Assessing the Performance of a Computer-Based Policy Model of HIV and AIDS

BACKGROUND. Model-based analyses, conducted within a decision analytic framework, provide a systematic way to combine information about the natural history of disease and effectiveness of clinical management strategies with demographic and epidemiological characteristics of the population. Among the challenges with disease-specific modeling include the need to identify influential assumptions and to assess the face validity and internal consistency of the model. METHODS AND FINDINGS. We describe a series of exercises involved in adapting a computer-based simulation model of HIV disease to the Women's Interagency HIV Study (WIHS) cohort and assess model performance as we re-parameterized the model to address policy questions in the U.S. relevant to HIV-infected women using data from the WIHS. Empiric calibration targets included 24-month survival curves stratified by treatment status and CD4 cell count. The most influential assumptions in untreated women included chronic HIV-associated mortality following an opportunistic infection, and in treated women, the 'clinical effectiveness' of HAART and the ability of HAART to prevent HIV complications independent of virologic suppression. Good-fitting parameter sets required reductions in the clinical effectiveness of 1st and 2nd line HAART and improvements in 3rd and 4th line regimens. Projected rates of treatment regimen switching using the calibrated cohort-specific model closely approximated independent analyses published using data from the WIHS. CONCLUSIONS. The model demonstrated good internal consistency and face validity, and supported cohort heterogeneities that have been reported in the literature. Iterative assessment of model performance can provide information about the relative influence of uncertain assumptions and provide insight into heterogeneities within and between cohorts. Description of calibration exercises can enhance the transparency of disease-specific models.National Institute of Allergy and Infectious Diseases (R37 AI042006, K24 AI062476

DNA Damage Induced by Hyperoxia: Quantitation and Correlation with Lung Injury

Inspired oxygen, an essential therapy for cardiorespiratory disorders, has the potential to generate reactive oxygen species that damage cellular DNA. Although DNA damage is implicated in diverse pulmonary disorders, including neoplasia and acute lung injury, the type and magnitude of DNA lesion caused by oxygen in vivo is unclear. We used single-cell gel electrophoresis (SCGE) to quantitate two distinct forms of DNA damage, base adduction and disruption of the phosphodiester backbone, in the lungs of mice. Both lesions were induced by oxygen, but a marked difference between the two was found. With 40 h of oxygen exposure, oxidized base adducts increased 3- to 4-fold in the entire population of lung cells. This lesion displayed temporal characteristics (a progressive increase over the first 24 h) consistent with a direct effect of reactive oxygen species attack upon DNA. DNA strand breaks, on the other hand, occurred in < 10% of pulmonary cells, which acquired severe levels of the lesion; dividing cells were preferentially affected. Characteristics of these cells suggested that DNA strand breakage was secondary to cell death, rather than a primary effect of reactive oxygen species attack on DNA. By analysis of IL-6– and IL-11–overexpressing transgenic animals, which are resistant to hyperoxia, we found that DNA strand breaks, but not base damage, correlated with acute lung injury. Analysis of purified alveolar type 2 preparations from hyperoxic mice indicated that strand breaks preferentially affected this cell type