Simon Grandjean Lapierre’s research while affiliated with McGill University and other places

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Publications (88)


Patients' clinical presentation and laboratory testing results for Mycobacterium tuberculosis pseudo-outbreak
Mycobacterium tuberculosis pseudo-outbreak due to laboratory cross-contamination: A molecular epidemiology outbreak investigation
  • Article
  • Full-text available

December 2024

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8 Reads

Canada Communicable Disease Report

Nayla Léveillé

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Josée Houde

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[...]

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Simon Grandjean Lapierre

Background Mycobacterial culture is routinely performed to diagnose tuberculosis (TB) in Canada. Globally, meta-analyses suggest that up to 2% of positive cultures are falsely positive for Mycobacterium tuberculosis due to laboratory cross-contamination. Five patients from distinct clinical institutions in Montréal were diagnosed with culture-positive TB as their clinical samples were processed in a centralized mycobacteria laboratory. Cross-contamination was suspected due to culture positivity in an organ donor with low TB pre-test probability. We describe a TB pseudo-outbreak due to laboratory cross-contamination and assess the role of conventional typing (i.e., mycobacterial interspersed repetitive unit variable number of tandem repeats [MIRU-VNTR]) and whole-genome sequencing (WGS) in supporting the investigation. Methods Patients’ epidemiological risk factors and clinical presentations were reviewed. The trajectories of pre- and per-analytic samples were retraced to identify potential cross-contamination events. Tuberculosis isolates were characterized by MIRU-VNTR and WGS using Oxford Nanopore Technology (ONT). The bioinformatic pipeline tbpore (v0.7.1) cluster was used for phylogenetic analyses. Results Two patients had previous exposure to endemic settings and clinical symptoms compatible with TB. Culture media inoculation overlapped in time for four patients, including one with suspected pulmonary cavitary disease and an organ donor whose organs had been transplanted in three different receivers. The MIRU-VNTR and WGS typing confirmed isolates from those four patients to be identical. Conclusion Clinical, laboratory and molecular typing data, including results from ONT sequencing, were considered sufficiently robust to confirm laboratory cross-contamination and TB therapy was discontinued including in all organ transplant recipients.

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cRCT study arms, sample size, anticipated outcomes, and intervention strategies
cRCT anticipated outcomes, data sources, and assumptions
Schedule of enrolment, interventions, and assessment SPIRIT figure
Whole genome sequencing of M. tuberculosis for disease control in high-burden settings: study protocol for a cluster randomized controlled trial evaluating different community-wide intervention strategies in rural Madagascar

October 2024

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40 Reads

Trials

Background Retrospective and descriptive molecular epidemiology studies have shown that Mycobacterium tuberculosis whole genome sequencing can identify outbreaks and disease transmission events with higher resolution than conventional epidemiological investigations. Those studies have strengthened our understanding of genomic polymorphisms correlating with person-to-person transmission and helped resolve putative transmission clusters. To date, systematic genomic surveillance programs implemented for M. tuberculosis were only implemented in low-incidence settings. The purpose of this study is to determine whether there is an impact of routine M. tuberculosis whole genome sequencing on tuberculosis case detection in a high-incidence setting. Methods A cluster randomized controlled trial will be performed. Forty-eight rural village groups (or Fokontany) in the Vohibato district of Madagascar will be randomized to one of three interventions arms. Arm 1 (standard of care) involves healthcare facility-based passive case detection with smear microscopy testing. Arm 2 (best practice) consists of active case finding and Xpert MTB/RIF Ultra PCR testing followed by household contact investigations. Arm 3 (novel intervention) includes the same interventions as arm 2, with addition of sputum culture and M. tuberculosis whole genome sequencing for all newly diagnosed cases. In arm 3, molecular suggested putative outbreaks are investigated, and additional TB suspects are appropriately tested. The intervention observational period will be 2 years. The primary outcome will be the number of detected cases/100,000/year in each arm after 1 year of intervention. Discussion This study is designed to determine whether there is an impact of prospective whole genome sequencing-based molecular typing on tuberculosis case detection in high-incidence settings. Investigating potential outbreaks and focusing active case finding in spatiotemporal settings where disease transmission is suggested by genomic typing is hypothesized to improve case detection in rural communities. Trial registration ClinicalTrials.gov NCT05406453. Retrospectively registered on June 6, 2022.


A dataset of Solicited Cough Sound for Tuberculosis Triage Testing

October 2024

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36 Reads

Scientific Data

Cough is a common and commonly ignored symptom of lung disease. Cough is often perceived as difficult to quantify, frequently self-limiting, and non-specific. However, cough has a central role in the clinical detection of many lung diseases including tuberculosis (TB), which remains the leading infectious disease killer worldwide. TB screening currently relies on self-reported cough which fails to meet the World Health Organization (WHO) accuracy targets for a TB triage test. Artificial intelligence (AI) models based on cough sound have been developed for several respiratory conditions, with limited work being done in TB. To support the development of an accurate, point-of-care cough-based triage tool for TB, we have compiled a large multi-country database of cough sounds from individuals being evaluated for TB. The dataset includes more than 700,000 cough sounds from 2,143 individuals with detailed demographic, clinical and microbiologic diagnostic information. We aim to empower researchers in the development of cough sound analysis models to improve TB diagnosis, where innovative approaches are critically needed to end this long-standing pandemic.


Figure 1
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Continuous digital cough monitoring during 6-month pulmonary tuberculosis treatment

October 2024

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33 Reads

ERJ Open Research

Introduction The recent advances in digital and wearable technologies with artificial intelligence (AI) enable the use of continuous cough monitoring (CCM) to objectively monitor symptoms as surrogate markers of treatment efficacy in pulmonary tuberculosis (PTB). The objectives of this study are to describe the evolution of cough during PTB treatment in adult and to assess the feasibility of community-based CCM. Methods We prospectively enrolled PTB adult participants upon treatment initiation. Participants’ coughs were continuously monitored during 6 months with a smartphone loaded with an app able to detect cough by using an AI algorithm. Results Twenty-two participants were included. The median age was 28.5 (IQR: 22–42) and 62% were male. The median cough per hour (medCPH) was 11.0 (IQR: 7.0–27.0) at week 1. By the end of the intensive phase of PTB treatment at week 8, the medCPH was 3.5 (IQR: 1.5–7.0), which was significantly lower than the medCPH at week 1 (p=0.002). At week 26 (end of treatment), the medCPH was 1.0 (IQR: 1.0–2.5). The adherence to CCM was high during the first 13 weeks of PTB treatment and then waned over time. The adherence was similar during daytime and nighttime. Conclusion Cough counts rapidly drop during the intensive phase of PTB treatment and then slowly decrease to a low baseline level by the end of the treatment. Community-based CCM using digital technology is feasible in low resource settings but requires evaluation of alternative approaches to overcome adherence issues and technical limitations (mobile internet and electricity availability).


Genomic Epidemiology of Mycobacterium abscessus on the Island of Montréal Not Suggestive of Healthcare-associated Person-to-Person Transmission

August 2024

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24 Reads

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1 Citation

The Journal of Infectious Diseases

Background Mycobacterium abscessus complex (MABC), an opportunistic nontuberculous mycobacteria (NTM), can lead to poor clinical outcomes in pulmonary infections. Conflicting data exist on person-to-person transmission of MABC within and across healthcare facilities. To investigate further, a comprehensive retrospective study across five healthcare institutions on the Island of Montréal was undertaken. Methods We analyzed the genomes of 221 MABC isolates obtained from 115 individuals (2010–2018) to identify possible links. Genetic similarity, defined as ≤25 single-nucleotide polymorphisms (SNPs), was investigated through a blinded epidemiological inquiry. Results Bioinformatics analyses identified 28 sequence types (STs), including globally observed dominant circulating clones (DCCs). Further analysis revealed 210 isolate pairs within the SNP threshold. Among these pairs, there was one possible lab contamination where isolates from different patients processed in the same lab differed by only 2 SNPs. There were 37 isolate pairs from patients who had provided specimens from the same hospital; however, epidemiological analysis found no evidence of healthcare-associated person-to-person transmission between these patients. Additionally, pan-genome analysis showed higher discriminatory power than core genome analysis for examining genomic similarity. Conclusions Genomics alone is insufficient to establish MABC transmission, particularly considering the genetic similarity and wide distribution of DCCs, although pan-genome analysis has the potential to add further insight. Our findings indicate that MABC infections in Montréal are unlikely attributable to healthcare-associated person-to-person transmission.


Time series for participant ID = 1 showing the trends in number of coughs per hour and average hourly PM2.5 exposure level
Hourly PM2.5 concentrations and hourly cough counts appear to fluctuate throughout the day. Both measures tend to be highest during the daytime hours that coincide with cooking and mealtimes.
Demographics, hourly PM2.5 exposure levels, and hourly cough rates of participants
Negative binomial generalized estimated equation (GEE) on the association between hourly PM2.5 exposure levels and coughs per hour
Incidence of cough from acute exposure to fine particulate matter (PM2.5) in Madagascar: A pilot study

July 2024

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60 Reads

Prolonged exposure to fine particulate matter (PM2.5) is a known risk to respiratory health, causing chronic lung impairment. Yet, the immediate, acute effects of PM2.5 exposure on respiratory symptoms, such as cough, are less understood. This pilot study aims to investigate this relationship using objective PM2.5 and cough monitors. Fifteen participants from rural Madagascar were followed for three days, equipped with an RTI Enhanced Children’s MicroPEM PM2.5 sensor and a smartphone with the ResApp Cough Counting Software application. Univariable Generalized Estimating Equation (GEE) models were applied to measure the association between hourly PM2.5 exposure and cough counts. Peaks in both PM2.5 concentration and cough frequency were observed during the day. A 10-fold increase in hourly PM2.5 concentration corresponded to a 39% increase in same-hour cough frequency (incidence rate ratio (IRR) = 1.40; 95% CI: 1.12, 1.74). The strength of this association decreased with a one-hour lag between PM2.5 exposure and cough frequency (IRR = 1.21; 95% CI: 1.01, 1.44) and was not significant with a two-hour lag (IRR = 0.93; 95% CI: 0.71, 1.23). This study demonstrates the feasibility of objective PM2.5 and cough monitoring in remote settings. An association between hourly PM2.5 exposure and cough frequency was detected, suggesting that PM2.5 exposure may have immediate effects on respiratory health. Further investigation is necessary in larger studies to substantiate these findings and understand the broader implications.


Head-to-head accuracy of each CAD algorithm
An independent, multi-country head-to-head accuracy comparison of automated chest x-ray algorithms for the triage of pulmonary tuberculosis

June 2024

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81 Reads

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1 Citation

Background. Computer-aided detection (CAD) algorithms for automated chest X-ray (CXR) reading have been endorsed by the World Health Organization for tuberculosis (TB) triage, but independent, multi-country assessment and comparison of current products are needed to guide implementation. Methods. We conducted a head-to-head evaluation of five CAD algorithms for TB triage across seven countries. We included CXRs from adults who presented to outpatient facilities with at least two weeks of cough in India, Madagascar, the Philippines, South Africa, Tanzania, Uganda, and Vietnam. The participants completed a standard evaluation for pulmonary TB, including sputum collection for Xpert MTB/RIF Ultra and culture. Against a microbiological reference standard, we calculated and compared the accuracy overall, by country and key groups for five CAD algorithms: CAD4TB (Delft Imaging), INSIGHT CXR (Lunit), DrAid (Vinbrain), Genki (Deeptek), and qXR (qure.AI). We determined the area under the ROC curve (AUC) and if any CAD product could achieve the minimum target accuracy for a TB triage test (≥90% sensitivity and ≥70% specificity). We then applied country- and population-specific thresholds and recalculated accuracy to assess any improvement in performance. Results. Of 3,927 individuals included, the median age was 41 years (IQR 29-54), 12.9% were people living with HIV (PLWH), 8.2% living with diabetes, and 21.2% had a prior history of TB. The overall AUC ranged from 0.774-0.819, and specificity ranged from 64.8-73.8% at 90% sensitivity. CAD4TB had the highest overall accuracy (73.8% specific, 95% CI 72.2-75.4, at 90% sensitivity), although qXR and INSIGHT CXR also achieved the target 70% specificity. There was heterogeneity in accuracy by country, and females and PLWH had lower sensitivity while males and people with a history of TB had lower specificity. The performance remained stable regardless of diabetes status. When country- and population-specific thresholds were applied, at least one CAD product could achieve or approach the target accuracy for each country and sub-group, except for PLWH and those with a history of TB. Conclusions. Multiple CAD algorithms can achieve or exceed the minimum target accuracy for a TB triage test, with improvement when using setting- or population-specific thresholds. Further efforts are needed to integrate CAD into routine TB case detection programs in high-burden communities.


Model performance for cough sound and clinical data model (Sub-challenge 2) 528
Accelerating cough-based algorithms for pulmonary tuberculosis screening: Results from the CODA TB DREAM Challenge

May 2024

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139 Reads

Importance. Open-access data challenges have the potential to accelerate innovation in artificial-intelligence (AI)-based tools for global health. A specimen-free rapid triage method for TB is a global health priority. Objective. To develop and validate cough sound-based AI algorithms for tuberculosis (TB) through the Cough Diagnostic Algorithm for Tuberculosis (CODA TB) DREAM challenge. Design. In this diagnostic study, participating teams were provided cough-sound and clinical and demographic data. They were asked to develop AI models over a four-month period, and then submit the algorithms for independent validation. Setting. Data was collected using smartphones from outpatient clinics in India, Madagascar, the Philippines, South Africa, Tanzania, Uganda, and Vietnam. Participants. We included data from 2,143 adults who were consecutively enrolled with at least two weeks of cough. Data were randomly split evenly into training and test partitions. Exposures. Standard TB evaluation was completed, including Xpert MTB/RIF Ultra and culture. At least three solicited coughs were recorded using the Hyfe Research app. Main Outcomes and Measures. We invited teams to develop models using 1) cough sound features only and/or 2) cough sound features with routinely available clinical data to classify microbiologically confirmed TB disease. Models were ranked by area under the receiver operating characteristic curve (AUROC) and partial AUROC (pAUROC) to achieve at least 80% sensitivity and 60% specificity. Results. Eleven cough models were submitted, as well as six cough-plus-clinical models. AUROCs for cough models ranged from 0.69-0.74, and the highest performing model achieved 55.5% specificity (95% CI 47.7-64.2) at 80% sensitivity. The addition of clinical data improved AUROCs (range 0.78-0.83), five of the six submitted models reached the target pAUROC, and highest performing model had 73.8% (95% CI 60.8-80.0) specificity at 80% sensitivity. In post-challenge subgroup analyses, AUROCs varied by country, and was higher among males and HIV-negative individuals. The probability of TB classification correlated with Xpert Ultra semi-quantitative levels. Conclusions and Relevance. In a short period, new and independently validated cough-based TB algorithms were developed through an open-source and transparent process. Open-access data challenges can rapidly advance and improve AI-based tools for global health.



Citations (54)


... Our findings, consistent with previous studies, revealed genetically distinct MABC isolates, indicated by deep branches in the phylogenetic tree. Additionally, we identified highly similar Mab A and Mab M isolates, known as DCCs, which are globally distributed yet lack established epidemiological connections (Lipworth et al., 2021;Wetzstein et al., 2022;Olawoye et al., 2024). The proportion of DCCs in China (33.3%) is lower than in other regions of the world, such as the United States, the United Kingdom, Australia, and Malaysia, where the proportion of DCCs exceeds 50%, and in Brazil, where it reaches 100% (Davidson et al., 2013;Ruis et al., 2021). ...

Reference:

Population genetic analysis of clinical Mycobacterium abscessus complex strains in China
Genomic Epidemiology of Mycobacterium abscessus on the Island of Montréal Not Suggestive of Healthcare-associated Person-to-Person Transmission
  • Citing Article
  • August 2024

The Journal of Infectious Diseases

... The inaccuracy of self-reported cough in traditional TB screening has led to the development of AI models for cough sound analysis. The goal of the study conducted by Sophie Huddart et al. [18] was to improve TB diagnosis with advanced cough sound analysis models by compiling a multi-country collection of over 700,000 cough sounds from 2,143 individuals. ...

Solicited Cough Sound Analysis for Tuberculosis Triage Testing: The CODA TB DREAM Challenge Dataset

... Consequently, reporting both the presence of MTB and the resistance genotypes may not occur ethambutol rather than culture-based phenotypic AST [31]. Previous studies have shown that tNGS can be used for the identification, drug resistance detection, and typing of tuberculosis, offering advantages such as cost-effectiveness, efficiency, accuracy, and flexibility [6,[32][33][34][35][36][37][38][39][40][41][42][43][44]. To date, there is a lack of studies systematically evaluating the use of tNGS in diagnosing tuberculosis using clinical isolates and samples, in comparison with culture, phenotypic AST, WGS, and Xpert MTB/RIF. ...

Concordance of Targeted and Whole Genome Sequencing for Mycobacterium tuberculosis Genotypic Drug Susceptibility Testing

Diagnostic Microbiology and Infectious Disease

... Long COVID is pathological condition characterized by persistent immunosuppression [42]. In Fournelle et al.'s intra-host analysis in 2024, distinct mutants of the virus were discovered from an immunosuppressed patient, suggesting the possibility of the emergence of mutations under immunosuppression [43]. Thus, individuals with long COVID are suggested to proactively adopt protective behaviors to reduce the risk of reinfection and prevent the virus from spreading to others. ...

Intra-Host Evolution Analyses in an Immunosuppressed Patient Supports SARS-CoV-2 Viral Reservoir Hypothesis

... effectiveness of TB treatment regimens in Botswana. Previous studies have shown that there is an association between specific drug resistance mutations and increased minimum inhibitory concentration (MIC) for different anti-TB drugs; mutations in the rpoB at codons 450 and 445 have been linked to increased MICs for RIF (Ruesen et al., 2018;Barilar et al., 2024). These findings further highlight the need to understand how strain genetic background and mutations impact MIC levels as this could provide a rapid and reliable alternative to pDST and improve TB diagnostics (Getahun et al., 2022). ...

Quantitative measurement of antibiotic resistance in Mycobacterium tuberculosis reveals genetic determinants of resistance and susceptibility in a target gene approach

... Hourly cough counts are necessarily non-negative integers and follow negative binomial distributions closely 16 , neither these counts nor any simple transformations thereof are normally distributed, precluding application of standard formulas for the SEs of the Pearson correlation or linear regression coefficients. A simulation based on data collected in previous studies 8,9,15,17 to estimate the sampling distribution of hourly cough rates and showed that a minimum of 18 participants contributing 20 h of monitoring each, yielding 360 paired personhours for analysis, would result in a standard error under 0.1 in average correlations and slopes (see online data supplement for the study protocol). This target was later expanded to 23 participants in order to have over 50% of the sample recruited in the US for regulatory purposes. ...

Performance evaluation of human cough annotators: optimal metrics and sex differences

... Understanding the factors that determine TB treatment outcomes and addressing barriers to highquality care are important steps for improving the effectiveness of TB services. Analysis of treatment outcomes and other surveillance data has been promoted to identify gaps in TB care cascades, reveal variation in outcomes, and target programmatic action towards areas with the greatest opportunities for improvement [3,4]. In a number of high TB burden countries, routinely collected TB outcomes data have been used to quantify sub-national differences in the fraction of patients successfully completing treatment [5][6][7][8][9][10][11]. ...

Improving measurement of tuberculosis care cascades to enhance people-centred care
  • Citing Article
  • August 2023

The Lancet Infectious Diseases

... The hypothesis that prospective recognition of transmission events could lead to diagnosis and treatment of additional patients and further limit transmission remains to be proven. TB transmission is impacted by community social, spatial, and cultural dynamics [11]. In high-incidence settings, TB control strategies are designed and implemented through programmatic planning by public health authorities. ...

A social network analysis model approach to understand tuberculosis transmission in remote rural Madagascar

BMC Public Health

... Furthermore, the smartphone model should have enough RAM and internal storage, and most importantly, must allow the Hyfe app to run continuously in the background. The application can differentiate coughs from other explosive sounds using an AI-based algorithm and showed an excellent performance in detecting (sensitivity of 91% and specificity of 98%), recording and counting coughs [22]. The Hyfe application was also previously used in COVID-19 studies and showed similar performance (sensitivity and specificity of 96%) for detecting cough sounds using human listeners as gold standard [23,24]. ...

Performance evaluation of the smartphone-based AI cough monitoring app - Hyfe Cough Tracker against solicited respiratory sounds

... Patients with rifampicin-resistant TB (RR-TB) or MDR-TB who are treated with regimes containing BDQ can expect better outcomes; these include higher absolute rates of treatment success, a lower risk of mortality post treatment, higher sputum culture conversion rates, and reduced loss to follow-up [7][8][9][10][11][12][13] . Despite BDQ's comparative success, antibiotic susceptibility testing (AST) is often not available and empirical treatment remains common 14 . Surveillance studies in South Africa estimate population or baseline levels of BDQ-resistance at 3.5-5.0% ...

Bedaquiline and clofazimine resistance in Mycobacterium tuberculosis: an in-vitro and in-silico data analysis
  • Citing Article
  • March 2023

The Lancet Microbe