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Microbiome research has grown exponentially over the past several years, but studies have been difficult to reproduce across investigations. Relevant variation in measurements between laboratories, from a variety of sources, has not been systematically assessed. This is coupled with a growing concern in the scientific community about the lack of reproducibility in biomedical research. The Microbiome Quality Control project (MBQC) was initiated to identify sources of variation in microbiome studies, to quantify their magnitudes, and to assess the design and utility of different positive and negative control strategies. Here we report on the first MBQC baseline study project and workshop.

The NIH Human Microbiome Project (HMP) has been carried out over ten years and two phases to provide resources, methods, and discoveries that link interactions between humans and their microbiomes to health-related outcomes. The recently completed second phase, the Integrative Human Microbiome Project, comprised studies of dynamic changes in the microbiome and host under three conditions: pregnancy and preterm birth; inflammatory bowel diseases; and stressors that affect individuals with prediabetes. The associated research begins to elucidate mechanisms of host–microbiome interactions under these conditions, provides unique data resources (at the HMP Data Coordination Center), and represents a paradigm for future multi-omic studies of the human microbiome. Over ten years, the Human Microbiome Project has provided resources for studying the microbiome and its relationship to disease; this Perspective summarizes the key achievements and findings of the project and its relationship to the broader field.

The Microbiome Quality Control project consortium reports outcomes of a baseline study (MBQC) that will guide future improvements in reproducibility of microbiome analyses. In order for human microbiome studies to translate into actionable outcomes for health, meta-analysis of reproducible data from population-scale cohorts is needed. Achieving sufficient reproducibility in microbiome research has proven challenging. We report a baseline investigation of variability in taxonomic profiling for the Microbiome Quality Control (MBQC) project baseline study (MBQC-base). Blinded specimen sets from human stool, chemostats, and artificial microbial communities were sequenced by 15 laboratories and analyzed using nine bioinformatics protocols. Variability depended most on biospecimen type and origin, followed by DNA extraction, sample handling environment, and bioinformatics. Analysis of artificial community specimens revealed differences in extraction efficiency and bioinformatic classification. These results may guide researchers in experimental design choices for gut microbiome studies.

The characterization of baseline microbial and functional diversity in the human microbiome has enabled studies of microbiome-related disease, diversity, biogeography, and molecular function. The National Institutes of Health Human Microbiome Project has provided one of the broadest such characterizations so far. Here we introduce a second wave of data from the study, comprising 1,631 new metagenomes (2,355 total) targeting diverse body sites with multiple time points in 265 individuals. We applied updated profiling and assembly methods to provide new characterizations of microbiome personalization. Strain identification revealed subspecies clades specific to body sites; it also quantified species with phylogenetic diversity under-represented in isolate genomes. Body-wide functional profiling classified pathways into universal, human-enriched, and body site-enriched subsets. Finally, temporal analysis decomposed microbial variation into rapidly variable, moderately variable, and stable subsets. This study furthers our knowledge of baseline human microbial diversity and enables an understanding of personalized microbiome function and dynamics. Updates from the Human Microbiome Project analyse the largest known body-wide metagenomic profile of human microbiome personalization. Delving deeper into the human microbiome The National Institutes of Health Human Microbiome Project, published in 2012, provided a broad overview of the baseline microbiome in healthy individuals using samples from 18 different body sites. In this second installment, the authors expand this dataset with new whole-metagenome sequences and additional time points to assess the diversity and spatiotemporal distributions of the microbiota at six of these body sites. Using a combination of strain profiling, species-level metagenomic functional profiling and longitudinal analyses, this study delivers deeper insights into human microbial communities and provides an important resource for understanding what constitutes a 'healthy' microbiota.

ObjectivesNeuromyelitis optica spectrum disorders (NMOSD) are inflammatory conditions of the central nervous system and an important differential diagnosis of multiple sclerosis (MS). Unlike MS, the course is usually relapsing, and it is unclear, if progressive neurodegeneration contributes to disability. Therefore, we aimed to investigate if progressive retinal neuroaxonal damage occurs in aquaporin4-antibody-seropositive NMOSD.MethodsOut of 157 patients with NMOSD screened, 94 eyes of 51 patients without optic neuritis (ON) during follow-up (F/U) and 56 eyes of 28 age-matched and sex-matched healthy controls (HC) were included (median F/U 2.3 years). The NMOSD cohort included 60 eyes without (EyeON −) and 34 eyes with a history of ON prior to enrolment (EyeON+). Peripapillary retinal nerve fibre layer thickness (pRNFL), fovea thickness (FT), volumes of the combined ganglion cell and inner plexiform layer (GCIP) and the inner nuclear layer (INL) and total macular volume (TMV) were acquired by optical coherence tomography (OCT).ResultsAt baseline, GCIP, FT and TMV were reduced in EyeON+ (GCIP p<2e−16; FT p=3.7e−4; TMV p=3.7e−12) and in EyeON − (GCIP p=0.002; FT p=0.040; TMV p=6.1e−6) compared with HC. Longitudinally, we observed GCIP thinning in EyeON− (p=0.044) but not in EyeON+. Seven patients had attacks during F/U; they presented pRNFL thickening compared with patients without attacks (p=0.003).ConclusionThis study clearly shows GCIP loss independent of ON attacks in aquaporin4-antibody-seropositive NMOSD. Potential explanations for progressive GCIP thinning include primary retinopathy, drug-induced neurodegeneration and retrograde neuroaxonal degeneration from lesions or optic neuropathy. pRNFL thickening in the patients presenting with attacks during F/U might be indicative of pRNFL susceptibility to inflammation.

Background Next-generation sequencing technologies have decentralized sequence acquisition, increasing the demand for new bioinformatics tools that are easy to use, portable across multiple platforms, and scalable for high-throughput applications. Cloud computing platforms provide on-demand access to computing infrastructure over the Internet and can be used in combination with custom built virtual machines to distribute pre-packaged with pre-configured software. Results We describe the Cloud Virtual Resource, CloVR, a new desktop application for push-button automated sequence analysis that can utilize cloud computing resources. CloVR is implemented as a single portable virtual machine (VM) that provides several automated analysis pipelines for microbial genomics, including 16S, whole genome and metagenome sequence analysis. The CloVR VM runs on a personal computer, utilizes local computer resources and requires minimal installation, addressing key challenges in deploying bioinformatics workflows. In addition CloVR supports use of remote cloud computing resources to improve performance for large-scale sequence processing. In a case study, we demonstrate the use of CloVR to automatically process next-generation sequencing data on multiple cloud computing platforms. Conclusion The CloVR VM and associated architecture lowers the barrier of entry for utilizing complex analysis protocols on both local single- and multi-core computers and cloud systems for high throughput data processing.

Microbial communities carry out the majority of the biochemical activity on the planet, and they play integral roles in processes including metabolism and immune homeostasis in the human microbiome. Shotgun sequencing of such communities' metagenomes provides information complementary to organismal abundances from taxonomic markers, but the resulting data typically comprise short reads from hundreds of different organisms and are at best challenging to assemble comparably to single-organism genomes. Here, we describe an alternative approach to infer the functional and metabolic potential of a microbial community metagenome. We determined the gene families and pathways present or absent within a community, as well as their relative abundances, directly from short sequence reads. We validated this methodology using a collection of synthetic metagenomes, recovering the presence and abundance both of large pathways and of small functional modules with high accuracy. We subsequently applied this method, HUMAnN, to the microbial communities of 649 metagenomes drawn from seven primary body sites on 102 individuals as part of the Human Microbiome Project (HMP). This provided a means to compare functional diversity and organismal ecology in the human microbiome, and we determined a core of 24 ubiquitously present modules. Core pathways were often implemented by different enzyme families within different body sites, and 168 functional modules and 196 metabolic pathways varied in metagenomic abundance specifically to one or more niches within the microbiome. These included glycosaminoglycan degradation in the gut, as well as phosphate and amino acid transport linked to host phenotype (vaginal pH) in the posterior fornix. An implementation of our methodology is available at http://huttenhower.sph.harvard.edu/humann. This provides a means to accurately and efficiently characterize microbial metabolic pathways and functional modules directly from high-throughput sequencing reads, enabling the determination of community roles in the HMP cohort and in future metagenomic studies.

Visual snow syndrome (VSS) is a neurological disorder characterized by a range of continuous visual disturbances. Little is known about the functional pathological mechanisms underlying VSS and their effect on brain network topology, studied using high‐resolution resting‐state (RS) 7 T MRI. Forty VSS patients and 60 healthy controls underwent RS MRI. Functional connectivity matrices were calculated, and global efficiency (network integration), modularity (network segregation), local efficiency (LE, connectedness neighbors) and eigenvector centrality (significance node in network) were derived using a dynamic approach (temporal fluctuations during acquisition). Network measures were compared between groups, with regions of significant difference correlated with known aberrant ocular motor VSS metrics (shortened latencies and higher number of inhibitory errors) in VSS patients. Lastly, nodal co‐modularity, a binary measure of node pairs belonging to the same module, was studied. VSS patients had lower modularity, supramarginal centrality and LE dynamics of multiple (sub)cortical regions, centered around occipital and parietal lobules. In VSS patients, lateral occipital cortex LE dynamics correlated positively with shortened prosaccade latencies (p = .041, r = .353). In VSS patients, occipital, parietal, and motor nodes belonged more often to the same module and demonstrated lower nodal co‐modularity with temporal and frontal regions. This study revealed reduced dynamic variation in modularity and local efficiency strength in the VSS brain, suggesting that brain network dynamics are less variable in terms of segregation and local clustering. Further investigation of these changes could inform our understanding of the pathogenesis of the disorder and potentially lead to treatment strategies. Visual snow syndrome (VSS) is a neurological disorder characterized by a range of continuous visual disturbances. Little is known about the functional pathological mechanisms underlying VSS and their effect on brain network topology, which was studied using high‐resolution resting‐state 7 T MRI. VSS patients demonstrated reduced dynamic variation in modularity and local efficiency strength, suggesting that brain network dynamics are less variable in terms of segregation and local clustering. Network dynamic alterations were centered around occipital cortices and related to ocular motor processing changes.

Visual snow syndrome (VSS) is a poorly understood neurological disorder that features a range of disabling sensory changes. Visual processing changes revealed previously in VSS appear consistent with poor attentional control, specifically, with difficulty controlling environmentally driven shifts of attention. This study sought to confirm this proposal by determining whether these changes were similarly evident where attention is internally driven. Sixty seven VSS patients and 37 controls completed two saccade tasks: the endogenously cued saccade task and saccadic Simon task. The endogenously cued saccade task correctly (valid trial) or incorrectly (invalid trial) pre-cues a target location using a centrally presented arrow. VSS patients generated significantly shorter saccade latencies for valid trials ( p  = 0.03), resulting in a greater magnitude cue effect ( p  = 0.02), i.e. the difference in latency between valid and invalid trials. The saccadic Simon task presents a peripheral cue which may be spatially congruent or incongruent with the subsequent target location. Latencies on this task were comparable for VSS patients and controls, with a normal Simon effect , i.e. shorter latencies for saccades to targets spatially congruent with the preceding cue. On both tasks, VSS patients generated more erroneous saccades than controls towards non-target locations (Endogenously cued saccade task: p  = 0.02, saccadic Simon task: p  = 0.04). These results demonstrate that cued shifts of attention differentially affect saccade generation in VSS patients. We propose that these changes are not due to impairment of frontally-mediated inhibitory control, but to heightened saccade-related activity in visual regions. These results contribute to a VSS ocular motor signature that may provide clinical utility as well as an objective measure of dysfunction to facilitate future research.

Microbial ecologists, realizing that >99% of environmental microbes could not be easily cultured, developed approaches to study microorganisms in situ [5], primarily by sequencing the 16S ribosomal RNA gene (16S) as a phylogenetic and taxonomic marker to identify members of microbial communities [6]. The HMP has thus greatly advanced our knowledge of the microbes in a healthy adult reference population, and provided much-needed infrastructure in terms of reference genomes, laboratory protocols, computational methods, and ELSI considerations [1],[2] to help enable a vast range of studies that will likely find associations between human-associated microbial communities and disease.