Publications by authors named "Pascal Roy"

79 Publications

Correcting the bias of the net benefit estimator due to right-censored observations.

Biom J 2021 Feb 22. Epub 2021 Feb 22.

Neurobiology Research Unit, Rigshospitalet, Copenhagen, Denmark.

Generalized pairwise comparisons (GPCs) are a statistical method used in randomized clinical trials to simultaneously analyze several prioritized outcomes. This procedure estimates the net benefit (Δ). Δ may be interpreted as the probability for a random patient in the treatment group to have a better overall outcome than a random patient in the control group, minus the probability of the opposite situation. However, the presence of right censoring introduces uninformative pairs that will typically bias the estimate of Δ toward 0. We propose a correction to GPCs that estimates the contribution of each uninformative pair based on the average contribution of the informative pairs. The correction can be applied to the analysis of several prioritized outcomes. We perform a simulation study to evaluate the bias associated with this correction. When only one time-to-event outcome was generated, the corrected estimates were unbiased except in the presence of very heavy censoring. The correction had no effect on the power or type-1 error of the tests based on the Δ. Finally, we illustrate the impact of the correction using data from two randomized trials. The illustrative datasets showed that the correction had limited impact when the proportion of censored observations was around 20% and was most useful when this proportion was close to 70%. Overall, we propose an estimator for the net benefit that is minimally affected by censoring under the assumption that uninformative pairs are exchangeable with informative pairs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/bimj.202000001DOI Listing
February 2021

Safety and efficacy of intravenous thrombolysis in stroke patients on prior antiplatelet therapy in the WAKE-UP trial.

Neurol Res Pract 2020 20;2:40. Epub 2020 Nov 20.

Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany.

Background: One quarter to one third of patients eligible for systemic thrombolysis are on antiplatelet therapy at presentation. In this study, we aimed to assess the safety and efficacy of intravenous thrombolysis in stroke patients on prescribed antiplatelet therapy in the WAKE-UP trial.

Methods: WAKE-UP was a multicenter, randomized, double-blind, placebo-controlled clinical trial to study the efficacy and safety of MRI-guided intravenous thrombolysis with alteplase in patients with an acute stroke of unknown onset time. The medication history of all patients randomized in the WAKE-UP trial was documented. The primary safety outcome was any sign of hemorrhagic transformation on follow-up MRI. The primary efficacy outcome was favorable functional outcome defined by a score of 0-1 on the modified Rankin scale at 90 days after stroke, adjusted for age and baseline stroke severity. Logistic regression models were fitted to study the association of prior antiplatelet treatment with outcome and treatment effect of intravenous alteplase.

Results: Of 503 randomized patients, 164 (32.6%) were on antiplatelet treatment. Patients on antiplatelet treatment were older (70.3 vs. 62.8 years,  <  0.001), and more frequently had a history of hypertension, atrial fibrillation, diabetes, hypercholesterolemia, and previous stroke or transient ischaemic attack. Rates of symptomatic intracranial hemorrhage and hemorrhagic transformation on follow-up imaging did not differ between patients with and without antiplatelet treatment. Patients on prior antiplatelet treatment were less likely to achieve a favorable outcome (37.3% vs. 52.6%,  = 0.014), but there was no interaction of prior antiplatelet treatment with intravenous alteplase concerning favorable outcome ( = 0.355). Intravenous alteplase was associated with higher rates of favorable outcome in patients on prior antiplatelet treatment with an adjusted odds ratio of 2.106 (95% CI 1.047-4.236).

Conclusions: Treatment benefit of intravenous alteplase and rates of post-treatment hemorrhagic transformation were not modified by prior antiplatelet intake among MRI-selected patients with unknown onset stroke. Worse functional outcome in patients on antiplatelets may result from a higher load of cardiovascular co-morbidities in these patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s42466-020-00087-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7678217PMC
November 2020

Chromosomal instability in the prediction of pituitary neuroendocrine tumors prognosis.

Acta Neuropathol Commun 2020 11 10;8(1):190. Epub 2020 Nov 10.

Fédération d'endocrinologie, Centre de Référence des Maladies Rares Hypophysaires, Groupement Hospitalier Est, Hospices Civils de Lyon, 8 av Doyen Lepine, 69677, Bron Cedex, France.

The purpose of this study was to analyze the impact of copy number variations (CNV) on sporadic pituitary neuroendocrine tumors (PitNETs) prognosis, to identify specific prognosis markers according to the known clinico-pathological classification. CGH array analysis was performed on 195 fresh-frozen PitNETs (56 gonadotroph, 11 immunonegative, 56 somatotroph, 39 lactotroph and 33 corticotroph), with 5 years post-surgery follow-up (124 recurrences), classified according to the five-tiered grading classification (invasion, Ki-67, mitotic index and p53 positivity). Effect of alterations on recurrence was studied using logistic regression models. Transcriptomic analysis of 32 lactotroph tumors was performed. The quantity of CNV was dependent on tumor type: higher in lactotroph (median(min-max) = 38% (0-97) of probes) compared to corticotroph (11% (0-77)), somatotroph (5% (0-99)), gonadotroph (0% (0-10)) and immunonegative tumors (0% (0-17). It was not predictive of recurrence in the whole cohort. In lactotroph tumors, genome instability, especially quantity of gains, significantly predicted recurrence independently of invasion and proliferation (p-value = 0.02, OR = 1.2). However, no specific CNV was found as a prognostic marker. Transcriptomic analysis of the genes included in the CNV and associated with prognosis didn't show significantly overrepresented pathway. In somatotroph and corticotroph tumors, USP8 and GNAS mutations were not associated with genome disruption or recurrence respectively. To conclude, CGH array analysis showed genome instability was dependent on PitNET type. Lactotroph tumors were highly altered and the quantity of altered genome was associated with poorer prognosis though the mechanism is unclear, whereas gonadotroph and immunonegative tumors showed the same 'quiet' profile, leaving the mechanism underlying tumorigenesis open to question.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s40478-020-01067-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7653703PMC
November 2020

Effectiveness and Safety of the Combined Use of Tranexamic Acid: A Comparative Observational Study of 1909 Cases.

Indian J Orthop 2020 Sep 24;54(Suppl 1):165-171. Epub 2020 Aug 24.

Department of Anesthesiology, Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, Lyon, France.

Background: Tranexamic acid (TA) use in lower‑limb arthroplasty has been valued in these surgeries high‑risk hemorrhagic due to its antifibrinolytic action. The objective of the present study was to determine the effectiveness of the combined intravenous (IV) and intraarticular (IA) administration of TA in lower‑limb arthroplasty.

Methods: We conduct a prospective observational study between January 1, 2014, and December 31, 2017, including all programmed lower‑limb arthroplasties. Patients were divided into four groups: no TA, 15 mg/kg IV TA, 3 g IA TA, and 15 mg/kg IV and 3 g IA. The effect on calculated total blood loss (milliliter of red blood cell [RBC]), hemoglobin, transfusion, and duration of hospitalization was studied after adjustment on age, American Society of Anesthesiologists, surgery, and postoperative curative anticoagulation. Complications related to TA administration were systematically reported.

Results: A total of 1909 patients were included - "no TA,"  = 184; "IV,"  = 1137; "IA,"  = 214; and "IV + IA,"  = 374. In the IV + IA group, a decrease in blood loss was observed compared to the no TA group (+ 220 ml 95% confidence interval [CI] [184; 255] of RBC  < 0.001) and in the IA group (+ 65 ml 95% CI [30; 99] of RBC  < 0.001). The length of hospital stay of the IV + IA group was shorter compared to the no TA group (hazard ratio [HR] 0.35, 95% CI [0.29; 0.43],  < 0.001) to the IA group (HR 0.57, 95% CI [0.48; 0.69],  < 0.001) and the IV group (HR 0.45, 95% CI [0.39; 0.50],  < 0.001). One case of deep vein thrombosis occurred in the group without TA.

Conclusion: Administration of combined TA appears effective and safe; further studies are needed in order to establish a consensual protocol.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s43465-020-00071-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7474016PMC
September 2020

Preoperative Topical Estrogen Treatment vs Placebo in 244 Children With Midshaft and Posterior Hypospadias.

J Clin Endocrinol Metab 2020 07;105(7)

Centre de Référence Maladies Rares Développement Génital: du Fœtus à l'Adulte, Hospices Civils de Lyon, Bron, France.

Purpose: Urethral fistula and dehiscence are common after hypospadias surgery. Preoperative androgens have been considered to reduce these complications although this consideration is not evidence-based. Dermatologists have reported the benefits of topical estrogens on skin healing. We investigated whether the preoperative use of topical promestriene could reduce healing complications in hypospadias surgery. Our primary objective was to demonstrate a reduction of healing complications with promestriene vs placebo. Impact on reoperations and other complications, clinical tolerance, bone growth, and biological systemic effects of the treatment were also considered.

Methods: We conducted a prospective, randomized, placebo-controlled, double-blind, parallel group trial between 2011 and 2015 in 4 French centers. One-stage transverse preputial island flap urethroplasty (onlay urethroplasty) was selected for severe hypospadias. Promestriene or placebo was applied on the penis for 2 months prior to surgery. The primary outcome was the presence of postoperative urethral fistula or dehiscence in the first year postsurgery. For safety reasons, hormonal and anatomical screenings were performed.

Results: Out of 241 patients who received surgery, 122 patients were randomized to receive placebo, and 119 patients received promestriene. The primary outcome was unavailable for 11 patients. Healing complications were assessed at 16.4% (19/116) in the placebo vs 14.9% (17/114) in the promestriene arm, and the odds ratio adjusted on center was 0.93 (95% confidence interval 0.45-1.94), P = 0.86.

Conclusions And Relevance: Although we observed an overall lower risk of complications compared to previous publications, postsurgery complications were not different between promestriene and placebo, because of a lack of power of the study or the inefficacy of promestriene.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/clinem/dgaa231DOI Listing
July 2020

Energy Expenditure in Older People Hospitalized for an Acute Episode.

Nutrients 2019 Dec 4;11(12). Epub 2019 Dec 4.

CarMeN, U1060 INSERM, 69921 Oullins CEDEX, France.

Weight loss and worsening of nutritional state is a frequent downfall of acute hospitalization in older people. It is usually accepted that acute inflammation is responsible for hypercatabolism. However, several studies suggest, on the contrary, a reduction in resting energy expenditure (REE). This study aimed to obtain a reliable measure of REE and total energy expenditure (TEE) in older patients hospitalized for an acute episode in order to better assess patients' energy requirements and help understand the mechanisms of weight loss in this situation. Nineteen hospitalized older patients (mean age 83 years) with C-reactive protein (CRP) level >20mg/L were recruited. REE and TEE were measured using gold standard methods of indirect calorimetry and doubly labeled water (DLW), respectively. REE was then compared to data from a previous study on aged volunteers from nursing homes who were free of an acute stressor event. Energy requirements measured by DLW were confirmed at 1.3 × REE. Energy intake covered the needs but did not prevent weight loss in these patients. TEE was not increased in hospitalized patients and was not influenced by inflammation, while the relationship between REE and inflammation was uncertain. Our results suggest that lean mass remains the major determinant of REE in hospitalized older people and that weight loss may not be explained solely by a state of hypercatabolism.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/nu11122946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6949974PMC
December 2019

Effectiveness and Safety of the Combined Use of Tranexamic Acid: A Comparative Observational Study of 1909 Cases.

Indian J Orthop 2019 Nov-Dec;53(6):708-713

Department of Anesthesiology, Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, Lyon, France.

Background: Tranexamic acid (TA) use in lower-limb arthroplasty has been valued in these surgeries high-risk hemorrhagic due to its antifibrinolytic action. The objective of the present study was to determine the effectiveness of the combined intravenous (IV) and intraarticular (IA) administration of TA in lower-limb arthroplasty.

Methods: We conduct a prospective observational study between January 1, 2014, and December 31, 2017, including all programmed lower-limb arthroplasties. Patients were divided into four groups: no TA, 15 mg/kg IV TA, 3 g IA TA, and 15 mg/kg IV and 3 g IA. The effect on calculated total blood loss (milliliter of red blood cell [RBC]), hemoglobin, transfusion, and duration of hospitalization was studied after adjustment on age, American Society of Anesthesiologists, surgery, and postoperative curative anticoagulation. Complications related to TA administration were systematically reported.

Results: A total of 1909 patients were included - "no TA," = 184; "IV," = 1137; "IA," = 214; and "IV + IA," = 374. In the IV + IA group, a decrease in blood loss was observed compared to the no TA group (+220 ml 95% confidence interval [CI] [184; 255] of RBC < 0.001) and in the IA group (+65 ml 95% CI [30; 99] of RBC < 0.001). The length of hospital stay of the IV + IA group was shorter compared to the no TA group (hazard ratio [HR] 0.35, 95% CI [0.29; 0.43], < 0.001) to the IA group (HR 0.57, 95% CI [0.48; 0.69], < 0.001) and the IV group (HR 0.45, 95% CI [0.39; 0.50], < 0.001). One case of deep vein thrombosis occurred in the group without TA.

Conclusion: Administration of combined TA appears effective and safe; further studies are needed in order to establish a consensual protocol.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4103/ortho.IJOrtho_148_19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6804382PMC
November 2019

Analysis of Outcome of Intravenous Thrombolysis in Infarcts of Infratentorial Localization in the WAKE-UP Trial.

Front Neurol 2019 11;10:983. Epub 2019 Sep 11.

Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

In WAKE-UP (Efficacy and Safety of MRI-based Thrombolysis in Wake-Up Stroke), patients with an acute stroke of unknown onset time were randomized to treatment with intravenous alteplase or placebo, guided by MRI. In this exploratory secondary analysis we compared clinical and imaging data, as well as treatment effects and safety of intravenous thrombolysis between patients with infra- vs. supratentorial stroke. Forty-eight out of 503 randomized patients (9.5%) presented with a stroke involving the cerebellum or brainstem. Patients with infratentorial stroke were younger compared to patients with supratentorial stroke (mean age 60 vs. 66 years), more frequently male (85 vs. 62%), and less severely affected (median NIHSS 4.5 vs. 6.0). There was no heterogeneity for treatment effect between supratentorial (OR 1.67 95% CI 1.11-2.51) and infratentorial (OR 1.31 95% CI 0.41-4.22) sub-groups (test for interaction = 0.70). In patients with infratentorial stroke, favorable outcome [a score of 0-1 on the modified Rankin scale (mRS) at 90 days] was observed in 12/22 patients (54.5%) in the alteplase group and in 13/25 patients (52.0%) in the placebo group ( = 0.59). The primary safety endpoint (death or mRS 4-6 at day 90) occurred in three patients of the alteplase group (13.6%) and three patients in the placebo group (12.0%); = 0.74. WAKE-UP was underpowered for demonstrating treatment effect in subgroup analyses however, based on our current results, there is no evidence to recommend withholding MRI-guided thrombolysis in patients with unknown onset stroke of infratentorial localization.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fneur.2019.00983DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6749039PMC
September 2019

Comparison of crossover and parallel-group designs for the identification of a binary predictive biomarker of the treatment effect.

Basic Clin Pharmacol Toxicol 2019 Jul 16. Epub 2019 Jul 16.

CNRS, UMR5558, Laboratory of Biometry and Evolutionary Biology, Lyon 1 University, Lyon, France.

Pros and cons of crossover design are well known for estimating the treatment effect compared to parallel-group design, but remain unclear for identifying and estimating an interaction between a potential biomarker and the treatment effect. Such 'predictive' biomarkers, or 'effect modifiers', help to predict the response to specific treatments. The purpose of this report was to better characterize the advantages and disadvantages of crossover versus parallel-group design to identify predictive biomarkers. The treatment effect, the effect of a binary biomarker and their interaction were modelled using a linear model. The intra-subject correlation in the crossover design was taken into account through an intra-class correlation coefficient. The variance-covariance matrix of the parameters was derived and compared. For both trial designs, the variance of the parameter estimating an interaction between the treatment effect and a potential predictive biomarker corresponds to the variance of the parameter estimating the treatment effect, multiplied by the inverse of the frequency of the candidate biomarker. The ratio of the variance of the interaction parameter in the crossover to the variance estimated in the parallel-group design depends on the complement of the intra-class correlation coefficient. When planning a clinical trial including a search for candidate biomarker, the frequency of the candidate biomarker helps design the sample size, and the intra-subject correlation of the outcome should be taken into account for choosing between parallel-group and crossover designs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bcpt.13293DOI Listing
July 2019

Individualized quantification of the benefit from reperfusion therapy using stroke predictive models.

Eur J Neurosci 2019 10 22;50(8):3251-3260. Epub 2019 Jul 22.

Service de Biostatistique, Hospices Civils de Lyon, Lyon, France.

Purpose: Recent imaging developments have shown the potential of voxel-based models in assessing infarct growth after stroke. Many models have been proposed but their relevance in predicting the benefit of a reperfusion therapy remains unclear. We searched for a predictive model whose volumetric predictions would identify stroke patients who are to benefit from tissue plasminogen activator (t-PA)-induced reperfusion.

Material And Methods: Forty-five cases were used to study retrospectively stroke progression from admission to end of follow-up. Predictive approaches based on various statistical models, predictive variables and spatial filtering methods were compared. The optimal approach was chosen according to the area under the precision-recall curve (AUPRC). The final lesion volume was then predicted assuming that the patient would or would not reperfuse. Patients, with an acute lesion of ≤50 ml and a predicted reduction in the presence of reperfusion >6 ml and >25% of the acute lesion, were classified as responders.

Results: The optimal model was a logistic regression using the voxel distance to the acute lesion, the volume of the acute lesion and Gaussian-filtered MRI contrast parameters as predictive variables. The predictions gave a median AUPRC of 0.655, a median AUC of 0.976 and a median volumetric error of 8.29 ml. Nineteen patients matched the responder profile. A non-significant trend of improved reduction in NIHSS score (-42.8%, p = .09) and in lesion volume (-78.1%, p = 0.21) following reperfusion was observed for responder patients.

Conclusion: Despite limited volumetric accuracy, predictive stroke models can be used to quantify the benefit of reperfusion therapies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ejn.14505DOI Listing
October 2019

Clinical Characteristics and Outcome of Patients with Lacunar Infarcts and Concurrent Embolic Ischemic Lesions.

Clin Neuroradiol 2020 Sep 3;30(3):511-516. Epub 2019 Jun 3.

Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany.

Purpose: Lacunar infarcts are thought to result from occlusion of small penetrating arteries due to microatheroma and lipohyalinosis, pathognomonic for cerebral small vessel disease (CSVD). Concurrent embolic ischemic lesions indicate a different stroke mechanism. The purpose of this study was to examine the clinical characteristics and outcome of patients with lacunar infarcts and concurrent embolic infarcts on diffusion-weighted imaging (DWI).

Methods: All patients screened for the WAKE-UP trial (ClinicalTrials.gov number, NCT01525290) were reviewed for acute lacunar infarcts and concurrent embolic lesions on baseline DWI. Clinical characteristics and outcome were compared between lacunar infarct patients with and without concurrent embolic lesions.

Results: Of 244 patients with an acute lacunar infarct, 20 (8.2%) had concurrent acute embolic infarcts. Compared to patients with a lacunar infarct only, patients with concurrent embolic infarcts were older (mean age 69 years vs. 63 years; p = 0.031), more severely affected (median National Institutes of Health Stroke Scale [NIHSS] score 5 vs. 4; p = 0.046), and-among those randomized-had worse functional outcome at 90 days (median modified Rankin Scale [mRS] 3 vs. 1; p = 0.011).

Conclusion: Approximately 8% of lacunar infarct patients show concurrent embolic lesions suggesting a stroke etiology other than CSVD. These patients are more severely affected and have a worse functional outcome illustrating the need for a thorough diagnostic work-up of possible embolic sources even in patients with an imaging-defined diagnosis of lacunar infarcts.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00062-019-00800-5DOI Listing
September 2020

Functional Outcome of Intravenous Thrombolysis in Patients With Lacunar Infarcts in the WAKE-UP Trial.

JAMA Neurol 2019 06;76(6):641-649

Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Importance: The rationale for intravenous thrombolysis in patients with lacunar infarcts is debated, since it is hypothesized that the microvascular occlusion underlying lacunar infarcts might not be susceptible to pharmacological reperfusion treatment.

Objective: To study the efficacy and safety of intravenous thrombolysis among patients with lacunar infarcts.

Design, Setting, And Participants: This exploratory secondary post hoc analysis of the WAKE-UP trial included patients who were screened and enrolled between September 2012 and June 2017 (with final follow-up in September 2017). The WAKE-UP trial was a multicenter, double-blind, placebo-controlled randomized clinical trial to study the efficacy and safety of intravenous thrombolysis with alteplase in patients with an acute stroke of unknown onset time, guided by magnetic resonance imaging. All 503 patients randomized in the WAKE-UP trial were reviewed for lacunar infarcts. Diagnosis of lacunar infarcts was based on magnetic resonance imaging and made by consensus of 2 independent investigators blinded to clinical information.

Main Outcomes And Measures: The primary efficacy variable was favorable outcome defined by a score of 0 to 1 on the modified Rankin Scale at 90 days after stroke, adjusted for age and severity of symptoms.

Results: Of the 503 patients randomized in the WAKE-UP trial, 108 patients (including 74 men [68.5%]) had imaging-defined lacunar infarcts, whereas 395 patients (including 251 men [63.5%]) had nonlacunar infarcts. Patients with lacunar infarcts were younger than patients with nonlacunar infarcts (mean age [SD], 63 [12] years vs 66 [12] years; P = .003). Of patients with lacunar infarcts, 55 (50.9%) were assigned to treatment with alteplase and 53 (49.1%) to receive placebo. Treatment with alteplase was associated with higher odds of favorable outcome, with no heterogeneity of treatment outcome between lacunar and nonlacunar stroke subtypes. In patients with lacunar strokes, a favorable outcome was observed in 31 of 53 patients (59%) in the alteplase group compared with 24 of 52 patients (46%) in the placebo group (adjusted odds ratio [aOR], 1.67 [95% CI, 0.77-3.64]). There was 1 death and 1 symptomatic intracranial hemorrhage according to Safe Implementation of Thrombolysis in Stroke-Monitoring Study criteria in the alteplase group, while no death and no symptomatic intracranial hemorrhage occurred in the placebo group. The distribution of the modified Rankin Scale scores 90 days after stroke also showed a nonsignificant shift toward better outcomes in patients with lacunar infarcts treated with alteplase, with an adjusted common odds ratio of 1.94 (95% CI, 0.95-3.93).

Conclusions And Relevance: While the WAKE-UP trial was not powered to demonstrate the efficacy of treatment in subgroups of patients, the results indicate that the association of intravenous alteplase with functional outcome does not differ in patients with imaging-defined lacunar infarcts compared with those experiencing other stroke subtypes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamaneurol.2019.0351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6563546PMC
June 2019

Assessing Long-Term Survival Benefits of Immune Checkpoint Inhibitors Using the Net Survival Benefit.

J Natl Cancer Inst 2019 11;111(11):1186-1191

Background: The treatment effect in survival analysis is commonly quantified as the hazard ratio, and tested statistically using the standard log-rank test. Modern anticancer immunotherapies are successful in a proportion of patients who remain alive even after a long-term follow-up. This new phenomenon induces a nonproportionality of the underlying hazards of death.

Methods: The properties of the net survival benefit were illustrated using the dataset from a trial evaluating ipilimumab in metastatic melanoma. The net survival benefit was then investigated through simulated datasets under typical scenarios of proportional hazards, delayed treatment effect, and cure rate. The net survival benefit test was computed according to the value of the minimal survival difference considered clinically relevant. As comparators, the standard and the weighted log-rank tests were also performed.

Results: In the illustrative dataset, the net survival benefit favored ipilimumab [Δ(0) = 15.8%, 95% confidence interval = 4.6% to 27.3%, P = .006]. This favorable effect was maintained when the analysis was focused on long-term survival differences (eg, >12 months, Δ(12) = 12.5% (95% confidence interval = 4.4% to 20.6%, P = .002). Under the scenarios of a delayed treatment effect and cure rate, the power of the net survival benefit test compared favorably to the standard log-rank test power and was comparable to the power of the weighted log-rank test for large values of the threshold of clinical relevance.

Conclusion: The net long-term survival benefit is a measure of treatment effect that is meaningful whether or not hazards are proportional. The associated statistical test is more powerful than the standard log-rank test when a delayed treatment effect is anticipated.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jnci/djz030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6855951PMC
November 2019

Optimism Bias Correction in Omics Studies with Big Data: Assessment of Penalized Methods on Simulated Data.

OMICS 2019 04 22;23(4):207-213. Epub 2019 Feb 22.

1 Service de Biostatistique-Bioinformatique, Pôle Santé Publique, Hospices Civils de Lyon, Lyon, France.

Big Data generated by omics technologies require simultaneous analyses of large numbers of variables. This leads to complex model selection and parameter estimates that show optimism bias. This study on simulated data sets examined optimism-bias correction by penalty regression methods in case-control studies that involve clinical and omics variables. Least absolute shrinkage and selection operator (LASSO)-based methods (LASSO-penalized logistic regression, adaptive LASSO, and regularized LASSO for selection + ridge regression) were evaluated using power, the false positive rate (FPR), false discovery rate (FDR), and by estimated versus theoretical parameter comparisons. The "ordinary" LASSO overcorrects the optimism bias. The adaptive LASSO with LASSO estimation of the weights was unable to provide a sufficient correction. Importantly, the adaptive LASSO with ridge estimation of the weights showed the best parameter estimation. The regularized LASSO selection showed a slight optimism bias that decreased with the increase in the training set size. The optimism bias decreased with the increase of the number of variables selected among truly differentially expressed variables; however, power, FPR, and FDR were correlated. A compromise between model selection and estimation accuracy should be found. These results might prove useful because Big Data analyses are becoming commonplace in omics/multiomics studies in integrative biology, precision medicine, and planetary health.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/omi.2018.0191DOI Listing
April 2019

20-year assessment of metastatic latency and subsequent time to death after proton therapy for uveal melanomas.

Melanoma Res 2020 06;30(3):272-278

Department of Ophthalmology, Croix-Rousse University Hospital.

The aim of this study was to evaluate metastatic latency and survival after the occurrence of metastases in patients with choroidal/ciliary body melanoma treated with proton therapy. This was a retrospective cohort study. All consecutive patients with choroidal/ciliary body melanoma treated with proton therapy between 1991 and 2010 were included. Overall survival, specific survival (SS), local recurrence-free interval, and metastasis-free interval (MFI) were calculated. There were 508 patients. The mean follow-up was 239.4 months. Overall survival and SS rates were 57.2 and 67.6% at 10 years. Pre-equatorial tumor location, advanced tumor stage, and initial exudative retinal detachment were associated independently with SS. Thirty-three percent of the patients (n = 169) had metastases. Local recurrence-free interval and MFI were 91.3 and 65.7% at 10 years, respectively. MFI was shorter in pre-equatorial, large tumors, and/or tumors with exudative retinal detachment. After the occurrence of metastases, the median survival time was 1.25 years and survival probabilities were 62.1% at 1 year, 26.0% at 2 years, and 6.0% at 5 years. Except for age, none of the baseline clinical factors was associated with survival after metastasis occurrence. SS after metastasis occurrence was longer for metastasis occurring more than 10 years after tumor diagnosis (P =0.010). Death after metastasis is independent of initial tumor characteristics. Small tumors still have a risk for metastases after 10 years. Thus, lifelong follow-up is necessary for uveal melanoma patients. Larger series of metastatic patients are needed to evaluate aggressive multimodal treatments of metastases. Death after metastasis is independent of the initial tumor characteristics. Small tumors contraintuitively have a long-life risk of metastases. MFI is associated independently with pre-equatorial location, tumor stage, and retinal detachment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/CMR.0000000000000519DOI Listing
June 2020

Cytomegalovirus infection in the first year after pediatric kidney transplantation.

Nephrol Ther 2019 Mar 8;15(1):44-50. Epub 2018 Jun 8.

Centre de référence des maladies rénales rares, service de néphrologie, rhumatologie dermatologie pédiatriques, hospices civils de Lyon, 69003 Lyon, France; Université Claude-Bernard Lyon 1, 69000 Lyon, France.

Cytomegalovirus is common in adult recipients (prevalence of 40-90%). Children are typically seronegative but immunosuppression may prone to primary-infection or viral reactivation, with potentially severe consequences. CMV infection incidence in pediatric kidney transplant recipients has seldom been investigated. The aim of our study was to evaluate the incidence and timing of CMV infection during the first year after renal transplantation. We assembled a retrospective cohort of 136 children who had received a kidney transplant between 2003 and 2014 with a year follow-up. The patients were classified regarding CMV infection as high risk (D+/R-), intermediate risk (R+) or low risk (D-/R-). CMV infection was defined by the viral replication remaining asymptomatic whereas CMV disease concerned viral replication with clinical and/or biological symptoms. Oral valganciclovir was used as prophylaxis for high-risk recipients. A total of 38 patients (27.9%) developed CMV infection, 13 (40.6%) of the 32 D+/R-, 24 (45.3%) of the 53 R+ and 1 (2.0%) of the 51 D-/R-. Of these 38 infected patients, 10 developed tissue-invasive disease. During the first year after kidney transplantation, 27.9% of recipients developed CMV infection. This study confirms the influence of donor and recipient CMV status on infection propensity and highlights the importance of adequate follow-up for intermediate risk patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.nephro.2018.04.003DOI Listing
March 2019

MRI-Guided Thrombolysis for Stroke with Unknown Time of Onset.

N Engl J Med 2018 08 16;379(7):611-622. Epub 2018 May 16.

From Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, Universitätsklinikum Hamburg-Eppendorf (G.T., B. Cheng, S.G., A.G., C.G.), the Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf (J.F.), and ZytoService Deutschland (E.S.), Hamburg, Universitätsklinik für Neurologie, Medizinische Universität Graz, Graz (F.F.), Centrum für Schlaganfallforschung Berlin (I.G., K.G.H., K.V., M. Ebinger, M. Endres, J.B.F.) and Klinik und Hochschulambulanz für Neurologie (K.G.H., L.N., M. Endres), Charité-Universitätsmedizin Berlin, and Neurologie der Rehaklinik Medical Park Humboldtmühle (M. Ebinger), Berlin, Mediri (J. Gregori, M.G.), the Department of Neurology, Medical Faculty Mannheim, University of Heidelberg (M.H.), and Neurologische Klinik, Universitätsklinikum Heidelberg (P. Ringleb), Heidelberg, Fraunhofer MEVIS and University of Bremen, Bremen (M.G.), and Institut für Neuroradiologie, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck (A.K.) - all in Germany; the Department of Neurology, Aarhus University Hospital, Aarhus (C.Z.S., G.A.), the Department of Neurology, Bispebjerg Hospital, Copenhagen University Hospital, Copenhagen (J.M.), and Department of Neurology, Stroke Unit, Aalborg University Hospital, Aalborg (B.M.) - all in Denmark; Hospices Civils de Lyon, Service de Biostatistique (F.B., P. Roy), the Neuroradiology Department, Neurological Hospital, University Lyon (Y.B.), and the Department of Stroke Medicine, Université Claude Bernard Lyon 1, and Hospices Civils de Lyon (T.-H.C., N.N.), Lyon, and Université Lyon 1 and Centre National de la Recherche Scientifique, UMR 5558, Laboratoire de Biométrie et Biologie Evolutive, Equipe Biostatistique-Santé, Villeurbanne (F.B., P. Roy) - all in France; the Institute of Neuroscience and Psychology (B. Cheripelli, K.W.M.) and the Robertson Centre for Biostatistics (I.F.), University of Glasgow, Glasgow, United Kingdom (I.F.); Fundació Salut Empordà Hospital, Figueres (J. Guibernau), Stroke Unit, Department of Neurosciences, Hospital Universitari Germans Trias i Pujol, Barcelona (N.P.O.), and the Department of Radiology (J.P., S.P.) and the Stroke Unit (J.S.), Hospital Universitari Doctor Josep Trueta, Institut d'Investigació Biomèdica de Girona, Girona - all in Spain; the Department of Neurology, St. Antonius Hospital, Nieuwegein, and University Medical Center Utrecht, Utrecht (W.S.) - both in the Netherlands; the Department of Imaging and Pathology, University of Leuven (S.S.), the Department of Neurology, University Hospitals Leuven (A.W., R.L.), KU Leuven-University of Leuven, Department of Neurosciences, Experimental Neurology (A.W., R.L.), and the VIB-KU Leuven Center for Brain and Disease Research, Laboratory of Neurobiology (A.W., R.L.), Leuven, Belgium; and Florey Institute of Neuroscience and Mental Health, Heidelberg, VIC, Australia (V.T.).

Background: Under current guidelines, intravenous thrombolysis is used to treat acute stroke only if it can be ascertained that the time since the onset of symptoms was less than 4.5 hours. We sought to determine whether patients with stroke with an unknown time of onset and features suggesting recent cerebral infarction on magnetic resonance imaging (MRI) would benefit from thrombolysis with the use of intravenous alteplase.

Methods: In a multicenter trial, we randomly assigned patients who had an unknown time of onset of stroke to receive either intravenous alteplase or placebo. All the patients had an ischemic lesion that was visible on MRI diffusion-weighted imaging but no parenchymal hyperintensity on fluid-attenuated inversion recovery (FLAIR), which indicated that the stroke had occurred approximately within the previous 4.5 hours. We excluded patients for whom thrombectomy was planned. The primary end point was favorable outcome, as defined by a score of 0 or 1 on the modified Rankin scale of neurologic disability (which ranges from 0 [no symptoms] to 6 [death]) at 90 days. A secondary outcome was the likelihood that alteplase would lead to lower ordinal scores on the modified Rankin scale than would placebo (shift analysis).

Results: The trial was stopped early owing to cessation of funding after the enrollment of 503 of an anticipated 800 patients. Of these patients, 254 were randomly assigned to receive alteplase and 249 to receive placebo. A favorable outcome at 90 days was reported in 131 of 246 patients (53.3%) in the alteplase group and in 102 of 244 patients (41.8%) in the placebo group (adjusted odds ratio, 1.61; 95% confidence interval [CI], 1.09 to 2.36; P=0.02). The median score on the modified Rankin scale at 90 days was 1 in the alteplase group and 2 in the placebo group (adjusted common odds ratio, 1.62; 95% CI, 1.17 to 2.23; P=0.003). There were 10 deaths (4.1%) in the alteplase group and 3 (1.2%) in the placebo group (odds ratio, 3.38; 95% CI, 0.92 to 12.52; P=0.07). The rate of symptomatic intracranial hemorrhage was 2.0% in the alteplase group and 0.4% in the placebo group (odds ratio, 4.95; 95% CI, 0.57 to 42.87; P=0.15).

Conclusions: In patients with acute stroke with an unknown time of onset, intravenous alteplase guided by a mismatch between diffusion-weighted imaging and FLAIR in the region of ischemia resulted in a significantly better functional outcome and numerically more intracranial hemorrhages than placebo at 90 days. (Funded by the European Union Seventh Framework Program; WAKE-UP ClinicalTrials.gov number, NCT01525290; and EudraCT number, 2011-005906-32 .).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1056/NEJMoa1804355DOI Listing
August 2018

Whole exome sequencing in three families segregating a pediatric case of sarcoidosis.

BMC Med Genomics 2018 03 6;11(1):23. Epub 2018 Mar 6.

AP-HP Pediatric pulmonology and Reference Center for rare lung diseases RespiRare, Hôpital Trousseau, INSERM UMR-S933, Sorbonne University, Paris, France.

Background: Sarcoidosis (OMIM 181000) is a multi-systemic granulomatous disorder of unknown origin. Despite multiple genome-wide association (GWAS) studies, no major pathogenic pathways have been identified to date. To find out relevant sarcoidosis predisposing genes, we searched for de novo and recessive mutations in 3 young probands with sarcoidosis and their healthy parents using a whole-exome sequencing (WES) methodology.

Methods: From the SARCFAM project based on a national network collecting familial cases of sarcoidosis, we selected three families (trios) in which a child, despite healthy parents, develop the disease before age 15 yr. Each trio was genotyped by WES (Illumina HiSEQ 2500) and we selected the gene variants segregating as 1) new mutations only occurring in affected children and 2) as recessive traits transmitted from each parents. The identified coding variants were compared between the three families. Allelic frequencies and in silico functional results were analyzed using ExAC, SIFT and Polyphenv2 databases. The clinical and genetic studies were registered by the ClinicalTrials.gov - Protocol Registration and Results System (PRS) ( https://clinicaltrials.gov ) receipt under the reference NCT02829853 and has been approved by the ethical committee (CPP LYON SUD EST - 2 - REF IRB 00009118 - September 21, 2016).

Results: We identified 37 genes sharing coding variants occurring either as recessive mutations in at least 2 trios or de novo mutations in one of the three affected children. The genes were classified according to their potential roles in immunity related pathways: 9 to autophagy and intracellular trafficking, 6 to G-proteins regulation, 4 to T-cell activation, 4 to cell cycle and immune synapse, 2 to innate immunity. Ten of the 37 genes were studied in a bibliographic way to evaluate the functional link with sarcoidosis.

Conclusions: Whole exome analysis of case-parent trios is useful for the identification of genes predisposing to complex genetic diseases as sarcoidosis. Our data identified 37 genes that could be putatively linked to a pediatric form of sarcoidosis in three trios. Our in-depth focus on 10 of these 37 genes may suggest that the formation of the characteristic lesion in sarcoidosis, granuloma, results from combined deficits in autophagy and intracellular trafficking (ex: Sec16A, AP5B1 and RREB1), G-proteins regulation (ex: OBSCN, CTTND2 and DNAH11), T-cell activation (ex: IDO2, IGSF3), mitosis and/or immune synapse (ex: SPICE1 and KNL1). The significance of these findings needs to be confirmed by functional tests on selected gene variants.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12920-018-0338-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5839022PMC
March 2018

Variance component analysis to assess protein quantification in biomarker validation: application to selected reaction monitoring-mass spectrometry.

BMC Bioinformatics 2018 03 1;19(1):73. Epub 2018 Mar 1.

Service de Biostatistique-Bioinformatique, Hospices Civils de Lyon, 162, avenue Lacassagne, F-69003, Lyon, France.

Background: In the field of biomarker validation with mass spectrometry, controlling the technical variability is a critical issue. In selected reaction monitoring (SRM) measurements, this issue provides the opportunity of using variance component analysis to distinguish various sources of variability. However, in case of unbalanced data (unequal number of observations in all factor combinations), the classical methods cannot correctly estimate the various sources of variability, particularly in presence of interaction. The present paper proposes an extension of the variance component analysis to estimate the various components of the variance, including an interaction component in case of unbalanced data.

Results: We applied an experimental design that uses a serial dilution to generate known relative protein concentrations and estimated these concentrations by two processing algorithms, a classical and a more recent one. The extended method allowed estimating the variances explained by the dilution and the technical process by each algorithm in an experiment with 9 proteins: L-FABP, 14.3.3 sigma, Calgi, Def.A6, Villin, Calmo, I-FABP, Peroxi-5, and S100A14. Whereas, the recent algorithm gave a higher dilution variance and a lower technical variance than the classical one in two proteins with three peptides (L-FABP and Villin), there were no significant difference between the two algorithms on all proteins.

Conclusions: The extension of the variance component analysis was able to estimate correctly the variance components of protein concentration measurement in case of unbalanced design.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12859-018-2075-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5831836PMC
March 2018

Centralization errors in comparative genomic hybridization array analysis of pituitary tumor samples.

Genes Chromosomes Cancer 2018 06 9;57(6):320-328. Epub 2018 Mar 9.

Univ Lyon, Université Lyon 1, Lyon, France.

Reliable interpretation of comparative genomic hybridization array (aCGH) results requires centralization and normalization of the data. We evaluated the reliability of aCGH centralization by comparing aCGH results (with classical centralization-normalization steps) to fluorescence in situ hybridization (FISH) results. In addition, we propose a method to correct centralization bias. Sixty-six pituitary tumors were analyzed (Agilent aCGH + SNP 4 × 180K microarray). For each tumor, the FISH-based log (ratios) of a subset of chromosomes were compared with the corresponding aCGH raw log (ratios). With our new normalization-centralization process, this difference was added to all log (ratios), before performing loess regression on non-altered probes only. Finally, the mean log (ratio) and the percentage of normal probes were compared between CGHnormaliter and our new FISH-based method. For 11 tumors, FISH results and raw CGH log (ratios) differed significantly. In addition, nine tumors showed discrepancies between results generated by CGHnormaliter and our new-method. Such discrepancies seemed to occur with tumours with many abnormalities (0%-40% normal probes), rather than in those tumours with fewer abnormalities (31%-100% normal probes). Five tumors had too few normal probes to allow normalization. In these tumors, which can exhibit many changes in DNA copy number, we found that centralization bias was frequent and uncorrected by current normalization methods. Therefore, an external control for centralization, such as FISH analysis, is required to insure reliable interpretation of aCGH data.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/gcc.22534DOI Listing
June 2018

Adding sufentanil to ropivacaine in continuous thoracic paravertebral block fails to improve analgesia after video-assisted thoracic surgery: A randomised controlled trial.

Eur J Anaesthesiol 2018 10;35(10):766-773

From the Hospices Civils de Lyon, Hôpital de la Croix Rousse, Service d'Anesthésie-Réanimation (CB), Hospices Civils de Lyon, Hôpital Cardiologique et Pneumologique Louis Pradel, Service d'Anesthésie-Réanimation (IP, CK, J-LF), Hospices Civils de Lyon, Service de Biostatistique - Bioinformatique (CM, PR), Faculté de Médecine, Université Claude Bernard Lyon 1 (CM, PR, J-LF), CNRS UMR5558, Laboratoire de Biométrie et Biologie Evolutive, Département Biostatistiques et modélisation pour la santé et l'environnement, Equipe Biostatistique-Santé (CM, PR) and Hospices Civils de Lyon, Hôpital Cardiologique et Pneumologique Louis Pradel, Service de Chirurgie Thoracique, Lyon, France (J-MM).

Background: The benefit of adding opioid to a local anaesthetic for continuous thoracic paravertebral analgesia after video-assisted thoracic surgery (VATS) is unclear.

Objectives: To analyse the analgesic efficacy of ropivacaine and sufentanil in combination compared with ropivacaine alone after VATS.

Design: A randomised, double-blinded, single-centre clinical trial.

Setting: A tertiary university hospital between March 2010 and April 2014.

Patients: Ninety patients were recruited, two were not included leaving 88 randomised into two groups. Eighteen patients were excluded from analysis and 70 completed the study.

Intervention: To receive thoracic paravertebral analgesia with either 2 mg ml ropivacaine and 0.25 μg ml sufentanil (ropivacaine + sufentanil group) or 2 mg ml ropivacaine alone (ropivacaine group) for 48 h postoperatively. Infusion rate was set at 0.15 ml kg h in both groups.

Main Outcome Measures: The primary endpoint was the mean total amount of self-administered morphine by the patients in each group at 48 h postoperatively.

Results: The mean ± SD total amount of self-administered morphine was not significantly different between groups (53.1 ± 27.2 mg in the ropivacaine + sufentanil group vs. 58.8 ± 34.3 mg in the ropivacaine group; P = 0.72). No significant differences were found between the two groups in either pain scores at rest or during movement, in opioid-related adverse reactions, in patient satisfaction or length of hospital stay.

Conclusion: Adding 0.25 μg ml sufentanil to 2 mg ml ropivacaine in continuous thoracic paravertebral analgesia for VATS did not reduce morphine consumption or pain scores when compared with ropivacaine alone. We cannot recommend its use for routine clinical practice. Further studies analysing different concentrations and infusion rates of sufentanil are needed before a lack of efficacy can be confirmed.

Trial Registration: Clinical trial registrations: EudraCT: 2009-014832-38. ClinicalTrials.gov: NCT 01082744.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/EJA.0000000000000777DOI Listing
October 2018

Renal transplantation in children under 3 years of age: Experience from a single-center study.

Pediatr Transplant 2018 03 17;22(2). Epub 2018 Jan 17.

Service de néphrologie rhumatologie dermatologie pédiatriques, Hôpital Femme Mère Enfant, Bron, France.

RTx remains challenging in children under 3 years of age. This single-center study reviewed the medical records of children <3 years transplanted since 1987 (N = 32, Group 1). They were matched for donor type and RTx period with children aged 3-13 years (N = 32, Group 2) and 13-18 years (N = 32, Group 3). There were no between-group significant differences regarding distributions of gender, primary renal disease, proportion of dialysis before RTx, and growth (SDS). Compared to Groups 2 and 3, Group 1 had more peritoneal dialyses (P < .001), more EBV mismatches (P = .04), and longer warm ischemia times (P < .001). The risk of graft loss was not significantly different among age groups (hazard ratio, 2.4 in Group 2 and 2.0 in Group 3 vs Group 1; P = .2). Death occurred in four patients (3 in Group 1 and 1 in Group 2) and graft loss occurred in 28 patients, mainly due to chronic allograft nephropathy. In recipients <3 years of age, the outcomes of RTx are close to those obtained in older pediatric age groups. Thus, young patients may be transplanted in experienced multidisciplinary teams without additional risks provided that particular attention is paid to donor selection and prevention/early diagnosis of comorbidities and complications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/petr.13116DOI Listing
March 2018

Variance component analysis to assess protein quantification in biomarker discovery. Application to MALDI-TOF mass spectrometry.

Biom J 2018 03 12;60(2):262-274. Epub 2017 Dec 12.

Service de Biostatistique-Bioinformatique, Hospices Civils de Lyon, Lyon, France.

Controlling the technological variability on an analytical chain is critical for biomarker discovery. The sources of technological variability should be modeled, which calls for specific experimental design, signal processing, and statistical analysis. Furthermore, with unbalanced data, the various components of variability cannot be estimated with the sequential or adjusted sums of squares of usual software programs. We propose a novel approach to variance component analysis with application to the matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) technology and use this approach for protein quantification by a classical signal processing algorithm and two more recent ones (BHI-PRO 1 and 2). Given the high technological variability, the quantification failed to restitute the known quantities of five out of nine proteins present in a controlled solution. There was a linear relationship between protein quantities and peak intensities for four out of nine peaks with all algorithms. The biological component of the variance was higher with BHI-PRO than with the classical algorithm (80-95% with BHI-PRO 1, 79-95% with BHI-PRO 2 vs. 56-90%); thus, BHI-PRO were more efficient in protein quantification. The technological component of the variance was higher with the classical algorithm than with BHI-PRO (6-25% vs. 2.5-9.6% with BHI-PRO 1 and 3.5-11.9% with BHI-PRO 2). The chemical component was also higher with the classical algorithm (3.6-18.7% vs. < 3.5%). Thus, BHI-PRO were better in removing noise from signal when the expected peaks are detected. Overall, either BHI-PRO algorithm may reduce the technological variance from 25 to 10% and thus improve protein quantification and biomarker validation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/bimj.201600198DOI Listing
March 2018

Effect of informed consent on patient characteristics in a stroke thrombolysis trial.

Neurology 2017 Sep 25;89(13):1400-1407. Epub 2017 Aug 25.

From Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum (G.T., C.H., B.C., C.G.), and Klinik und Poliklinik für Neuroradiologische Diagnostik und Intervention, Diagnostikzentrum (J.F.), Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany; Service de Biostatistique (F.B., P.R.) and Department of Neurology (N.N., T.-H.C.), Hospices Civils de Lyon; Université Lyon 1 (F.B., P.R.), Villeurbanne; CNRS, UMR 5558 (F.B., P.R.), Laboratoire de Biométrie et Biologie Evolutive, Equipe Biostatistique-Santé, Villeurbanne, France; Centrum für Schlaganfallforschung Berlin (CSB) (J.B.F., M. Ebinger, M. Endres) and Klinik und Hochschulambulanz für Neurologie (M. Ebinger, M. Endres), Charité-Universitätsmedizin Berlin, Germany; Department of Neurology (C.Z.S.), Aarhus University Hospital, Denmark; Department of Radiology (S.P., J.P.), Institut de Diagnostic per la Image (IDI), Hospital Dr Josep Trueta, Institut d'Investgació Biomèdica de Girona (IDIBGI), Girona, Spain; Department of Neurosciences, Experimental Neurology, and Leuven Research Institute for Neuroscience and Disease (LIND) (R.L.), KU Leuven-University of Leuven; VIB, Laboratory of Neurobiology (R.L.), Center for Brain & Disease Research, Leuven; Department of Neurology (R.L.), University Hospitals Leuven, Belgium; Institute of Neuroscience & Psychology (K.W.M.) and Robertson Centre for Biostatistics (I.F.), University of Glasgow, UK; Stroke Division (V.T.), Florey Institute of Neuroscience and Mental Health; and Department of Neurology (V.T.), Austin Health, Heidelberg, Australia.

Objective: To determine whether the manner of consent, i.e., informed consent by patients themselves or informed consent by proxy, affects clinical characteristics of samples of acute stroke patients enrolled in clinical trials.

Methods: We analyzed the manner of obtaining informed consent in the first 1,005 patients from WAKE-UP, an investigator-initiated, randomized, placebo-controlled trial of MRI-based thrombolysis in stroke patients with unknown time of symptom onset running in 6 European countries. Patients providing informed consent by themselves were compared with patients enrolled by proxy consent. Baseline clinical measures were compared between groups.

Results: In 359 (35.7%) patients, informed consent was by proxy. Patients with proxy consent were older (median 71 vs 66 years, < 0.0001) and had a higher frequency of arterial hypertension (58.2% vs 43.4%, < 0.0001). They showed higher scores on the NIH Stroke Scale (median 11 vs 5, < 0.0001) and more frequently aphasia (73.7% vs 20.0%, < 0.0001). The rate of proxy consent varied among countries ( < 0.0001), ranging from 77.1% in Spain to 1.2% in Denmark.

Conclusions: Patients recruited by proxy consent were older, had more severe strokes, and had higher prevalence of aphasia than those with capacity to give personal consent. Variations in the manner of consent across countries may influence trial results.

Clinicaltrialsgov And Clinicaltrialsregistereu Identifiers: NCT01525290 (clinicaltrials.gov); 2011-005906-32 (clinicaltrialsregister.eu).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000004414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5649757PMC
September 2017

Predicting thyroid nodule malignancy at several prevalence values with a combined Bethesda-molecular test.

Transl Res 2017 10 22;188:58-66.e1. Epub 2017 Jul 22.

Université Lyon 1, Lyon, France; Service de Biostatistique, Hospices Civils de Lyon, Lyon, France; CNRS UMR5558, Laboratoire de Biométrie et Biologie Évolutive, Équipe Biostatistique-Santé, Villeurbanne, France.

Investigation of thyroid nodules using fine-needle aspiration cytology (FNAC) gives indeterminate results in up to 30% of samples using the Bethesda System for Reporting Thyroid Cytopathology (TBSRTC). We present a combined Bethesda-molecular predictor of nodule malignancy to improve the accuracy of the preoperative diagnosis of thyroid nodules. To detect a molecular signature of thyroid nodule malignancy, a molecular test was performed on FNACs from 128 thyroid nodules from prospectively included patients, collected in a tertiary center. The test relied on a transcriptomic array of 20 genes selected from a previous study. An optimal set of seven genes was identified using a logistic regression model. Comparison between the combined predictor (TBSRTC + molecular) and TBSRTC alone used the area under the ROC curve (AUC). Performance of the combined predictor was calculated according to various malignancy prevalence values and benefit-to-harm ratios (B/Hr) (favoring sensitivity or specificity). In our population (36% malignancy prevalence) and with a B/Hr of 1, the combined predictor achieved 95% specificity and 76% sensitivity. The AUC was 93.5%; higher than that of TBSRTC (P = 0.004). Among indeterminate nodules (30% malignancy prevalence), sensitivity and specificity were 52.2% and 96.2%, respectively, with a B/Hr of 1, or 95.7% and 64.2% with a B/Hr of 4 (favoring sensitivity), allowing avoidance of 64% of unnecessary surgeries at the cost of only one false-positive result. In conclusion, this predictor could improve the detection of thyroid nodule malignancy, taking into account malignancy prevalence and B/Hr, and reduce the number of unnecessary thyroidectomies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.trsl.2017.07.005DOI Listing
October 2017

Bayesian inference for biomarker discovery in proteomics: an analytic solution.

EURASIP J Bioinform Syst Biol 2017 Dec 14;2017(1). Epub 2017 Jul 14.

Service de Biostatistique - Bioinformatique, Hospices Civils de Lyon, Lyon, France.

This paper addresses the question of biomarker discovery in proteomics. Given clinical data regarding a list of proteins for a set of individuals, the tackled problem is to extract a short subset of proteins the concentrations of which are an indicator of the biological status (healthy or pathological). In this paper, it is formulated as a specific instance of variable selection. The originality is that the proteins are not investigated one after the other but the best partition between discriminant and non-discriminant proteins is directly sought. In this way, correlations between the proteins are intrinsically taken into account in the decision. The developed strategy is derived in a Bayesian setting, and the decision is optimal in the sense that it minimizes a global mean error. It is finally based on the posterior probabilities of the partitions. The main difficulty is to calculate these probabilities since they are based on the so-called evidence that require marginalization of all the unknown model parameters. Two models are presented that relate the status to the protein concentrations, depending whether the latter are biomarkers or not. The first model accounts for biological variabilities by assuming that the concentrations are Gaussian distributed with a mean and a covariance matrix that depend on the status only for the biomarkers. The second one is an extension that also takes into account the technical variabilities that may significantly impact the observed concentrations. The main contributions of the paper are: (1) a new Bayesian formulation of the biomarker selection problem, (2) the closed-form expression of the posterior probabilities in the noiseless case, and (3) a suitable approximated solution in the noisy case. The methods are numerically assessed and compared to the state-of-the-art methods (t test, LASSO, Battacharyya distance, FOHSIC) on synthetic and real data from proteins quantified in human serum by mass spectrometry in selected reaction monitoring mode.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13637-017-0062-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5511129PMC
December 2017

Risk of Recurrence in Pituitary Neuroendocrine Tumors: A Prospective Study Using a Five-Tiered Classification.

J Clin Endocrinol Metab 2017 09;102(9):3368-3374

Faculté de Médecine Lyon Est, Université Lyon 1, Lyon F-69372, France.

Background: Most pituitary neuroendocrine tumors (PitNETs) show benign behavior, but a substantial number are invasive, recur, or resist medical treatment. Based on a retrospective case-control study, we recently proposed a classification of PitNETs of prognostic relevance. This prospective study aims to test the value of this classification in an independent patient cohort.

Methods: All patients who underwent PitNET surgery from 2007 to 2012 in one single center were included. Using a grading system based on invasion on magnetic resonance imaging, immunocytochemical profile, Ki-67, mitotic index, and p53 positivity, tumors were classified. Progression-free survival of the graded tumors was calculated by the Kaplan-Meier method and compared using the log-rank test. A multivariate analysis, using a Cox regression model, was also performed.

Results: In total, 365 patients had grade 1a PitNETs (51.2%), followed by grade 2a (32.3%), 2b (8.8%), and 1b tumors (7.7%). Of 213 patients with a follow-up, 42% had recurrent (n = 52) or progressive disease (n = 37) at 3.5 years. Grade was a significant predictor of progression-free survival (P < 0.001). Multivariate analysis indicated grade (P < 0.001), age (P = 0.035), and tumor type (P = 0.028) as independent predictors of recurrence and/progression. This risk was 3.72-fold higher for a grade 2b tumor compared with grade 1a tumor.

Conclusions: Our data suggest that classification of PitNETs into five grades is of prognostic value to predict postoperative tumor behavior and identifies patients who have a high risk of early recurrence or progression. It therefore will allow clinicians to adapt their therapeutic strategies and stratify patients in future clinical trials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/jc.2017-00773DOI Listing
September 2017

Clinical characteristics of unknown symptom onset stroke patients with and without diffusion-weighted imaging and fluid-attenuated inversion recovery mismatch.

Int J Stroke 2018 01 20;13(1):66-73. Epub 2017 Apr 20.

1 Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.

Background Diffusion-weighted imaging (DWI) and fluid-attenuated inversion recovery (FLAIR) mismatch was suggested to identify stroke patients with unknown time of symptom onset likely to be within the time window for thrombolysis. Aims We aimed to study clinical characteristics associated with DWI-FLAIR mismatch in patients with unknown onset stroke. Methods We analyzed baseline MRI and clinical data from patients with acute ischemic stroke proven by DWI from WAKE-UP, an investigator-initiated, randomized, placebo-controlled trial of MRI-based thrombolysis in stroke patients with unknown time of symptom onset. Clinical characteristics were compared between patients with and without DWI-FLAIR mismatch. Results Of 699 patients included, 418 (59.8%) presented with DWI-FLAIR mismatch. A shorter delay between last seen well and symptom recognition (p = 0.0063), a shorter delay between symptom recognition and arrival at hospital (p = 0.0025), and history of atrial fibrillation (p = 0.19) were predictors of DWI-FLAIR mismatch in multivariate analysis. All other characteristics were comparable between groups. Conclusions There are only minor differences in measured clinical characteristics between unknown symptom onset stroke patients with and without DWI-FLAIR mismatch. DWI-FLAIR mismatch as an indicator of stroke onset within 4.5 h shows no relevant association with commonly collected clinical characteristics of stroke patients. Clinical Trial Registration URL: http://www.clinicaltrials.gov . Unique identifier: NCT01525290; URL: https://www.clinicaltrialsregister.eu . Unique identifier: 2011-005906-32.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1747493017706245DOI Listing
January 2018

Stroke With Unknown Time of Symptom Onset: Baseline Clinical and Magnetic Resonance Imaging Data of the First Thousand Patients in WAKE-UP (Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke: A Randomized, Doubleblind, Placebo-Controlled Trial).

Stroke 2017 03 7;48(3):770-773. Epub 2017 Feb 7.

From the Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum (G.T., B.C., C.G.) and Klinik und Poliklinik für Neuroradiologische Diagnostik und Intervention, Diagnostikzentrum (J.F.), Universitätsklinikum Hamburg-Eppendorf, Germany; Service de Biostatistique, Hospices Civils de Lyon, France (F.B., P.R.); Université Lyon 1, Villeurbanne, France (F.B., P.R.); CNRS, UMR 5558, Laboratoire de Biométrie et Biologie Evolutive, Equipe Biostatistique-Santé, Villeurbanne, France (F.B., P.R.); Centrum für Schlaganfallforschung Berlin (CSB) (J.B.F., I.G., M. Ebinger, M. Endres) and Klinik und Hochschulambulanz für Neurologie (M. Ebinger, M. Endres), Charité-Universitätsmedizin Berlin, Germany; Department of Neurology, Aarhus University Hospital, Denmark (C.Z.S.); Department of Neurology, Hospices Civils de Lyon, France (N.N., T.-H.C.); Department of Radiology, Institut de Diagnostic per la Image (IDI), Hospital Dr Josep Trueta, Institut d'Investgació Biomèdica de Girona (IDIBGI), Spain (S.P., J.P.); Department of Neurosciences, Experimental Neurology, KU Leuven-University of Leuven, VIB Center for Brain & Disease Research, and Department of Neurology, University Hospitals Leuven, Belgium (R.L.); Institute of Neuroscience and Psychology (K.W.M.) and Robertson Centre for Biostatistics (I.F.), University of Glasgow, United Kingdom; and Florey Institute of Neuroscience and Mental Health, Heidelberg, Victoria, Australia (V.T.).

Background And Purpose: We describe clinical and magnetic resonance imaging (MRI) characteristics of stroke patients with unknown time of symptom onset potentially eligible for thrombolysis from a large prospective cohort.

Methods: We analyzed baseline data from WAKE-UP (Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke: A Randomized, Doubleblind, Placebo-Controlled Trial), an investigator-initiated, randomized, placebo-controlled trial of MRI-based thrombolysis in stroke patients with unknown time of symptom onset. MRI judgment included assessment of the mismatch between visibility of the acute ischemic lesion on diffusion-weighted imaging and fluid-attenuated inversion recovery.

Results: Of 1005 patients included, diffusion-weighted imaging and fluid-attenuated inversion recovery mismatch was present in 479 patients (48.0%). Patients with daytime-unwitnessed stroke (n=138, 13.7%) had a shorter delay between symptom recognition and hospital arrival (1.5 versus 1.8 hours; =0.002), a higher National Institutes of Stroke Scale score on admission (8 versus 6; <0.001), and more often aphasia (72.5% versus 34.0%; <0.001) when compared with stroke patients waking up from nighttime sleep. Frequency of diffusion-weighted imaging and fluid-attenuated inversion recovery mismatch was comparable between both groups (43.7% versus 48.7%; =0.30).

Conclusions: Almost half of the patients with unknown time of symptom onset stroke otherwise eligible for thrombolysis had MRI findings making them likely to be within a time window for safe and effective thrombolysis. Patients with daytime onset unwitnessed stroke differ from wake-up stroke patients with regards to clinical characteristics but are comparable in terms of MRI characteristics of lesion age.

Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01525290. URL: https://www.clinicaltrialsregister.eu. Unique identifier: 2011-005906-32.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/STROKEAHA.116.015233DOI Listing
March 2017