Potential Cost-effectiveness of Early Identification of Hospital-acquired Infection in Critically Ill Patients

Limitations in methods for the rapid diagnosis of hospital-acquired infections often delay initiation of effective antimicrobial therapy. New diagnostic approaches offer potential clinical and cost-related improvements in the management of these infections. We developed a decision modeling framework to assess the potential cost-effectiveness of a rapid biomarker assay to identify hospital-acquired infection in high-risk patients earlier than standard diagnostic testing. The framework includes parameters representing rates of infection, rates of delayed appropriate therapy, and impact of delayed therapy on mortality, along with assumptions about diagnostic test characteristics and their impact on delayed therapy and length of stay. Parameter estimates were based on contemporary, published studies and supplemented with data from a four-site, observational, clinical study. Extensive sensitivity analyses were performed. The base-case analysis assumed 17.6% of ventilated patients and 11.2% of nonventilated patients develop hospital-acquired infection and that 28.7% of patients with hospital-acquired infection experience delays in appropriate antibiotic therapy with standard care. We assumed this percentage decreased by 50% (to 14.4%) among patients with true-positive results and increased by 50% (to 43.1%) among patients with false-negative results using a hypothetical biomarker assay. Cost of testing was set at $110/d. In the base-case analysis, among ventilated patients, daily diagnostic testing starting on admission reduced inpatient mortality from 12.3 to 11.9$1,640 per patient, resulting in an incremental cost-effectiveness ratio of $21,389 per life-year saved. Among nonventilated patients, inpatient mortality decreased from 7.3 to 7.1$1,381 with diagnostic testing. The resulting incremental cost-effectiveness ratio was $42,325 per life-year saved. Threshold analyses revealed the probabilities of developing hospital-acquired infection in ventilated and nonventilated patients could be as low as 8.4 and 9.8$50,000 per life-year saved. Development and use of serial diagnostic testing that reduces the proportion of patients with delays in appropriate antibiotic therapy for hospital-acquired infections could reduce inpatient mortality. The model presented here offers a cost-effectiveness framework for future test development

Recombination Modulates How Selection Affects Linked Sites in <em>Drosophila</em>

<div><p>One of the most influential observations in molecular evolution has been a strong association between local recombination rate and nucleotide polymorphisms across the genome. This is interpreted as evidence for ubiquitous natural selection. The alternative explanation, that recombination is mutagenic, has been rejected by the absence of a similar association between local recombination rate and nucleotide divergence between species. However, many recent studies show that recombination rates are often very different even in closely related species, questioning whether an association between recombination rate and divergence between species has been tested satisfactorily. To circumvent this problem, we directly surveyed recombination across approximately 43% of the <em>D. pseudoobscura</em> physical genome in two separate recombination maps and 31% of the <em>D. miranda</em> physical genome, and we identified both global and local differences in recombination rate between these two closely related species. Using only regions with conserved recombination rates between and within species and accounting for multiple covariates, our data support the conclusion that recombination is positively related to diversity because recombination modulates Hill–Robertson effects in the genome and not because recombination is predominately mutagenic. Finally, we find evidence for dips in diversity around nonsynonymous substitutions. We infer that at least some of this reduction in diversity resulted from selective sweeps and examine these dips in the context of recombination rate.</p> </div

Footprints of diversity around substitutions.

<p>Fitted values for a model with nearly identical covariates as <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1001422#pbio-1001422-t005" target="_blank">Table 5</a> and <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1001422#pbio-1001422-t006" target="_blank">Table 6</a>. Recombination rate and distance from substitution were not included in the model because they were physically plotted. Diversity of 4-fold degenerate sites was fitted as a response in the general linear model, instead of numerator (and denominator was not included in the covariates) for ease of interpretation. Center of <i>x</i>-axis represents substitutions identified along the <i>D. pseudoobscura</i>+<i>D. persimilis</i> lineage. For all graphs, a Lowess smoothing factor of 0.06 was used. Red, nonsynonymous substitutions; grey, synonymous substitutions.</p

Test for relationship between recombination rate and number of nonsynonymous substitutions; response: nonsynonymous substitutions along the <i>D. pseudoobscura+D. persimilis</i> lineage.

<p>A generalized linear mixed model with Poisson distribution used to compare nonsynonymous substitutions along the <i>D. pseudoobscura</i>+<i>D. persimilis</i> lineage per gene to recombination rates measured in the Flagstaff cross. Interval was included as a random effect to account for multiple genes per interval. For this analysis, the “neutral mutation rate” was set as the average pairwise <i>D. lowei</i>–<i>D. persimilis</i> divergence at 4-fold degenerate sites of unpreferred codons. An asterisk indicates significance at an α of 0.05.</p

Factors affecting divergence between species at 4-fold degenerate sites for unpreferred codons using intervals with conserved recombination rate.

<p>The relationship of the average pairwise <i>D. pseudoobscura–D. miranda</i> divergence for 4-fold synonymous sites of unpreferred codons to various factors. All parameters are the same as <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1001422#pbio-1001422-t002" target="_blank">Table 2</a>.</p

Analysis of the diversity around synonymous substitutions; response: number of fourfold degenerate polymorphisms around synonymous substitutions.

<p>A generalized linear mixed model with Poisson distribution used to compare the diversity around synonymous substitutions along the <i>D. pseudoobscura+D. persimilis</i> lineage in relation to recombination rates measured in the Flagstaff cross. All parameters and transformations were identical to those in <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1001422#pbio-1001422-t005" target="_blank">Table 5</a>. <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1001422#pbio.1001422.s025" target="_blank">Table S12</a> gives the mean and standard deviation for each factor in the model.</p

Fine-scale recombination rates on chromosome 2.

<p>Uncondensed raw recombination rates and 95% CI for intervals along chromosome 2. Top, <i>D. pseudoobscura</i> Flagstaff map; middle, <i>D. pseudoobscura</i> Pikes Peak map; bottom, <i>D. miranda</i>. Recombination rates are given in Kosambi centiMorgans per Megabase (cM/Mb).</p