Studies of the human microbiome have revealed that even healthy individuals differ remarkably in the microbes that occupy habitats such as the gut, skin, and vagina. Much of this diversity remains unexplained, although diet, environment, host genetics, and early microbial exposure have all been implicated. Accordingly, to characterize the ecology of human-associated microbial communities, the Human Microbiome Project has analyzed the largest cohort and set of distinct, clinically relevant body habitats to date. We found the diversity and abundance of each habitat’s signature microbes to vary widely even among healthy subjects, with strong niche specialization both within and among individuals. The project encountered an estimated 81–99% of the genera, enzyme families, and community configurations occupied by the healthy Western microbiome. Metagenomic carriage of metabolic pathways was stable among individuals despite variation in community structure, and ethnic/racial background proved to be one of the strongest associations of both pathways and microbes with clinical metadata. These results thus delineate the range of structural and functional configurations normal in the microbial communities of a healthy population, enabling future characterization of the epidemiology, ecology, and translational applications of the human microbiome.

A variety of microbial communities and their genes (microbiome) exist throughout the human body, playing fundamental roles in human health and disease. The NIH funded Human Microbiome Project (HMP) Consortium has established a population-scale framework which catalyzed significant development of metagenomic protocols resulting in a broad range of quality-controlled resources and data including standardized methods for creating, processing and interpreting distinct types of high-throughput metagenomic data available to the scientific community. Here we present resources from a population of 242 healthy adults sampled at 15 to 18 body sites up to three times, which to date, have generated 5,177 microbial taxonomic profiles from 16S rRNA genes and over 3.5 Tb of metagenomic sequence. In parallel, approximately 800 human-associated reference genomes have been sequenced. Collectively, these data represent the largest resource to date describing the abundance and variety of the human microbiome, while providing a platform for current and future studies.

Initiation of warfarin therapy using trial-and-error dosing is problematic. our goal was to develop and validate a pharmacogenetic algorithm. in the derivation cohort of 1,015 participants, the independent predictors of therapeutic dose were: VKORC1 polymorphism −1639/3673 g>a (−28% per allele), body surface area (Bsa) (+11% per 0.25 m 2 ), CYP2C9*3 (−33% per allele), CYP2C9*2 (−19% per allele), age (−7% per decade), target international normalized ratio (inr) (+11% per 0.5 unit increase), amiodarone use (−22%), smoker status (+10%), race (−9%), and current thrombosis (+7%). This pharmacogenetic equation explained 53−54% of the variability in the warfarin dose in the derivation and validation (N = 292) cohorts. For comparison, a clinical equation explained only 17−22% of the dose variability (P < 0.001). in the validation cohort, we prospectively used the pharmacogenetic-dosing algorithm in patients initiating warfarin therapy, two of whom had a major hemorrhage. To facilitate use of these pharmacogenetic and clinical algorithms, we developed a nonprofit website, http://www.WarfarinDosing.org.Correspondence: BF Gage (E-mail: bgage@im.wustl.edu). CONFLICT OF INTEREST Dr Gage has consulted for Bristol-Myers Squibb on work unrelated to this article. Drs Rieder and Rettie report having applied for a patent (application serial no. 10/967,879) on the use of VKORC1 haplotypes and SNPs. The other authors declared no conflict of interest. NIH Public Access RESULTSIn the derivation cohort (N = 1,015), the daily therapeutic warfarin dose ranged from 1 to 18 mg/day. The mean age was 65 (range of 18−93); 83% were Caucasian, and 64% were male. The (geometric) mean daily warfarin dose was 4.8 mg ( Table 1). The most common indications for warfarin therapy were atrial fibrillation (N = 392) and prior venous thromboembolism (N = 376; 13 of whom also had atrial fibrillation). Patients in the validation cohort (N = 292) were younger, more often female, and had more often (77%) undergone joint replacement as their indication for warfarin therapy (Table 1).VKORC1 alleles were highly heterogeneous (Table 2), reflecting their original selection as common (>5% allele frequency), informative tagging SNPs (Table 2). 12 VKORC1 3673G>A was in high linkage disequilibrium with VKORC1 6853G>C (D' = 0.97). In both cohorts, all alleles were in Hardy-Weinberg equilibrium. Genotype data from all participants at Washington University and University of Florida have been submitted to the PharmGKB (accession numbers: PS207479 and PS207480 pending). Pharmacogenetic model developmentThe VKORC1 3673G>A SNP was the first variable to enter the stepwise regression model (Table 3); each VKORC1 3673A allele was associated with a 28% reduction (95% confidence interval 25−30%) in the therapeutic warfarin dose. Once VKORC1 3673G>A entered the model, none of the other VKORC1 SNPs was an independent predictor of warfarin dose. Body surface area (BSA) was the second variable to enter the model, and each 0.25 m 2 increase in BSA was associated with an 11% ...

The authors note that on page 12527, left column, second full paragraph, line 7, "Sequences meeting the above criteria were further classified by the Ribosomal Database Project (RDP) Naive Bayesian Classifier version 2.5 using training set 9 (46) from phylum to genus level." should instead appear as "Sequences meeting the above criteria were further classified by the Ribosomal Database Project (RDP) Naive Bayesian Classifier version 2.2 using training set 6 (46) from phylum to genus level."www.pnas.org/cgi

A current controversy is whether patients with sepsis progress to an immunosuppressed state. We hypothesized that reactivation of latent viruses occurred with prolonged sepsis thereby providing evidence of clinically-relevant immunosuppression and potentially providing a means to serially-monitor patients' immune status. Secondly, if viral loads are markedly elevated, they may contribute to morbidity and mortality. This study determined if reactivation of herpesviruses, polyomaviruses, and the anellovirus TTV occurred in sepsis and correlated with severity. Serial whole blood and plasma samples from 560 critically-ill septic, 161 critically-ill non-septic, and 164 healthy age-matched patients were analyzed by quantitative-polymerase-chain-reaction for cytomegalovirus (CMV), Epstein-Barr (EBV), herpes-simplex (HSV), human herpes virus-6 (HHV-6), and TTV. Polyomaviruses BK and JC were quantitated in urine. Detectable virus was analyzed with respect to secondary fungal and opportunistic bacterial infections, ICU duration, severity of illness, and survival. Patients with protracted sepsis had markedly increased frequency of detectable virus. Cumulative viral DNA detection rates in blood were: CMV (24.2%), EBV (53.2%), HSV (14.1%), HHV-6 (10.4%), and TTV (77.5%). 42.7% of septic patients had presence of two or more viruses. The 50% detection rate for herpesviruses was 5–8 days after sepsis onset. A small subgroup of septic patients had markedly elevated viral loads (>104–106 DNA copies/ml blood) for CMV, EBV, and HSV. Excluding TTV, DNAemia was uncommon in critically-ill non-septic patients and in age-matched healthy controls. Compared to septic patients without DNAemia, septic patients with viremia had increased fungal and opportunistic bacterial infections. Patients with detectable CMV in plasma had higher 90-day mortality compared to CMV-negative patients; p<0.05. Reactivation of latent viruses is common with prolonged sepsis, with frequencies similar to those occurring in transplant patients on immunosuppressive therapy and consistent with development of an immunosuppressive state. Whether reactivated latent viruses contribute to morbidity and mortality in sepsis remains unknown.