Abstract
Clinical metagenomics (CMg) is the discipline that refers to the sequencing of all nucleic acid material present within a clinical specimen with the intent to recover clinically relevant microbial information. From a diagnostic perspective, next-generation sequencing (NGS) offers the ability to rapidly identify putative pathogens and predict their antimicrobial resistance profiles to optimize targeted treatment regimens. Since the introduction of metagenomics nearly a decade ago, numerous reports have described successful applications in an increasing variety of biological specimens, such as respiratory secretions, cerebrospinal fluid, stool, blood and tissue. Considerable advancements in sequencing and computational technologies in recent years have made CMg a promising tool in clinical microbiology laboratories. Moreover, costs per sample and turnaround time from specimen receipt to clinical management continue to decrease, making the prospect of CMg more feasible. Many difficulties, however, are associated with CMg and warrant further improvements such as the informatics infrastructure and analytical pipelines. Thus, the current review focuses on comprehensively assessing applications of CMg for diagnostic and subtyping purposes.
Highlights
Infectious diseases are a leading cause of morbidity and mortality worldwide
Given that no gold standard pipeline exists for metagenomics assays and there are many critical steps whereby bias or variability may be introduced, it is important that both consistency and thorough documentation are followed to ensure that maximal transparency and reproducibility are achieved for reported outcomes [27,40]
Another aspect to consider is the amount of sequencing required to ensure the limit of detection (LOD) is achieved for a broad range of infectious agents in the sample type being investigated and that the pathogen signal is discriminatory against ‘background noise’. These considerations highlight the importance of including a mock community and/or positivecontrol to ensure the sensitivity and LOD of the method is adequate for the particular specimen, sequencing and analytical strategy being used [28]
Summary
Infectious diseases are a leading cause of morbidity and mortality worldwide. Recent estimates suggest that approximately 19% of global deaths are attributed to infectious diseases [1]. Rapid developments have recently been made in the modernization of clinical microbiology laboratories with the employment of multiplex syndromic panels (e.g. BDMax, FilmArray and others), matrix assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) and whole genome sequencing (WGS). These methods have played an increasingly important role in clinical microbiology laboratories due to their ability to reduce turnaround time (TAT) from specimen collection to clinically actionable result and through the detection of non-cultivable or fastidious pathogens. The application of next-generation sequencing (NGS) approaches such as WGS in clinical microbiology laboratories is wide-ranging including for purposes of outbreak management, pathogen surveillance and subtyping and zoonotic transmission determination. We discuss the rapidly emerging field of CMg and provide a comprehensive review of NGS culture-independent diagnostic applications thereby describing the potential suitability of this diagnostic assay to be routinely implemented in frontline laboratories
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