Gérard Duru

Limitations of the methods used for calculating quality-adjusted life-year values.

AbstractObjective: To test the validity of the techniques used to calculate quality-adjusted life-year (QALY) values based on utility functions, using a real population dataset. Design: Using the standard gamble technique, we gathered the preferences of a population sample of 189 individuals on a combination of probabilities concerning four simple health states (no physical disability, limp, walk with crutches and need a wheelchair), and three life-year spans (5, 10 and 15 years). Each of the four assumptions of the multiplicative model was tested based on the results of the experiment. Results: The utility of the health state ‘limp’ was high at 0.89 and that of ‘walk with crutches’ only slightly lower at 0.85. However, of the 189 individuals, only 57 are not in contradiction with the assumption of mutual utility independence since they strictly preferred (15 years, ‘need a wheelchair’) over (10 years, ‘need a wheelchair’) and (15 years, ‘need a wheelchair’) over (5 years, ‘need a wheelchair’). For these 57 individuals, the results of this study do not fit the assumptions underpinning the multiplicative model. Conclusion: This work suggests that the techniques used as a basis from which to calculate QALY values are flawed. In particular, the underlying assumptions of the multiattribute utility model do not correspond to behaviour patterns observed in a real population. It therefore appears that use of the QALY technique should be questioned in healthcare decision-making settings.

Systematic review of appropriate cognitive assessment instruments used in clinical trials of schizophrenia, major depressive disorder and bipolar disorder

Cognitive dysfunction is increasingly recognized as a symptom in mental conditions including schizophrenia, major depressive disorder (MDD), and bipolar disorder (BPD). Despite the many available cognitive assessment instruments, consensus is lacking on their appropriate use in clinical trials. We conducted a systematic literature review in Embase, PubMed/Medline and PsychINFO to identify appropriate cognitive function instruments for use in clinical trials of schizophrenia, MDD, and BPD. Instruments were identified from the articles. Instruments and articles were excluded if they did not address schizophrenia, MDD, or BPD. Instrument appropriateness was further assessed by the criteria of the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) initiative: test-retest reliability, utility, relationship to functional status, potential changeability to pharmacological agents, and tolerability and practicality for clinical trials. The database search yielded 173 articles describing 150 instruments used to assess cognitive function. Seventeen additional instruments were identified through Google and clinicaltrials.gov. Among all these, only 30 (18%) were deemed appropriate for use in the diseases of interest. Of these, 27 were studied in schizophrenia, one in MDD and two in BPD. These findings suggest the need for careful selection of appropriate cognitive assessment instruments, as not all may be valid in these disorders.

Cost savings of anti-TNF therapy using a test-based strategy versus an empirical dose escalation in Crohn's disease patients who lose response to infliximab

Background The use of pharmacokinetics is associated with cost savings in anti-tumor necrosis factor (anti-TNF) therapy, but the long-term cost savings in a large cohort of Crohns disease (CD) patients are unknown. Aim The goal of this study was to compare the cost of anti-TNF therapy in two cohorts of CD patients losing response to infliximab, one using a test-based strategy and one an empirical dose escalation. Methods We used a selected mathematical model to describe the trajectories of CD patients based on a discrete event system. This design allowed us to track over a given period a double cohort of patients who moved randomly and asynchronously from one state to another, while keeping all the information on their entire trajectory. Both cohorts were modeled using state diagram parameters where transition probabilities from one state to another are derived from literature data. Costs were estimated based on the French health care system. Results Cost savings among the 10,000 CD patients using a test-based strategy were €131,300,293 at 5 years. At 5 years the mean cost saving was €13,130 per patient. The direct cost of the test had no impact on the results until the cost per test reached €2,000. Conclusions A test-based strategy leads to major cost savings related to anti-TNF therapy in CD.

Development and Internal Validation of a Model Using Fecal Calprotectin in Combination with Infliximab Trough Levels to Predict Clinical Relapse in Crohnʼs Disease

Background: The best noninvasive method predicting clinical relapse remains undetermined in infliximab (IFX)-treated patients with Crohns disease. Methods: All patients with CD on IFX maintenance treatment and in clinical remission for at least 16 weeks, between 2011 and 2014, were enrolled in a prospective single-center study. The Crohns Disease Activity Index (CDAI), fecal calprotectin, C-reactive protein levels, antibodies (ATI), and trough level (TLI) of IFX were measured at every IFX infusion. The best thresholds of TLI (2 versus 3 &mgr;g/mL) and calprotectin (50 versus 250 &mgr;g/g stools) were identified across four logistic regression models. Results: One hundred nineteen patients (mean age: 34 ± 12 yrs, mean disease duration: 7.8 yrs) were included. Mean follow-up was 20.4 months, and 17% of the patients were on IFX and azathioprine at inclusion. During follow-up, 37 patients (31.1%) relapsed, 78% within the first 6 months. The clinical characteristics of the relapsed and nonrelapsed patients were similar. After logistic regression, fecal calprotectin >250 &mgr;g/g stools (OR: 4.09; 95% CI, 1.01–16.21; P = 0.049) and TLI <2 &mgr;g/mL (OR: 14.85; 95% CI, 3.67–60; P < 0.0001) were associated with loss of response. A training cohort of 55 patients was isolated randomly to implement prediction rules for loss of response. The best predictive rules were the combination of a TLI <2 &mgr;g/mL and a fecal calprotectin level >250 &mgr;g/g stools (78.3%). These rules were validated on a test cohort of 64 patients with an accuracy of 87%, (sensitivity = 0.94, specificity = 0.84, positive predictive value = 0.73, and negative predictive value = 0.97). Conclusions: In IFX-treated patients with CD in clinical remission, a combination of TLI (<2 &mgr;g/mL) and fecal calprotectin (>250 &mgr;g/g of stools) is a good model for predicting loss of response. In contrast with previous data, low TLIs ranging from 2 to 3 &mgr;g/mL should neither systematically lead to the optimization of IFX use nor a switch in the treatment.

Is the Pharmacokinetic Profile of a First Anti-TNF Predictive of the Clinical Outcome and Pharmacokinetics of a Second Anti-TNF?

Aim The aim of this study was to evaluate prospectively the clinical outcomes and pharmacokinetics of a second anti-TNF according to the pharmacokinetics of the first anti-TNF in patients with inflammatory bowel disease (IBD). Methods In patients in loss of response (LOR) to a first optimized anti-TNF and switched to a second anti-TNF, pharmacokinetics of anti-TNF were measured at the switch time, 30 weeks later, at the time of LOR, or at the end of the study (102 weeks). Results At the switch time, patients (n = 59) belonged to 4 groups according to the pharmacokinetics of the first anti-TNF: group 1 (n = 18), therapeutic trough levels; group 2 (n = 13) undetectable trough levels with antibodies against anti-TNF; group 3 (n = 13) without antibodies against anti-TNF; and group 4 (n = 15) subtherapeutic trough levels. After switching, the failure rates at week 30 and during the follow-up were as follows, respectively: in group 1 with therapeutic levels, 50% and 78%, despite therapeutic levels of the second anti-TNF in 83% of cases; in group 2 with undetectable levels and antibodies, 15% and 69% with undetectable levels of the second anti-TNF and antibodies in 85% of cases; in group 3 with undetectable levels without antibodies, 0% and 31% with therapeutic levels in 77% of cases; in group 4 with subtherapeutic levels, 13% and 33% with therapeutic levels in 73% of cases. Clinical remission rates were significantly lower (P ≤ 0.05) in groups 1 and 2 with therapeutic or undetectable levels with antibodies than in the 2 other groups. Conclusion In the case of LOR with therapeutic levels of the first anti-TNF or undetectable levels with antibodies, the switch to a second anti-TNF results in pharmacokinetic profile similar to the first one and again in LOR in most of the patients.

A pre-topological analysis of the input-output model

Abstract The letter proposes a new method for analyzing the industrial structures. This method is founded on the pre-topological properties of the set of activities.