Kristy Horan’s research while affiliated with University of Melbourne and other places

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Publications (33)


Overview of BenchAMRking platform and workflows. Selected AMR gene prediction workflows (WFs) are translated into Galaxy workflows and stored in Workflow Hub. Researchers can load them into a Galaxy instance of their choice and either use the published data to reproduce the results or analyse their own data. Published Salmonella spp A WF3 (from broiler chickens) and published Salmonella spp B WF4 (from human infections) represent different workflows
Correlation matrix of AMR gene presence/absence vectors among different workflows included in BenchAMRking. WF1 - AbritAMR; WF2 - Sciensano; WF3 - CFIA; WF4 - Staramr. Numbers on the top right indicate the correlation among workflows. Colour indicates a positive (red) or negative (blue) correlation, and shape indicates the strength of correlation. The more circular the shape, the stronger the correlation; the more oval the shape, the weaker the correlation. SA: same assembler; DA: different assembler (part of AMR identification and input of BenchAMRking). The supplemental data for the heatmaps are both the binary and identity excel files in the scripts repository at https://github.com/ErasmusMC-Bioinformatics/BenchAMRking-scripts/tree/main
(a) Heatmap representation of the relationships of AMR genes detected in the workflows included in BenchAMRking. Green colour represents gene presence/absence. AMR genes are clustered based on identification by different workflows. SA: same assembler; DA: different assembler. WF – Workflow number SA: same assembler; DA: different assembler. Samples are numbered in the order shown in Table 4. The supplemental data for the heatmaps are both the Binary and Identity excel files in the scripts repository at https://github.com/ErasmusMC-Bioinformatics/BenchAMRking-scripts/tree/main. (b) Heatmap representation of the identity of AMR genes detected in the workflows included in BenchAMRking. Colours represent different values of AMR gene identity between the different workflows. SA: same assembler; DA: different assembler. Samples are numbered in the order shown in Table 4. The supplemental data for the heatmaps are both the Binary and Identity excel files in the scripts repository at https://github.com/ErasmusMC-Bioinformatics/BenchAMRking-scripts/tree/main
A comparison of the results obtained by WF1 (abritAMR) with those of WF2-4 via BenchAMRking. The AMR genes identified by both WF1 and WF2-4 are shown in light blue; those identified only by WF1 are shown in dark blue; those identified only by WF2-4 are shown in green
Version and licence information for the different workflow tools used in the BenchAMRking platform

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BenchAMRking: a Galaxy-based platform for illustrating the major issues associated with current antimicrobial resistance (AMR) gene prediction workflows
  • Article
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January 2025

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52 Reads

BMC Genomics

Nikolaos Strepis

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Dennis Dollee

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Donny Vrins

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[...]

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Background The Joint Programming Initiative on Antimicrobial Resistance (JPIAMR) networks ‘Seq4AMR’ and ‘B2B2B AMR Dx’ were established to promote collaboration between microbial whole genome sequencing (WGS) and antimicrobial resistance (AMR) stakeholders. A key topic discussed was the frequent variability in results obtained between different microbial WGS-related AMR gene prediction workflows. Further, comparative benchmarking studies are difficult to perform due to differences in AMR gene prediction accuracy and a lack of agreement in the naming of AMR genes (semantic conformity) for the results obtained. To illustrate this problem, and as a capacity-building exercise to encourage stakeholder involvement, a comparative Galaxy-based BenchAMRking platform was developed and validated using datasets from bacterial species with PCR-verified AMR gene presence or absence information from abritAMR. Results The Galaxy-based BenchAMRking platform (https://erasmusmc-bioinformatics.github.io/benchAMRking/) specifically focusses on the steps involved in identifying AMR genes from raw reads and sequence assemblies. The platform currently comprises four well-characterised and published workflows that have previously been used to identify AMR genes using WGS data from several different bacterial species. These four workflows, which include the ISO certified abritAMR workflow, make use of different computational tools (or tool versions), and interrogate different AMR gene sequence databases. By utilising their own data, users can investigate potential AMR gene-calling problems associated with their own in silico workflows/protocols, with a potential use case outlined in this publication. Conclusions BenchAMRking is a Galaxy-based comparison platform where users can access, visualise, and explore some of the major discrepancies associated with AMR gene prediction from microbial WGS data.

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Meningococcal C Disease Outbreak Caused by Multidrug-Resistant Neisseria meningitidis, Fiji

January 2025

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1 Read

Emerging Infectious Diseases

We describe an outbreak of invasive meningococcal disease (IMD) caused by Neisseria meningitidis serogroup C in Fiji. We created surveillance case definitions and collected data by using standard investigation forms. Bacterial identification, antimicrobial susceptibility testing, and PCR were performed in Fiji. Molecular testing was conducted at the Microbiological Diagnostic Unit in Melbourne, Victoria, Australia. During January 2016-December 2018, a total of 96 confirmed or probable IMD cases were reported. Of case-patients, 61.5% (59/96) were male and 38.5% (37) female, 84.4% (81) were indigenous people of Fiji, and 70.8% (68) were children <15 years of age. Annual incidence increased from 1.8/100,000 population in 2016 to 5.2/100,000 population in 2018. Serogroup C multilocus serotype 4821 that is resistant to ciprofloxacin was prevalent (62.1%, 41/66). Public health measures, which included targeted mass vaccination with monovalent meningitis C vaccine, were effective in controlling the outbreak. We observed a rapid decline in meningitis C cases in subsequent years.


Vibrio parahaemolyticus Foodborne Illness Associated with Oysters, Australia, 2021-2022

November 2024

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11 Reads

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3 Citations

Emerging Infectious Diseases

The bacterium Vibrio parahaemolyticus is ubiquitous in tropical and temperate waters throughout the world and causes infections in humans resulting from water exposure and from ingestion of contaminated raw or undercooked seafood, such as oysters. We describe a nationwide outbreak of enteric infections caused by Vibrio parahaemolyticus in Australia during September 2021-January 2022. A total of 268 persons were linked with the outbreak, 97% of whom reported consuming Australia-grown oysters. Cases were reported from all states and territories of Australia. The outbreak comprised 2 distinct strains of V. parahaemolyticus, sequence types 417 and 50. We traced oysters with V. parahaemolyticus proliferation back to a common growing region within the state of South Australia. The outbreak prompted a national recall of oysters and subsequent improvements in postharvest processing of the shellfish.




Figure 1. Maximum likelihood phylogenetic tree for all serogroup B, C, W, Y, W/ Y, and nongenogroupable (NG) invasive meningococcal disease isolates submitted to the Microbiological Diagnostic Unit Public Health Laboratory, collected between 1 January 2017 and 23 May 2019. Isolate metadata are shown by the colored rings surrounding the tree. Isolate serogroup is displayed by the inner ring and jurisdiction by the outer ring; see legend for color scheme. ACT, Australian Capital Territory; NSW, New South Wales; NT, Northern Territory; QLD, Queensland; SA, South Australia; TAS, Tasmania; VIC, Victoria; WA, Western Australia.
Figure 2. Dot plot displaying genomic clusters identified among invasive meningococcal disease isolates submitted to the Microbiological Diagnostic Unit Public Health Laboratory, collected between 1 January 2017 and 23 May 2019. Cluster designation is displayed on the y-axis; clusters are grouped according to their predominant serogroup. The colored dots correspond to isolates, with the size of the dot relative to the number of isolates collected on a given day; the date of collection is displayed on the x-axis. Dots are colored according to jurisdiction; see legend for color scheme. ACT, Australian Capital Territory; NSW, New South Wales; NT, Northern Territory; QLD, Queensland; SA, South Australia; TAS, Tasmania; VIC, Victoria; WA, Western Australia.
Figure 3. Maximum likelihood phylogenetic tree for Australian and international serogroup W clonal complex 11 isolates. Australian isolates submitted to the Microbiological Diagnostic Unit Public Health Laboratory were collected between 1 January 2017 and 23 May 2019 and represent instances of invasive disease. International isolates were identified through the PubMLST Neisseria database and represent instances of carriage and invasive disease. Isolates' continent of collection is displayed by the colored ring surrounding the tree; see legend for color scheme.
Genomic Surveillance of Invasive Meningococcal Disease During a National MenW Outbreak in Australia, 2017–2018

May 2024

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66 Reads

Open Forum Infectious Diseases

Background In Australia, invasive meningococcal disease (IMD) incidence rapidly increased between 2014 and 2017 due to rising serogroup W (MenW) and MenY infections. We aimed to better understand the genetic diversity of IMD during 2017-18 using whole-genome sequencing (WGS) data. Methods Whole-genome sequencing data from 440 Australian IMD isolates collected during 2017-18 and 1737 international MenW:CC11 isolates collected in Europe, Africa, Asia, North America, and South America between 1974 and 2020 were used in phylogenetic analyses; genetic relatedness was determined from single nucleotide polymorphisms. Results Australian isolates comprised 181 MenW (41%), 144 MenB (33%), 88 MenY (20%), 16 MenC (4%), 1 MenW/Y (0.2%), and 10 non-genogroupable (2%) isolates. Eighteen clonal complexes (CC) were identified; three (CC11, CC23, CC41/44) accounted for 78% of isolates (343/440). These CCs were associated with specific serogroups; CC11 (199) predominated among MenW (181) & MenC (15), CC23 (80) among MenY (78), and CC41/44 (64) among MenB (64). MenB isolates were highly diverse, MenY intermediately diverse, and MenW & MenC isolates demonstrated the least genetic diversity. Thirty serogroup and CC-specific genomic clusters were identified. International CC11 comparison revealed diversification of MenW in Australia. Conclusions WGS comprehensively characterised Australian IMD isolates, indexed their genetic variability, provided increased within-CC resolution, and further elucidated the evolution of CC11 in Australia.



Bringing TB genomics to the clinic: A comprehensive pipeline to predict antimicrobial susceptibility from genomic data, validated and accredited to ISO standards

November 2023

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82 Reads

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1 Citation

Background Whole genome sequencing shows promise to improve the clinical management of tuberculosis, but bioinformatic tools tailored for clinical reporting and suitable for accreditation to ISO standards are currently lacking. Methods We developed tbtAMR, a comprehensive pipeline for analysis of Mycobacterium tuberculosis genomic data, including inference of phenotypic susceptibility and lineage calling from both solid and broth (MGIT) cultures. We used local and publicly-availably real-world data (phenotype and genotype) and synthetic genomic data to determine the appropriate quality control metrics and extensively validate the pipeline for clinical use. We combined and curated the large global databases of resistance mutations, fine-tuned for clinical purposes, by minimising false-positives whilst maintaining accuracy. Findings tbtAMR accurately predicted lineages and phenotypic susceptibility for first- and second-line drugs, including from broth (MGIT) cultures. We designed and implemented a reporting template suitable for clinical and public health users and accredited the pipeline to ISO standards. Interpretation The tbtAMR pipeline is accurate and fit-for-purpose for clinical and public health uses. Report templates, validation methods and datasets are provided here to offer a pathway for laboratories to adopt and seek their own accreditation for this critical test, to improve the management of tuberculosis globally. Funding No specific funding was received for this study.



Midpoint-rooted maximum likelihood phylogenetic tree of all study isolates (n = 1,474). Minor serotypes, sequence types (STs), and global pneumococcal sequence cluster (GPSC) were defined as those that contained less than 10 isolates over the study period. The reference was ASM966447v1 (GCA_009664475.1), collected 2014, serotype 19A, ST199.
of the key characteristics of the overrepresented sub-populations. The antibiotics included in the diagram are those that had a significant difference between the two populations (as per Table 1). Trimeth-sulfa refers to trimethoprim-sulfamethoxazole. The overrepresented sub-populations are colored based on which data set had the larger proportion of isolates: red for invasive and blue for non-invasive. The percentages displayed under the overrepresented population type/clusters are the differences in proportion between the two populations. A count of isolates for each typing method is displayed at the top of the bar chart. The proportion of isolates that were susceptible (blue), intermediate (orange), or resistant (red) to the antibiotics listed is also displayed [CLSI (21) breakpoints, meningitis/oral breakpoints used where indicated]. Minor types/clusters are defined as those having <10 isolates over the whole study period.
Validation of the in silico resistance prediction method. Proportion of isolates classified as major or minor errors for each in silico resistance prediction method. Major errors were defined as isolates that were phenotypically resistant or intermediate but labeled as susceptible by genotype. Minor errors were defined as isolates that were phenotypically susceptible but labeled as resistant/intermediate by genotype. Isolates phenotypically classified as intermediate or resistant were grouped to allow uniform comparison between all the methods.
Proportion of pbp alleles that were unique to each data set. The category pbp1a_2x is based on a combined pbp1a and pbp2x allele.
Midpoint rooted maximum likelihood phylogenetic tree of PBP2x. Tree has been built using an amino acid sequence alignment of all unique proteins that had at least one isolate with at least one dilution difference between the phenotypic and genotypic MICs. The number of isolates is based on counts of isolates that had contained the PBP2x alleles. The resistance motifs are the motifs used by WamR-Pneumo to determine the beta-lactam MIC, and the amino acids have been colored based on their side-chain chemistry. The MIC panels [penicillin (oral breakpoints), cefuroxime (meningitis breakpoints) and ceftriaxone (meningitis breakpoints)] show the proportion of isolates with each MIC for each of the PBP2x alleles (blue for susceptible and orange/red for intermediate/resistant). The panels displaying the number of dilutions different between the phenotype and the genotype used WamR-Pneumo to infer the MIC from the genotype.
Comparison of contemporary invasive and non-invasive Streptococcus pneumoniae isolates reveals new insights into circulating anti-microbial resistance determinants

October 2023

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93 Reads

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3 Citations

Streptococcus pneumoniae is a major human pathogen with a high burden of disease. Non-invasive isolates (those found in non-sterile sites) are thought to be a key source of invasive isolates (those found in sterile sites) and a reservoir of anti-microbial resistance (AMR) determinants. Despite this, pneumococcal surveillance has almost exclusively focused on invasive isolates. We aimed to compare contemporaneous invasive and non-invasive isolate populations to understand how they interact and identify differences in AMR gene distribution. We used a combination of whole-genome sequencing and phenotypic anti-microbial susceptibility testing and a data set of invasive ( n = 1,288) and non-invasive ( n = 186) pneumococcal isolates, collected in Victoria, Australia, between 2018 and 2022. The non-invasive population had increased levels of antibiotic resistance to multiple classes of antibiotics including beta-lactam antibiotics penicillin and ceftriaxone. We identified genomic intersections between the invasive and non-invasive populations and no distinct phylogenetic clustering of the two populations. However, this analysis revealed sub-populations overrepresented in each population. The sub-populations that had high levels of AMR were overrepresented in the non-invasive population. We determined that WamR-Pneumo was the most accurate in silico tool for predicting resistance to the antibiotics tested. This tool was then used to assess the allelic diversity of the penicillin-binding protein genes, which acquire mutations leading to beta-lactam antibiotic resistance, and found that they were highly conserved (≥80% shared) between the two populations. These findings show the potential of non-invasive isolates to serve as reservoirs of AMR determinants.


Citations (22)


... Regarding SM resistance, the most frequent mutation among MDR-TB patients was rpsL Lys43Arg (68.13%), consistent with studies conducted in Taiwan (24), Hainan (25), China (22,26), and southern China (27). Mutations rrs 514a > c and 517c > t were also reported in previous studies by Zhao (28) and Dorji (29). Furthermore, a novel mutation, rpsL Lys43Thr, identified in Mejía-Ponce's study, was associated with reduced fitness (30). ...

Reference:

Genetic diversity and transmission pattern of multidrug-resistant tuberculosis based on whole-genome sequencing in Wuhan, China
Whole genome sequencing of drug resistant Mycobacterium tuberculosis isolates in Victoria, Australia
  • Citing Article
  • November 2023

International Journal of Infectious Diseases

... To address this, abriTAMR, tailored for detecting AMR with command line capabilities and compatibility with most bacterial species, including some phenotypic inference was developed and validated to ISO standards 42 . In the tuberculosis (TB) context, a wish-list for mutational resistance detection, command line functionality, high accuracy, and ISO standard validation was pursued, leading to validated AMR detection from broth cultures, integrating genomic and phenotypic data 43 . Combining these efforts, in the case of carbapenemaseproducing Enterobacterales (CPE), prospective genomic surveillance proved instrumental in untangling outbreaks of CPE in Victoria, Australia and implementing state-wide surveillance programs, helping to stabilize notifications 44 . ...

Bringing TB genomics to the clinic: A comprehensive pipeline to predict antimicrobial susceptibility from genomic data, validated and accredited to ISO standards

... This observation is worrisome as β-lactams are still the first line antimicrobials used for treatment of pneumococcal infections [3]. It is possible that PCV vaccinations, in combination with the continued high use of specific antimicrobials, such as amoxicillin, in Belgium [58], have enabled certain penicillin-resistant S. pneumoniae, of serotypes not included in PCV13, to thrive (such as serotype 11A isolates). The MIC50 values for penicillin and cefotaxime between our study and the 2007-2008 study were at comparable levels, whereas we observed an increase in the MIC90 values for penicillin, amoxicillin, cefotaxime and imipenem. ...

Comparison of contemporary invasive and non-invasive Streptococcus pneumoniae isolates reveals new insights into circulating anti-microbial resistance determinants

... In this study, for non-meningitis patients, regardless of whether they had invasive infections, the resistance proportions remained low, even though some pathogenic isolates were nonsusceptible to penicillin and amoxicillin. The nonsusceptibility rate to penicillins was higher than that reported in recent research in Australia (PEN: 2.6%, AMX: 2.6%) (33) and Canada (PEN: 1.4%) (34) but lower than that reported in Taiwan (PEN: 43.41%) (28) and much lower than that reported in Vietnam (PEN: 100.0%) (35). ...

Population structure, serotype distribution and antibiotic resistance of Streptococcus pneumoniae causing invasive disease in Victoria, Australia

Microbial Genomics

... 9,10 The incorporation of sequencing data into real-time TB case management and control efforts assists clinical decision-making and guides better targeted public health control efforts. 11 Genomic differences between respiratory and non-respiratory isolates have not been comprehensively assessed in a programmatic setting. The implementation of routine sequencing (since 2016) of all culture-confirmed TB cases in New South Wales (NSW), Australia, presented a unique opportunity to compare genomic characteristics of M. tuberculosis strains isolated from different anatomical disease sites. ...

The use of whole genome sequencing for tuberculosis public health activities in Australia: a joint statement of the National Tuberculosis Advisory Committee and Communicable Diseases Genomics Network

Communicable Diseases Intelligence

... Multi-locus sequence typing is performed using mlst v2.16 [16,17]. Genes related to virulence and antimicrobial resistance are identified by running abritamr v1.0.14 [18] on the nucleotide sequences of the isolates. ...

An ISO-certified genomics workflow for identification and surveillance of antimicrobial resistance

... TB is also the eighth leading cause of death in Timor-Leste [2]. The disease predominantly affects individuals aged 15-34 years, with a concerning prevalence of multidrug-resistant tuberculosis (MDR-TB)/rifampicin-resistant tuberculosis (R-R TB) of 2.5% among new cases and 14% among retreatment cases [3]. ...

Mycobacterium tuberculosis Genotypes and Drug Susceptibility Test Results from Timor-Leste: A Pilot Study

Genes

... Due to the high cost of WGS, low-income countries often rely on genotyping tools like MIRU-VNTR for tracking the spread of diseases [5,22,23]. While WGS is considered more powerful, and capable of resolving clusters than 24-MIRU-VNTR [6,7], this advantage mostly applies to highly similar isolates [24,25]. We therefore used both techniques to evaluate the extent of transmission and distribution of the emerging Mtb genotype (SIT2517/T1) associated with MDR-TB in Pará/Brazil ...

Whole genome sequencing for tuberculosis in Victoria, Australia: A genomic implementation study from 2017 to 2020

The Lancet Regional Health - Western Pacific

... У N. gonorrhoeae, как и у N. meningitidis, еще одного облигатного патогена рода Neisseria, обнаружены OMV [214]. Они наиболее интенсивно вырабатываются в экспоненциальной фазе либо в ответ на стресс [218] и могут содержать фосфолипиды, нуклеиновые кислоты, компоненты клеточной стенки, метаболиты, сигнальные молекулы и белки [223]. ...

Neisseria gonorrhoeae -derived outer membrane vesicles package β-lactamases to promote antibiotic resistance

microLife

... The SARS-CoV-2 pandemic exemplified the value of sequence data [3] in developing intervention strategies against viruses [4,5], such as diagnostics, therapeutics, and prophylactics. Sequence data are a treasure trove to better understand viral evolution and interaction with the host. ...

Proficiency testing for SARS-CoV-2 whole genome sequencing
  • Citing Article
  • June 2022

Pathology