Biology subjects

Lipkin, W. I.

Publications and source records attributed to Lipkin, W. I..

7 recordsLinked to original sources

bioRxiv2022

Bayesian statistics improves biological interpretability of metabolomics data from human cohorts

BackgroundUnivariate analyses of metabolomics data currently follow a frequentist approach, using p-values to reject a null-hypothesis. However, the usability of p-values is plagued by many misconceptions and inherent pitfalls. We here propose the use of Bayesian statistics to quantify evidence supporting different hypotheses and discriminate between the null hypothesis versus lack of statistical power. MethodsWe use metabolomics data from three independent human cohorts that studied plasma signatures of subjects with myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS). Data are publicly available, covering 84-197 subjects in each study with 562-888 identified metabolites of which 777 were common between two studies, and 93 compounds reported in all three studies. By comparing results from classic multiple regression against Bayesian multiple regression we show how Bayesian statistics incorporates results from one study as prior information into the next study, thereby improving the overall assessment of the likelihood of finding specific differences between plasma metabolite levels and disease outcomes in ME/CFS. ResultsWhereas using classic statistics and Benjamini-Hochberg FDR-corrections, study 1 detected 18 metabolic differences, study 2 detected no differences. Using Bayesian statistics on the same data, we found a high likelihood that 97 compounds were altered in concentration in study 2, after using the results of study 1 as prior distributions. These findings included lower levels of peroxisome-produced ether-lipids, higher levels of long chain, unsaturated triacylglycerides, and the presence of exposome compounds that are explained by difference in diet and medication between healthy subjects and ME/CFS patients. Although study 3 reported only 92 reported compounds in common with the other two studies, these major differences were confirmed. We also found that prostaglandin F2alpha, a lipid mediator of physiological relevance, was significantly reduced in ME/CFS patients across all three studies. ConclusionsThe use of Bayesian statistics led to biological conclusions from metabolomic data that were not found through the frequentist analytical approaches more commonly employed. We propose that Bayesian statistics to be highly useful for studies with similar research designs if similar metabolomic assays are used.

bioinformatics↗

bioRxiv2021

Natural history of nonhuman primates after conjunctival exposure to Ebola virus

Transmission of Ebola virus (EBOV) primarily occurs via contact exposure of mucosal surfaces with infected body fluids. Historically, nonhuman primate (NHP) challenge studies have employed intramuscular or small particle aerosol exposure, which are uniformly lethal routes of infection, but mimic worst-case scenarios such as a needlestick. When exposed by more likely routes of natural infection, limited NHP studies have shown delayed onset of disease and reduced mortality. Here we performed a series of systematic natural history studies in cynomolgus macaques with a range of conjunctival exposure doses. Challenge with 10,000 plaque forming units (PFU) of EBOV was uniformly lethal, whereas 5/6 subjects survived low and moderate dose challenges (100 or 500 PFU). Conjunctival challenge resulted in a protracted time-to death. Asymptomatic disease was observed in survivors with limited detection of EBOV replication. Inconsistent seropositivity in survivors may suggest physical or natural immunological barriers are sufficient to prevent widespread viral dissemination.

microbiology↗

bioRxiv2020

Immunoreactive peptide maps of SARS-CoV-2 and other human coronaviruses

Serodiagnosis of SARS-CoV-2 infection is impeded by immunological cross-reactivity to the human coronaviruses (HCoV) SARS-CoV-2, SARS-CoV-1, MERS-CoV, OC43, 229E, HKU1, and NL63. Here we report the identification of humoral immune responses to SARS-CoV-2 and other HCoV peptides that can be used to detect asymptomatic, mild and, severe SARS-CoV-2 infections, and may enable the discovery of biomarkers for immunity following infection or vaccination.

microbiology↗

bioRxiv2020

From SARS-CoV to Wuhan 2019-nCoV: Will History Repeat Itself?

This manuscript has been withdrawn as it was submitted without the full consent of all the authors. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.

microbiology↗

bioRxiv2019

Combined use of metagenomic sequencing and host response profiling for the diagnosis of suspected sepsis.

BackgroundCurrent diagnostic techniques are inadequate for rapid microbial diagnosis and optimal management of patients with suspected sepsis. We assessed the clinical impact of three powerful molecular diagnostic methods. MethodsWith blood samples from 200 consecutive patients with suspected sepsis, we evaluated 1) metagenomic shotgun sequencing together with a Bayesian inference approach for contaminant sequence removal, for detecting bacterial DNA; 2) viral capture sequencing; and 3) transcript-based host response profiling for classifying patients as infected or not, and if infected, with bacteria or viruses. We then evaluated changes in diagnostic decision-making among three expert physicians by unblinding the results of these methods in a staged fashion. ResultsMetagenomic shotgun sequencing confirmed positive blood culture results in 14 of 26 patients. In 17 of 200 patients, metagenomic sequencing and viral capture sequencing revealed organisms that were 1) not detected by conventional hospital tests within 5 days after presentation, and 2) classified as of probable clinical relevance by physician consensus. Host response profiling led at least two of three physicians to change their diagnostic decisions in 46 of 100 patients. The data suggested possible bacterial DNA translocation in 8 patients who were originally classified by physicians as noninfected and illustrate how host response profiling can guide interpretation of metagenomic shotgun sequencing results. ConclusionsThe integration of host response profiling, metagenomic shotgun sequencing, and viral capture sequencing enhances the utility of each, and may improve the diagnosis and management of patients with suspected sepsis.

microbiology↗

bioRxiv2019

Trypsin treatment unlocks barrier for zoonotic coronaviruses infection

Traditionally, the emergence of coronaviruses (CoVs) has been attributed to a gain in receptor binding in a new host. Our previous work with SARS-like viruses argued that bats already harbor CoVs with the ability to infect humans without adaptation. These results suggested that additional barriers limit the emergence of zoonotic CoV. In this work, we describe overcoming host restriction of two MERS-like bat CoVs using exogenous protease treatment. We found that the spike protein of PDF2180-CoV, a MERS-like virus found in a Ugandan bat, could mediate infection of Vero and human cells in the presence of exogenous trypsin. We subsequently show that the bat virus spike can mediate infection of human gut cells, but is unable to infect human lung cells. Using receptor-blocking antibodies, we show that infection with the PDF2180 spike does not require MERS-CoV receptor DPP4 and antibodies developed against the MERS spike receptor-binding domain and S2 portion are ineffective in neutralizing the PDF2180 chimera. Finally, we found that addition of exogenous trypsin also rescues replication of HKU5-CoV, a second MERS-like group 2c CoV. Together, these results indicate that proteolytic cleavage of the spike, not receptor binding, is the primary infection barrier for these two group 2c CoVs. Coupled with receptor binding, proteolytic activation offers a new parameter to evaluate emergence potential of CoVs and offer a means to recover previously unrecoverable zoonotic CoV strains.\n\nImportanceOverall, our studies demonstrate that proteolytic cleavage is the primary barrier to infection for a subset of zoonotic coronaviruses. Moving forward, the results argue that both receptor binding and proteolytic cleavage of the spike are critical factors that must be considered for evaluating the emergence potential and risk posed by zoonotic coronaviruses. In addition, the findings also offer a novel means to recover previously uncultivable zoonotic coronavirus strains and argue that other tissues, including the digestive tract, could be a site for future coronavirus emergence events in humans.

microbiology↗

bioRxiv2019

Identification of immunoreactive linear epitopes of Borrelia miyamotoi

Borrelia miyamotoi is an emerging tick-borne spirochete transmitted by Ixodid ticks. Current serologic assays for B. miyamotoi are impacted by genetic similarities to other Borrelia and limited understanding of optimal antigenic targets. In this study, we employed the TBD-Serochip, a peptide array platform, to identify new linear targets for serologic detection of B. miyamotoi. We examined a wide range of suspected B. miyamotoi antigens and identified 352 IgM and 91 IgG reactive peptides, with the majority mapping to variable membrane proteins. These included peptides within conserved fragments of variable membrane proteins that may have greater potential for differential diagnosis. We also identified reactive regions on FlaB, and demonstrate crossreactivity of B. burgdorferi C6 with a B. miyamotoi C6-like peptide. The panel of linear peptides identified in this study can be used to enhance serodiagnosis of B. miyamotoi.

microbiology↗