P<10(-6)). Neurovisual impairments affected equally the total scores of the three tests. Concordance between these scores was poor and only the CASP could specifically assess unilateral spatial neglect. CONCLUSION: The sole visual format of the CASP scale seems suitable for administration in post-stroke patients.

Feasibility of the cognitive assessment scale for stroke patients (CASP) vs. MMSE and MoCA in aphasic left hemispheric stroke patients.

INTRODUCTION: Post-stroke aphasia makes it difficult to assess cognitive deficiencies. We thus developed the CASP, which can be administered without using language. Our objective was to compare the feasibility of the CASP, the Mini Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) in aphasic stroke patients. MATERIAL AND METHODS: All aphasic patients consecutively admitted to seven French rehabilitation units during a 4-month period after a recent first left hemispheric stroke were assessed with CASP, MMSE and MoCA. We determined the proportion of patients in whom it was impossible to administer at least one item from these 3 scales, and compared their administration times. RESULTS: Forty-four patients were included (age 64±15, 26 males). The CASP was impossible to administer in eight of them (18%), compared with 16 for the MMSE (36%, P=0.05) and 13 for the MoCA (30%, P=0.21, NS). It was possible to administer the CASP in all of the patients with expressive aphasia, whereas the MMSE and the MoCA could not be administered. Administration times were longer for the CASP (13±4min) than for the MMSE (8±3min, P<10(-6)) and the MoCA (11±5min, P=0.23, NS). CONCLUSION: The CASP is more feasible than the MMSE and the MoCA in aphasic stroke patients.

[Cost of multiple sclerosis in France]. / Coûts de la sclérose en plaques en France.

Multiple sclerosis (MS) is one of the 30 chronic conditions specifically listed by the French healthcare system as a long-term disease (affections de longue durée [ALD]) for which the main health insurance fund (Caisse nationale d'assurance maladie des travailleurs salariés [CNAMTS]) provides full (100%) coverage of healthcare costs. The CNAMTS insures 87% of the French population (52,359,912 of the 60,028,292 inhabitants). The objectives of this study were to evaluate the direct and indirect medical costs of MS among the entire population insured by the CNAMTS in France in 2004. The CNAMTS provided us with access to the ALD database of patients with MS that contains different MS-related expenditures made in 2004. We calculated the overall direct and indirect cost of MS and the cost per patient and per item of expenditure. In 2004, 49,413 patients were registered on the ALD list for MS. Direct cost for MS patients was 469,719,967 €. The direct cost per patient and per year was 9,506 € with variations between regions (French administrative divisions) ranging from 10,800 € in northeastern France (Champagne-Ardenne) to 8,217 € in western France (Pays de la Loire). The different items of expenditure were treatments (44.5%), hospitalization (27.9%), nursing care (5.8%), physiotherapy (5.7%), transport (4%), biology (1.1%), and other (1.5%). During the course of the disease, the overall cost of MS increased slowly during the first 15 years (from 8,000 to 11,000 €), but dramatically the last year of life (23,410 €). The costs of immunomodulator treatments were higher during the first six years after registration on the ALD list. Conversely, physiotherapy costs increased linearly with time during the course of MS. Indirect costs were an estimated 116 million euros in 2004. A disability pension (8,918 € per patient) was perceived by 9,430 patients (19.1%) and a daily allowance (3,317 € per patient) by 9,894 patients (20%). In France, MS has an important economic impact, comparable to human immunodeficiency virus infection.

A decision tree to help determine the best timing and antiretroviral strategy in HIV-infected patients.

Optimal antiretroviral strategies for HIV-infected patients still need to be established. To this end a decision tree including different antiretroviral strategies that could be adopted for HIV-infected patients was built. A 10-year follow-up was simulated by using transitional probabilities estimated from a large cohort using a time-homogeneous Markov model. The desired outcome was for patients to maintain a CD4 cell count of >500 cells/mm3 without experiencing AIDS or death. For patients with a baseline HIV viral load ≥5 log10 copies/ml, boosted protease inhibitor-based immediate highly active antiretroviral therapy (HAART) allowed them to spend 12% more time with CD4 ≥500/mm3 than did delayed HAART (6·40 vs. 5·69 and 5·57 vs. 4·90 years for baseline CD4 ≥500 and 350-499/mm3, respectively). In patients with a baseline HIV viral load ≤3·5 log10 copies/ml, delayed HAART performed better than immediate HAART (6·43 vs. 6·26 and 5·95 vs. 5·18 for baseline CD4 ≥500 and 350-499/mm3, respectively). Immediate HAART is beneficial in patients with a baseline HIV viral load 5 log10 copies/ml, whereas deferred HAART appears to be the best option for patients with CD4 ≥350/mm3 and baseline HIV viral load <3·5 log10 copies/ml.

[Conducting a cost-effectiveness trial in oncology: justification and method]. / Pertinence et méthodes pour la conduite d'un essai de supériorité médico-économique en cancérologie.

The occurrence of scarce financial resources and the aim of an adequate allocation of available budgets for public community induce to conduct trials where primary endpoint could be a medico-economic criterion. In oncology, the emergent place of "stop and go" strategy and or the diminution of chemotherapy administration induce initially to demonstrate non-inferiority of these strategies for efficacy. Another underlying objective for these trials could be also to demonstrate the medico-economic superiority of these strategies. In this context, medico-economic trials using cost and efficacy composite endpoint as primary endpoint for therapeutical strategies comparison could be an interesting alternative of classical clinical trials using only an efficacy endpoint. Based on a review, the aim of this paper is to focus about design of medico-economic trials: objectives, methods and sample size calculations.

Markov modelling of HIV infection evolution in the HAART era.

The aim was to investigate the impact of the main prognostic factors on HIV evolution. A multi-state Markov model was applied in a cohort of 2126 patients to estimate impact of these factors on patients' clinical and immunological evolutions. Clinical progression and immunological deterioration shared most of their prognostic factors: male gender, intravenous drug use, weight loss, low haemoglobin level (<110 g/l), CD8 cell count (<500/mm(3)) and HIV viral load (>5 log(10) copies/ml). Highly active retroviral therapy reduced the risks of clinical progression and immune deterioration whatever patients' CD4 cell count. Risk reductions were 41-60% for protease inhibitor-based and 27-68% for non-nucleoside reverse transcriptase inhibitor-based regimens. Three-year transition probabilities showed that only patients with a CD4 cell count >or=350 CD4/mm(3) could in most cases maintain their immunity. This model provides 'real life' transition probabilities from one immunological stage to another, allowing decision analyses that could help determine the beneficial therapeutic strategies for HIV-infected patients.

Disability evolution in multiple sclerosis: how to deal with missing transition times in the Markov model?

Markov modeling of disability progression in multiple sclerosis requires knowledge of all times of transitions from a given level of disability to the next level, but such data are often missing. We address methodological challenges due to partly missing transition times. To estimate the effects of prognostic factors on the risk of transitions between three consecutive disability levels, two methods were used to deal with missing data. Listwise deletion limited the analysis to subjects with complete data. Multiple imputation of missing data revealed that data were missing at random (MAR mechanism) and imputed the missing transition times from the Weibull model. The results were then compared with the full data set with the actual times established through chart review. Multiple imputation estimates were systematically closer to those from the full data set than the listwise deletion estimates.

A population-based assessment of the prognostic value of the CD19 positive lymphocyte count in B-cell chronic lymphocytic leukemia using Cox and Markov models.

No population-based study has assessed the prognostic impact on survival of the CD19 positive lymphocyte count, evaluated by immunophenotyping at diagnosis, in B-cell chronic lymphocytic leukemia (B-CLL). Aiming at addressing this issue, we investigated the clinical outcome of a well-defined population of B-CLL patients. Survival of B-CLL patients, diagnosed between 1990 and 1999 and recorded by the Registry of Hematological Malignancies of the Côte d'Or, was analysed applying Cox's regression model to the 237 included cases and to the 195 Binet stage A patients. To assess simultaneously the predictive value of each parameter on the risk of disease progression and on the risk of death, we completed this analysis by applying a three-states homogeneous Markov model to the whole study population. Analysis of the entire population showed that age (p < 0.001), Binet stage (p = 0.008) and CD19 positive lymphocyte count (p = 0.038) were three independent prognostic factors. However, in stage A patients, only progression into a more advanced stage, analysed as a time-dependent variable, and age had a clear impact on survival (p < 0.001 for both). Markov model revealed that an increased CD19 positive lymphocyte count increased the risk of disease progression in stage A patients (p = 0.002) but did not have direct impact on survival of either stage A patients with stable disease or stage B or C patients. An increased CD19 positive lymphocyte count at diagnosis is a marker of an increased risk of disease progression in stage A patients. Thus, it can be a useful tool for the clinical management of these patients.

Decision analysis for the assessment of a record linkage procedure: application to a perinatal network.

OBJECTIVES: According to European legislation, we must develop computer software allowing the linkage of medical records previously rendered anonymous. Some of them, like AUTOMATCH, are used in daily practice either to gather medical files in epidemiologic studies or for clinical purpose. In the first situation, the aim is to avoid homonymous errors, and in the second one, synonymous errors. The objective of this work is to study the effect of different parameters (number of identification variables, phonetic treatments of names, direct or probabilistic linkage procedure) on the reliability of the linkage in order to determine which strategy is the best according to the purpose of the linkage. METHODS: The assessment of the Burgundy Perinatal Network requires the linking of discharge abstracts of mothers and neonates, collected in all the hospitals of the region. Those data are used to compare direct and probabilistic linkage, using different parameterization strategies. RESULTS: If the linkage has to be performed in real time, so that no validation of indecisions generated by probabilistic linkage is possible, probabilistic linkage using three variables without any phonetic treatment seems to be the most appropriate approach, combined with a direct linkage using four variables applied to non-conclusive links. If a validation of indecisions is possible in an epidemiological study, probabilistic linkage using five variables, with a phonetic treatment adapted to the local language has to be preferred. For medical purpose, it should be combined with a direct linkage with four or five variables. CONCLUSION: This paper reveals that the time and money available to manage indecision as well as the purpose of the linkage are of paramount importance for choosing a linkage strategy.

[Assessment of the discriminating power of identifiers for record linkage]. / Estimation de la valeur discriminante des traits d'identification utilisés pour le rapprochement des données d'un patient.

BACKGROUND: To reconstruct a patient's medical history, one has often to combine information from different sources, whatever the context of this reconstitution: epidemiological studies or health care. As a linkage using less informative identifiers could lead to linkage errors, it is essential to quantify the information associated to each identifier. METHODS: The aim of this study was to estimate the discriminating power of different identifiers which could be used in a record linkage process based on the means of the likelihood ratio proposed by Jaro as a probabilistic record linkage method. Six identifiers were considered: date of birth, maiden name, usual last name, first and second christian names and the gender. Two types of phonetic treatment were taken into account: the Soundex and a phonetic treatment adapted to the French language. Three situations were considered: 1) and 2) linkage of the data collected during two consecutive years in a university hospital (CHU de Dijon; 100000x100000 records) and a Paris hospital (50000x50000 records), 3) linkage of two files obtained through a healthcare network (Burgundy Perinatal Network; 200x2500 records). RESULTS: Whatever the situation, this work showed the interest of three identifiers when linking data concerning a same patient. The date of birth had the best discriminating power followed by the first and the last names. Including a poorly discriminating identifier like gender did not improve the results. Moreover, adding a second Christian name, often missing, increased linkage errors. On the contrary, it seemed that using a phonetic treatment adapted to the French language could slightly improve the results of linkage in comparison to Soundex. CONCLUSION: Whatever the method used, it seems necessary to improve the quality of identifier collection, in particular of the date of birth and of the first and last names as it could make the linkage of data obtained from different sources easier. Further research is needed to estimate the discriminating power of other identifiers (birth place and parents identifiers).

[A diagnostic strategy for isolated pulmonary nodules less than 2 cm in diameter]. / Gestion diagnostique d'un nodule isolé de plus de 2 cm de diamètre.

The object of this study is to determine the best diagnostic strategy for isolated pulmonary nodules less than 2 cm in diameter starting from decision analysis. The diagnostic pathway included strategies: 1. Observation with a thoracic tomodensitometry (TDM) every 3 months. 2. Percutaneous needle biopsy. 3. Video-assisted thoracoscopic surgery (VATS) resection. 4. Resection by thoracotomy. Observation was the best strategy for non-smokers in their 40's with a cost of 57-69 Francs per year of life gained. Needle biopsy was the best strategy for a 1 cm nodule in patients of 50 years, smokers and non-smokers (life expectancy 29.38 and 24.44 years). The best strategy for a 2 cm nodule was needle biopsy in 40 year old smokers (life expectancy 34.18 years) and in non-smokers aged 50-60 years with a life expectancy from 20.0 to 28.2 years. VATS was the best strategy for a 1 cm nodule in smokers over the age of 60 for a 2 cm nodule over the age of 50. The costs were 1 811, 3 214, 1 873, 1 811 and 6 093 Francs respectively per year of life gained. During the sensitivity analysis VATS remained the best strategy provided the post-operative mortality remained below 2%. When the risk of malignancy is only moderate needle biopsy may be recommended but when the risk of malignancy is high it is preferable to advise VATS as the method of diagnosis.

[Evaluation of prevention strategies for congenital toxoplasmosis: a critical review of medico-economic studies]. / Evaluation de stratégies de prévention de la toxoplasmose congénitale: revue critique des études médico-économiques.

BACKGROUND: Congenital toxoplasmosis (CT) may lead to serious neurological or sensory consequences. A serological screening of women at risk of acquiring toxoplasmosis became mandatory in France, first during the visit before wedding (1978), then during the visit for pregnancy declaration (1985) and at last with a monthly follow-up during pregnancy since 1992. The efficacy and the profitability of the program was never assessed, in spite of the modification of the epidemiological context. However medico-economical studies were conducted in countries in which no prevention program for CT was available to determine the interest of an antenatal screening similar to the French one or of other prevention strategies. METHODS: Eight studies comparing at least two strategies were selected. Methodologies used in those studies were analyzed by two independent readers with the help of a standardized scale. A score was calculated for each study. RESULTS: Each study analyzed suffered from methodological limitations, in particular concerning the estimation of antenatal treatment efficacy, which could lead to invalidate their conclusion. The most reliable studies in regard to methodological guidelines, that is with the higher score, concluded that antenatal screening was not contributive. However, they could not be transposed directly in the present French situation, because of the difference of the epidemiological and economical context. CONCLUSIONS: Given the difficulty to obtain a clear conclusion, it seems necessary to perform a rigorous decision analysis to identify the more effective and acceptable program in terms of human and financial costs for preventing congenital toxoplasmosis.

[Medico-economic impact of the Program of Medicalization of the Information System on hospital stay for myocardial infarction: influence of the quality of data collection and hospitalization length]. / Impact médico-économique du PMSI sur les séjours pour infarctus du myocarde: influence de la qualité du recueil et de la durée d'hospitalisation.

The aim of the Medicalisation Program of the Information System was to describe the activity of hospital for budget allocation. This work concerned the whole hospitalizations in the unit of intensive care of cardiology of Dijon for a myocardial infarction (MI) during the 1st half of 1998 (59 patients). The objectives of this study were: 1) the estimate of the real cost of MI management; 2) the comparison of this cost with the reference cost, determined from the data of the National Basis of Costs (BNC); 3) the economic impact of the quality of coding. The real global cost of MI was estimated at 2,323,542 FF (average by patient: 39,382 +/- 15,718 FF). Sixty eight per cent of the costs are directly related to the standing fixed overheads; in contrast, the medical and the therapeutic acts accounted for only 32% of the estimated real cost. A 52% over-estimation was highlighted between the estimated real cost and the cost of reference (p < 0.001). The errors of coding accounted for an under-estimation of only 3.6% of the cost of reference. The duration of hospitalization was significantly higher than the stay length taken from the national reference database (12.9 +/- 5.4 versus 9.2 +/- 2.1 days; p < 0.001), and was mainly responsible for these discrepancies of costs.