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1.  Performance and Cost Efficiency of KRAS Mutation Testing for Metastatic Colorectal Cancer in Routine Diagnosis: The MOKAECM Study, a Nationwide Experience 
PLoS ONE  2013;8(7):e68945.
Purpose
Rapid advances in the understanding of cancer biology have transformed drug development thus leading to the approval of targeted therapies and to the development of molecular tests to select patients that will respond to treatments. KRAS status has emerged as a negative predictor of clinical benefit from anti-EGFR antibodies in colorectal cancer, and anti-EGFR antibodies use was limited to KRAS wild type tumors. In order to ensure wide access to tumor molecular profiling, the French National Cancer Institute (INCa) has set up a national network of 28 regional molecular genetics centers. Concurrently, a nationwide external quality assessment for KRAS testing (MOKAECM) was granted to analyze reproducibility and costs.
Methods
96 cell-line DNAs and 24 DNA samples from paraffin embedded tumor tissues were sent to 40 French laboratories. A total of 5448 KRAS results were collected and analyzed and a micro-costing study was performed on sites for 5 common methods by an independent team of health economists.
Results
This work provided a baseline picture of the accuracy and reliability of KRAS analysis in routine testing conditions at a nationwide level. Inter-laboratory Kappa values were >0.8 for KRAS results despite differences detection methods and the use of in-house technologies. Specificity was excellent with only one false positive in 1128 FFPE data, and sensitivity was higher for targeted techniques as compared to Sanger sequencing based methods that were dependent upon local expertise. Estimated reagent costs per patient ranged from €5.5 to €19.0.
Conclusion
The INCa has set-up a network of public laboratories dedicated to molecular oncology tests. Our results showed almost perfect agreements in KRAS testing at a nationwide level despite different testing methods ensuring a cost-effective equal access to personalized colorectal cancer treatment.
doi:10.1371/journal.pone.0068945
PMCID: PMC3723748  PMID: 23935912
2.  Small bowel polypectomy by double balloon enteroscopy: Correlation with prior capsule endoscopy 
AIM: To investigate the feasibility of small bowel polypectomy using double balloon enteroscopy and to evaluate the correlation with capsule endoscopy (CE).
METHODS: This is a retrospective review of a single tertiary hospital. Twenty-five patients treated by enteroscopy for small bowel polyps diagnosed by CE or other imaging techniques were included. The correlation between CE and enteroscopy (correlation coefficient of Kendall for the number of polyps, intra-class coefficient for the size and coefficient of correlation kappa for the location) was evaluated.
RESULTS: There were 31 polypectomies and 12 endoscopic mucosal resections with limited morbidity and no mortality. Histological analysis revealed 27 hamartomas, 6 adenomas and 3 lipomas. Strong agreement between CE and optical enteroscopy was observed for both location (Kappa value: 0.90) and polyp size (Kappa value: 0.76), but only moderate agreement was found for the number of polyps (Kendall value: 0.47).
CONCLUSION: Double balloon enteroscopy is safe for performing polypectomy. Previous CE is useful in selecting the endoscopic approach and to predicting the difficulty of the procedure.
doi:10.4253/wjge.v5.i5.219
PMCID: PMC3653020  PMID: 23678374
Small bowel polyps; Double balloon enteroscopy; Capsule endoscopy; Polypectomy; Correlation
3.  Adjustment for reporting bias in network meta-analysis of antidepressant trials 
Background
Network meta-analysis (NMA), a generalization of conventional MA, allows for assessing the relative effectiveness of multiple interventions. Reporting bias is a major threat to the validity of MA and NMA. Numerous methods are available to assess the robustness of MA results to reporting bias. We aimed to extend such methods to NMA.
Methods
We introduced 2 adjustment models for Bayesian NMA. First, we extended a meta-regression model that allows the effect size to depend on its standard error. Second, we used a selection model that estimates the propensity of trial results being published and in which trials with lower propensity are weighted up in the NMA model. Both models rely on the assumption that biases are exchangeable across the network. We applied the models to 2 networks of placebo-controlled trials of 12 antidepressants, with 74 trials in the US Food and Drug Administration (FDA) database but only 51 with published results. NMA and adjustment models were used to estimate the effects of the 12 drugs relative to placebo, the 66 effect sizes for all possible pair-wise comparisons between drugs, probabilities of being the best drug and ranking of drugs. We compared the results from the 2 adjustment models applied to published data and NMAs of published data and NMAs of FDA data, considered as representing the totality of the data.
Results
Both adjustment models showed reduced estimated effects for the 12 drugs relative to the placebo as compared with NMA of published data. Pair-wise effect sizes between drugs, probabilities of being the best drug and ranking of drugs were modified. Estimated drug effects relative to the placebo from both adjustment models were corrected (i.e., similar to those from NMA of FDA data) for some drugs but not others, which resulted in differences in pair-wise effect sizes between drugs and ranking.
Conclusions
In this case study, adjustment models showed that NMA of published data was not robust to reporting bias and provided estimates closer to that of NMA of FDA data, although not optimal. The validity of such methods depends on the number of trials in the network and the assumption that conventional MAs in the network share a common mean bias mechanism.
doi:10.1186/1471-2288-12-150
PMCID: PMC3537713  PMID: 23016799
Network meta-analysis; Publication bias; Small-study effect
4.  Determination of the best method to estimate glomerular filtration rate from serum creatinine in adult patients with sickle cell disease: a prospective observational cohort study 
BMC Nephrology  2012;13:83.
Background
Sickle cell disease (SCD) leads to tissue hypoxia resulting in chronic organ dysfunction including SCD associated nephropathy. The goal of our study was to determine the best equation to estimate glomerular filtration rate (GFR) in SCD adult patients.
Methods
We conducted a prospective observational cohort study. Since 2007, all adult SCD patients in steady state, followed in two medical departments, have had their GFR measured using iohexol plasma clearance (gold standard). The Cockcroft-Gault, MDRD-v4, CKP-EPI and finally, MDRD and CKD-EPI equations without adjustment for ethnicity were tested to estimate GFR from serum creatinine. Estimated GFRs were compared to measured GFRs according to the graphical Bland and Altman method.
Results
Sixty-four SCD patients (16 men, median age 27.5 years [range 18.0-67.5], 41 with SS-genotype were studied. They were Sub-Saharan Africa and French West Indies natives and predominantly lean (median body mass index: 22 kg/m2 [16-33]). Hyperfiltration (defined as measured GFR >110 mL/min/1.73 m2) was detected in 53.1% of patients. Urinary albumin/creatinine ratio was higher in patients with hyperfiltration than in patients with normal GFR (4.05 mg/mmol [0.14-60] versus 0.4 mg/mmol [0.7-81], p = 0.01). The CKD-EPI equation without adjustment for ethnicity had both the lowest bias and the greatest precision. Differences between estimated GFRs using the CKP-EPI equation and measured GFRs decreased with increasing GFR values, whereas it increased with the Cockcroft-Gault and MDRD-v4 equations.
Conclusions
We confirm that SCD patients have a high rate of glomerular hyperfiltration, which is frequently associated with microalbuminuria or macroalbuminuria. In non-Afro-American SCD patients, the best method for estimating GFR from serum creatinine is the CKD-EPI equation without adjustment for ethnicity. This equation is particularly accurate to estimate high GFR values, including glomerular hyperfiltration, and thus should be recommended to screen SCD adult patients at high risk for SCD nephropathy.
doi:10.1186/1471-2369-13-83
PMCID: PMC3465224  PMID: 22866669
Sickle cell disease; Glomerular hyperfiltration; Albuminuria; Glomerular filtration rate; CKD-EPI equation; Iohexol plasma clearance; Ethnicity
5.  Readability of the Written Study Information in Pediatric Research in France 
PLoS ONE  2011;6(4):e18484.
Background
The aim was to evaluate the readability of research information leaflets (RIL) for minors asked to participate in biomedical research studies and to assess the factors influencing this readability.
Methods and Findings
All the pediatric protocols from three French pediatric clinical research units were included (N = 104). Three criteria were used to evaluate readability: length of the text, Flesch's readability score and presence of illustrations. We compared the readability of RIL to texts specifically written for children (school textbooks, school exams or extracts from literary works). We assessed the effect of protocol characteristics on readability. The RIL had a median length of 608 words [350 words, 25th percentile; 1005 words, 75th percentile], corresponding to two pages. The readability of the RIL, with a median Flesch score of 40 [30; 47], was much poorer than that of pediatric reference texts, with a Flesch score of 67 [60; 73]. A small proportion of RIL (13/91; 14%) were illustrated. The RIL were longer (p<0.001), more readable (p<0.001) and more likely to be illustrated (p<0.009) for industrial than for institutional sponsors.
Conclusion
Researchers should routinely compute the reading ease of study information sheets and make greater efforts to improve the readability of written documents for potential participants.
doi:10.1371/journal.pone.0018484
PMCID: PMC3071832  PMID: 21494689
6.  The Readability of Information and Consent Forms in Clinical Research in France 
PLoS ONE  2010;5(5):e10576.
Background
Quantitative tools have been developed to evaluate the readability of written documents and have been used in several studies to evaluate information and consent forms. These studies all showed that such documents had a low level of readability. Our objective is to evaluate the readability of Information and Consent Forms (ICFs) used in clinical research.
Methods and Findings
Clinical research protocols were collected from four public clinical research centers in France. Readability was evaluated based on three criteria: the presence of an illustration, the length of the text and its Flesch score. Potential effects of protocol characteristics on the length and readability of the ICFs were determined. Medical and statutory parts of the ICF form were analyzed separately. The readability of these documents was compared with that of everyday contracts, press articles, literary extracts and political speeches. We included 209 protocols and the corresponding 275 ICFs. The median length was 1304 words. Their Flesch readability scores were low (median: 24), and only about half that of selected press articles. ICF s for industrially sponsored and randomized protocols were the longest and had the highest readability scores. More than half (52%) of the text in ICFs concerned medical information, and this information was statistically (p<0.05) more readable (Flesch: 28) than statutory information (Flesch: 21).
Conclusion
Regardless of the field of research, the ICFs for protocols included had poor readability scores. However, a prospective analysis of this test in French should be carried out before it is put into general use.
doi:10.1371/journal.pone.0010576
PMCID: PMC2868027  PMID: 20485505
8.  Diagnosis of Tetanus Immunization Status: Multicenter Assessment of a Rapid Biological Test 
Diagnosis of tetanus immunization status by medical interview of patients with wounds is poor. Many protected patients receive unnecessary vaccine or immunoglobulin, and unprotected patients may receive nothing. The aim of this study is to evaluate the feasibility and accuracy of the Tetanos Quick Stick (TQS) rapid finger prick stick test in the emergency department for determining immunization status. We designed a prospective multicenter study for blinded comparison of TQS with an enzyme-linked immunosorbent assay (ELISA). Adults referred for open wounds in 37 French hospital emergency departments had the TQS after receiving standard care (emergency-TQS). TQS was also performed in the hospital laboratory on total blood (blood/lab-TQS) and serum (serum/lab-TQS). ELISA was performed with the same blood sample at a central laboratory. We assessed concordance between emergency-TQS and blood/lab-TQS by the kappa test and the diagnostic accuracy (likelihood ratios) of medical interview, emergency-TQS, and lab-TQS. ELISA was positive in 94.6% of the 988 patients included. Concordance between blood/emergency-TQS and blood/lab-TQS results was moderate (κ = 0.6), with a high proportion of inconclusive blood/emergency-TQS tests (9.8%). Likelihood ratios for immunization were 3.0 (95% confidence interval [CI], 1.8 to 5.1), 36.6 (95% CI, 5.3 to 255.3), 89.1 (95% CI, 5.6 to 1,405.0), and 92.7 (95% CI, 5.9 to 1,462.0) for medical interview, blood/emergency-TQS, blood/lab-TQS, and serum/lab-TQS, respectively. The sensitivity of the blood/emergency-TQS was 76.7%, and the specificity was 98% by reference to the ELISA. TQS use in the emergency room could make tetanus prevention more accurate if its technical feasibility were improved, and our assessment will be supplemented by a cost effectiveness study.
doi:10.1128/CDLI.12.9.1057-1062.2005
PMCID: PMC1235798  PMID: 16148171
9.  Systematic review and meta-analysis of strategies for the diagnosis of suspected pulmonary embolism 
BMJ : British Medical Journal  2005;331(7511):259.
Objectives To assess the likelihood ratios of diagnostic strategies for pulmonary embolism and to determine their clinical application according to pretest probability.
Data sources Medline, Embase, and Pascal Biomed and manual search for articles published from January 1990 to September 2003.
Study selection Studies that evaluated diagnostic tests for confirmation or exclusion of pulmonary embolism.
Data extracted Positive likelihood ratios for strategies that confirmed a diagnosis of pulmonary embolism and negative likelihood ratios for diagnostic strategies that excluded a diagnosis of pulmonary embolism.
Data synthesis 48 of 1012 articles were included. Positive likelihood ratios for diagnostic tests were: high probability ventilation perfusion lung scan 18.3 (95% confidence interval 10.3 to 32.5), spiral computed tomography 24.1 (12.4 to 46.7), and ultrasonography of leg veins 16.2 (5.6 to 46.7). In patients with a moderate or high pretest probability, these findings are associated with a greater than 85% post-test probability of pulmonary embolism. Negative likelihood ratios were: normal or near normal appearance on lung scan 0.05 (0.03 to 0.10), a negative result on spiral computed tomography along with a negative result on ultrasonography 0.04 (0.03 to 0.06), and a d-dimer concentration < 500 μg/l measured by quantitative enzyme linked immunosorbent assay 0.08 (0.04 to 0.18). In patients with a low or moderate pretest probability, these findings were associated with a post-test probability of pulmonary embolism below 5%. Spiral computed tomography alone, a low probability ventilation perfusion lung scan, magnetic resonance angiography, a quantitative latex d-dimer test, and haemagglutination d-dimers had higher negative likelihood ratios and can therefore only exclude pulmonary embolism in patients with a low pretest probability.
Conclusions The accuracy of tests for suspected pulmonary embolism varies greatly, but it is possible to estimate the range of pretest probabilities over which each test or strategy can confirm or rule out pulmonary embolism.
PMCID: PMC1181264  PMID: 16052017
10.  Coccygectomy for instability of the coccyx 
International Orthopaedics  2004;28(3):176-179.
Between 1993 and 2000, 61 patients with instability-related coccygodynia were operated on by a single surgeon using the same technique. There were 49 women and 12 men, mean age 45.3 (18–72) years. Twenty-seven patients had hypermobility of the coccyx and 33 subluxation. In all cases, the unstable portion was removed through a limited incision directly over the coccyx. The outcome was assessed using a detailed questionnaire. Follow-up was between 12 months and more than 30 months. The outcome was rated excellent or good in 53 patients, fair in one, and poor in seven. There were nine patients with infection requiring reoperation.
doi:10.1007/s00264-004-0544-3
PMCID: PMC3474500  PMID: 15188086
11.  Personalized versus non-personalized computerized decision support system to increase therapeutic quality control of oral anticoagulant therapy: an alternating time series analysis 
Background
The quality control of oral anticoagulant therapy (OAT) during the initiation and maintenance treatment is generally poor. Physicians' ordering of OAT (especially fluindione and warfarin) can be improved by dose adjustment algorithms, taking into account the results of International Normalized Ratio (INR). Reminders at the point of care, computerized or not, have been demonstrated to be effective in changing physicians prescription behavior.
However, few studies have addressed the benefit of personalized reminders versus non personalized reminders, whereas the personalized reminders require more development to access patient record data and integrate with the computerized physician order entry system.
The Hospital Information System of George Pompidou European Hospital integrates an electronic medical record, lab test and drugs order entry system. This system allows to evaluate such reminders and to consider their implementation for routine use as well as the continuous evaluation of their impact on medical practice quality indicators.
The objective of this study is to evaluate the impact of two types of reminders on overtreatment by oral anticoagulant: a simple reminder of text formatted dose adjustment table and a personalized recommendation for oral anticoagulant dose and next date of INR control, adapted to patient data. Both types of reminders appear to the physician at the moment of drug ordering.
Methods
The study is an alternating time series experiment with three 6 months periods, each one including every 2 months according to a Latin square scheme: a control period without any reminder, a period with the simple non personalized reminder, a period with personalized reminder. All patients hospitalized in departments using the computerized physician order entry system and ordered fluindione or warfarin, will be included in the study between November 2004 and May 2006.
Main outcome will be the proportion of overcoagulation, as expressed by the proportion of observation time with INR over 4.5, assuming INR change linearly. Secondary outcome is the incidence of major haemorrhagic events. Data will be collected thanks to Hospital Information Systems databases.
Data will be analyzed taking into account patient and physician clustering effect.
doi:10.1186/1472-6963-4-27
PMCID: PMC526261  PMID: 15456515
12.  Extra vertebrae in Ingres' La Grande Odalisque 
La Grande Odalisque, a painting by Jean-Auguste Ingres (1780-1867), was throughout the 19th century notorious for its anatomical inaccuracy; in particular, the woman was said to have three lumbar vertebrae too many. This view was accepted by all art critics, but never tested and proven. We measured the length of the back and of the pelvis in human models, expressed the mean values in terms of head height, and transferred them to the painting. The deformation was found to be greater than originally assumed (five, rather than three, extra lumbar vertebrae), and to involve both the back and the pelvis. Ingres' paintings skilfully combine realism and symbolism. We suggest that the deformation may have been introduced for psychological reasons. By placing the harem woman's head further away from her pelvis the artist may have been marking the gulf between her thoughts (expressed by her aloof, resigned look) and her social role (symbolized by her deliberately lengthened pelvis).
PMCID: PMC1079534  PMID: 15229267
13.  Effects of low dose ramipril on cardiovascular and renal outcomes in patients with type 2 diabetes and raised excretion of urinary albumin: randomised, double blind, placebo controlled trial (the DIABHYCAR study) 
BMJ : British Medical Journal  2004;328(7438):495.
Objective To investigate whether a low dose of the angiotensin converting enzyme (ACE) inhibitor ramipril lowers cardiovascular and renal events in patients with type 2 diabetes who have microalbuminuria or proteinuria.
Design Randomised, double blind, parallel group trial comparing ramipril (1.25 mg/day) with placebo (on top of usual treatment) for cardiovascular and renal outcomes for at least three years.
Setting Multicentre, primary care study conducted mostly by general practitioners in 16 European and north African countries.
Participants 4912 patients with type 2 diabetes aged >50 years who use oral antidiabetic drugs and have persistent microalbuminuria or proteinuria (urinary albumin excretion ≥ 20 mg/l in two consecutive samples), and serum creatinine ≤ 150 μmol/l.
Main outcome measures The primary outcome measure was the combined incidence of cardiovascular death, non-fatal myocardial infarction, stroke, heart failure leading to hospital admission, and end stage renal failure.
Results Participants were followed for 3 to 6 (median 4) years. There were 362 primary events among the 2443 participants taking ramipril (37.8 per 1000 patient years) and 377 events among the 2469 participants taking placebo (38.8 per 1000 patient years; hazard ratio 1.03 (95% confidence interval 0.89 to 1.20, P = 0.65)). None of the components of the primary outcome was reduced. Ramipril lowered systolic and diastolic blood pressures (by 2.43 and 1.06 mm Hg respectively after two years) and favoured regression from microalbuminuria (20-200 mg/l) or proteinuria (> 200mg/l) to normal level (< 20 mg/l) or microalbuminuria (P < 0.07) in 1868 participants who completed the study.
Conclusions Low dose (1.25 mg) ramipril once daily has no effect on cardiovascular and renal outcomes of patients with type 2 diabetes and albuminuria, despite a slight decrease in blood pressure and urinary albumin. The cardiovascular benefits of a daily higher dose (10 mg) ramipril observed elsewhere are not found with an eightfold lower daily dose.
doi:10.1136/bmj.37970.629537.0D
PMCID: PMC351842  PMID: 14960504
14.  A computer decision aid for medical prevention: a pilot qualitative study of the Personalized Estimate of Risks (EsPeR) system 
Background
Many preventable diseases such as ischemic heart diseases and breast cancer prevail at a large scale in the general population. Computerized decision support systems are one of the solutions for improving the quality of prevention strategies.
Methods
The system called EsPeR (Personalised Estimate of Risks) combines calculation of several risks with computerisation of guidelines (cardiovascular prevention, screening for breast cancer, colorectal cancer, uterine cervix cancer, and prostate cancer, diagnosis of depression and suicide risk). We present a qualitative evaluation of its ergonomics, as well as it's understanding and acceptance by a group of general practitioners. We organised four focus groups each including 6–11 general practitioners. Physicians worked on several structured clinical scenari os with the help of EsPeR, and three senior investigators leaded structured discussion sessions.
Results
The initial sessions identified several ergonomic flaws of the system that were easily corrected. Both clinical scenarios and discussion sessions identified several problems related to the insufficient comprehension (expression of risks, definition of familial history of disease), and difficulty for the physicians to accept some of the recommendations.
Conclusion
Educational, socio-professional and organisational components (i.e. time constraints for training and use of the EsPeR system during consultation) as well as acceptance of evidence-based decision-making should be taken into account before launching computerised decision support systems, or their application in randomised trials.
doi:10.1186/1472-6947-3-13
PMCID: PMC317339  PMID: 14641924
15.  A generic computerized method for estimate of familial risks. 
Most guidelines developed for cancers screening and for cardiovascular risk management use rules to estimate familial risk. These rules are complex, difficult to memorize, and need to collect a complete pedigree. This paper describes a generic computerized method to estimate familial risks and its implementation in an internet-based application. The program is based on 3 generic models: a model of the family; a model of familial risk; a display model for the pedigree. The model of family allows to represent each member of the family and to construct and display a family tree. The model of familial risk is generic and allows easy update of the program with new diseases or new rules. It was possible to implement guidelines dealing with breast and colorectal cancer and cardiovascular diseases prevention. First evaluation with general practitioners showed that the program was usable. Impact on quality of familial risk estimate should be more documented.
PMCID: PMC2244401  PMID: 12463810

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