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Seeking Elusive Microbiome Standards

Microbiome Futures Roadmap

“The two reports chart the ecological landscape of microbiome methods ‘in the wild’ and should engender a newfound sense of urgency to optimize methods and to improve reproducibility between laboratories.”

These comments by Daryl M. Gohl about two recent papers in Nature Biotechnology, one on standards for human fecal sample processing in metagenomic studies (Costea, P.I. et al.) and one by the Microbiome Quality Control (MBQC) project consortium on variation in microbial community amplicon sequencing (Sinha, R. et al.), encapsulate one of the most basic challenges faced by microbiome R&D labs worldwide – poor interlab comparability of microbiome measurements.

Gohl is CSO of microbiome profiling company CoreBiome and R&D lead at the University of Minnesota Genomics Center.

In a 2016 consensus statement on the status of US microbiome research, the US National Institute of Standards and Technology (NIST) laid out the problem of lack of standards in the space in all its different facets: “Biases exist along every step of the measurement process, from sample collection, extraction techniques, measurement technology employed (e.g.NGS, mass spec, NMR), and, finally, to data analysis and interpretation. There is a need for the adoption of reference materials, reference data, and reference protocols in order to identify and eliminate measurement bias.”

“Standardization in the microbiome space is still in its infancy, although a lot of progress has been made in recent years,” echoes Johan van Hylckama Vlieg. “For microbiome-based products to make it through the rigorous translational process, experts in a number of areas, including microbiology, ecology, epidemiology, statistics, and bioinformatics need to work together to identify sources of potential measurement variability and to develop best practices.”

van Hylckama Vlieg is VP of Microbiome and Human Health Innovation at Chr. Hansen Holding A/S, a leader in the development of technological platforms for the production of microbes.

Because this is a challenge no organization can answer independently, a number of consortia have emerged to tackle specific aspects of standardization in microbiome R&D.

Hosted by the NIST, the International Metagenomics and Microbiome Standards Alliance (IMMSA) provides a forum for members of the microbiome community to share information and coordinate efforts toward the establishment of research and industry standards in the space.

The MBQC project, a global consortium headed by Curtis Huttenhower, associate professor of computational biology and bioinformatics at the Harvard School of Public Health, aims to comprehensively evaluate methods for measuring the human microbiome to develop standard operating procedures (SOPs) and best practices for the field. Initially, the consortium has focused on the human gut, and in particular on stool sampling protocols and the computational analysis pipeline. Future phases of the project will incorporate additional microenvironments, and sampling methods.

The Metagenomics Research Group (MGRG) of the Association of Biomolecular Resource Facilities (ABRF), a consortium of government, academia, research, industry and commercial laboratories, is working on assembling microbial standards, optimizing DNA extraction protocols and library synthesis methods for different new generation sequencing platforms, and developing best approaches for bioinformatics.

The Genomic Standards Consortium (GSC), an ongoing international effort started in 2005 by academic, industry and government partners, generates community-driven standards for genomic data integration, discovery and comparison. The GSC has also developed a number of standards for reporting genomic data.

The International Human Microbiome Standards (IHMS) project, which was one of the first consortia to address the issue and operated under the auspices of the European Union’s 7th Framework Programme, coordinated the development of some of the first SOPs in sampling, sequencing and data analysis to optimize data quality and comparability.

And new efforts are always on the horizon.

In early 2018, the Janssen Human Microbiome Institute will be hosting the Mosaic Community Challenge: Standards. This community-based challenge will run on Mosaic, a microbiome-focused computational analysis platform recently launched by DNAnexus, and will focus on identifying sources of variability in microbiome analyses, provide a mechanism for participants to identify how both their results and protocol(s) vary from others, and begin to explore issues around reproducibility.

Over the past few years, the above efforts, plus others not included in this compilation, have helped us gain a better appreciation for and a deeper understanding of the influence method variability has on microbiome R&D. Despite these advances, however, big hurdles persist including the inherent biological complexity of microbiome samples, quickly evolving analytical platforms, and continuously improving bioinformatic tools, all of which make it much harder to establish definitive standards.

Ultimately, the availability of robust standards to help validate each step along the microbiome R&D process and to improve reproducibility remains one of the central needs and most elusive goals in the space.

Microbiome Futures 2018-Global Engage
Gaspar Taroncher-Oldenburg
 is Consultant-in-Residence for Global Engage. He was previously Founding and Managing Editor of Nature’s SciBX: Science-Business eXchange (now BioCentury Innovations) and scientific editor of Nature Biotechnology.


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