Economic evaluation of DNA ploidy analysis vs liquid-based cytology for cervical screening.

BACKGROUND: DNA ploidy analysis involves automated quantification of chromosomal aneuploidy, a potential marker of progression toward cervical carcinoma. We evaluated the cost-effectiveness of this method for cervical screening, comparing five ploidy strategies (using different numbers of aneuploid cells as cut points) with liquid-based Papanicolaou smear and no screening. METHODS: A state-transition Markov model simulated the natural history of HPV infection and possible progression into cervical neoplasia in a cohort of 12-year-old females. The analysis evaluated cost in 2012 US$ and effectiveness in quality-adjusted life-years (QALYs) from a health-system perspective throughout a lifetime horizon in the US setting. We calculated incremental cost-effectiveness ratios (ICERs) to determine the best strategy. The robustness of optimal choices was examined in deterministic and probabilistic sensitivity analyses. RESULTS: In the base-case analysis, the ploidy 4 cell strategy was cost-effective, yielding an increase of 0.032 QALY and an ICER of $18 264/QALY compared to no screening. For most scenarios in the deterministic sensitivity analysis, the ploidy 4 cell strategy was the only cost-effective strategy. Cost-effectiveness acceptability curves showed that this strategy was more likely to be cost-effective than the Papanicolaou smear. CONCLUSION: Compared to the liquid-based Papanicolaou smear, screening with a DNA ploidy strategy appeared less costly and comparably effective.

BACH1 is a DNA repair protein supporting BRCA1 damage response.

The link between defects in BRCA1 and breast cancer development may be best understood by deciphering the role of associated proteins. BRCA1 associated C-terminal helicase (BACH1) interacts directly with the BRCA1 C-terminal BRCT repeats, which are important for BRCA1 DNA repair and are mutated in the majority of BRCA1 familial cancers. Thus, BACH1 is a likely candidate for mediating BRCA1 DNA repair and tumor suppression functions. Although previous evidence using overexpression of a dominant negative BACH1 has suggested that BACH1 is involved in BRCA1-DNA repair function, our results using BACH1 deficient cells provide direct evidence for involvement of BACH1 in DNA repair as well as for localizing BRCA1. Following DNA damage BACH1 is modified by phosphorylation, displays a BRCA1-like nuclear foci pattern and colocalizes with gamma-H2AX. Given that the BACH1/BRCA1 complex is unaltered by DNA damage and the intensity of BRCA1 foci is diminished in BACH1 deficient cells, BACH1 may serve to not only facilitate DNA repair, but also maintain BRCA1 in DNA damage foci.

Identification and characterization of Ral-binding protein 1, a potential downstream target of Ral GTPases.

Ral proteins constitute a distinct family of Ras-related GTPases. Although similar to Ras in amino acid sequence, Ral proteins are activated by a unique nucleotide exchange factor and inactivated by a distinct GTPase-activating protein. Unlike Ras, they fail to promote transformed foci when activated versions are expressed in cells. To identify downstream targets that might mediate a Ral-specific function, we used a Saccharomyces cerevisiae-based interaction assay to clone a novel cDNA that encodes a Ral-binding protein (RalBP1). RalBP1 binds specifically to the active GTP-bound form of RalA and not to a mutant Ral with a point mutation in its putative effector domain. In addition to a Ral-binding domain, RalBP1 also contains a Rho-GTPase-activating protein domain that interacts preferentially with Rho family member CDC42. Since CDC42 has been implicated in bud site selection in S. cerevisiae and filopodium formation in mammalian cells, Ral may function to modulate the actin cytoskeleton through its interactions with RalBP1.

Costs of blood transfusion: a process-flow analysis.

PURPOSE: To determine the cost of transfusing 2 units (U) of packed RBCs at a comprehensive cancer center. METHODS: We performed a process-flow analysis to identify all costs of transfusing 2 U of allogeneic packed RBCs on an outpatient basis to patients with either (1) solid tumor who did not undergo bone marrow transplantation (BMT), (2) solid tumor who underwent BMT, (3) hematologic malignancy who did not undergo BMT, (4) hematologic malignancy who underwent allogeneic BMT, or (5) hematologic malignancy who underwent autologous BMT. We conducted structured interviews to determine the personnel time used and physical resources necessary at all steps of the transfusion process. RESULTS: The mean cost of a 2-U transfusion of allogeneic packed RBCs was $548, $565, $569, $569, and $566 for patients with non-BMT solid tumor, BMT solid tumor, non-BMT hematologic malignancy, allogeneic BMT hematologic malignancy, and autologous BMT hematologic malignancy, respectively. Sensitivity analysis showed that total transfusion costs were sensitive to variations in the amount of clinician compensation and overhead costs, but were relatively insensitive to reasonable variations in the direct costs of blood tests and the blood itself, or the probability or extent of transfusion reaction. CONCLUSION: The costs of the transfusion of packed RBCs are greater than previously analyzed, particularly in the cancer care setting.

Time to clinical response: an outcome of antibiotic therapy of febrile neutropenia with implications for quality and cost of care.

PURPOSE: To determine whether antibiotic regimens with similar rates of response differ significantly in the speed of response and to estimate the impact of this difference on the cost of febrile neutropenia. METHODS: The time point of clinical response was defined by comparing the sensitivity, specificity, and predictive values of alternative objective and subjective definitions. Data from 488 episodes of febrile neutropenia, treated with either of two commonly used antibiotics (coded A or B) during six clinical trials, were pooled to compare the median time to clinical response, days of antibiotic therapy and hospitalization, and estimated costs. RESULTS: Response rates were similar; however, the median time to clinical response was significantly shorter with A-based regimens (5 days) compared with B-based regimens (7 days; P =.003). After 72 hours of therapy, 33% of patients who received A but only 18% of those who received B had responded (P =.01). These differences resulted in fewer days of antibiotic therapy and hospitalization with A-based regimens (7 and 9 days) compared with B-based regimens (9 and 12 days, respectively; P <.04) and in significantly lower estimated median costs ($8,491 v $11,133 per episode; P =.03). Early discharge at the time of clinical response should reduce the median cost from $10,752 to $8,162 (P <.001). CONCLUSION: Despite virtually identical rates of response, time to clinical response and estimated cost of care varied significantly among regimens. An early discharge strategy based on our definition of the time point of clinical response may further reduce the cost of treating non-low-risk patients with febrile neutropenia.

Incidence, cost, and outcomes of bleeding and chemotherapy dose modification among solid tumor patients with chemotherapy-induced thrombocytopenia.

PURPOSE: To describe the incidence and outcomes of bleeding and chemotherapy dose modifications associated with chemotherapy-induced thrombocytopenia (platelets < 50,000/microL). PATIENTS AND METHODS: Six hundred nine patients with solid tumors or lymphoma were followed-up during 1,262 chemotherapy cycles complicated by thrombocytopenia for development of bleeding, delay or dose reduction of the subsequent cycle, survival, and resource utilization. The association between survival and bleeding or dose modification was examined using the Cox proportional hazards model. Predisposing factors were identified by logistic regression. RESULTS: Bleeding occurred during 9% of cycles among patients with previous bleeding episodes (P <.0001), baseline platelets less than 75,000/microL (P <.0001), bone marrow metastases (P =.001), poor performance status (P =.03), and cisplatin, carboplatin, carmustine or lomustine administration (P =.0002). Major bleeding episodes resulted in shorter survival and higher resource utilization (P <.0001). Chemotherapy delays occurred during 6% of cycles among patients with more than five previous cycles (P =.003), radiotherapy (P =.03), and disseminated disease (P =.04). They experienced similar clinical outcomes but used significantly more resources. Dose reductions occurred during 15% of cycles but were not associated with poor clinical outcomes or excess resource utilization. Significantly shorter survival and higher resource utilization were observed among the 20% of patients who failed to achieve an adequate response to platelet transfusion. CONCLUSION: The incidence of bleeding is low among solid tumor patients overall but exceeds 20% in some subgroups. These subgroups are easily identifiable using routinely available clinical information. A clinical prediction rule is being developed. Poor response to platelet transfusion is a clinically and financially significant downstream effect of thrombocytopenia and warrants further investigation.

Incremental cost-effectiveness analysis: the optimal strategy depends on the strategy set.

Evaluating the incremental cost-effectiveness of a technology is critical to understanding the impact of its adoption. The purpose of this study was to evaluate, using a particular example, how the specific alternatives selected for a cost-effectiveness analysis may influence the results of the analysis. In this example, we analyzed the incremental cost-effectiveness of estriol screening for Down syndrome. Model assumptions of expected costs and effectiveness were based on previously published work involving four clinical strategies, including a "do nothing" (no screening) strategy. When the analysis started with all four strategies, two of the strategies could not be considered cost-effective because of extended dominance. However, when we eliminated the "do nothing" from the strategy set because of its clinical irrelevance, all three remaining strategies might be considered cost-effective from a policy perspective. We concluded that the incremental cost-effectiveness of clinical strategies could be strongly affected by the starting point for the analysis.

A comparison of C/B ratios from studies using receiver operating characteristic curve analysis.

In receiver operating characteristic (ROC) curve analysis, the optimal cutoff value for a diagnostic test can be found on the ROC curve where the slope of the curve is equal to (C/B) x (1-p[D])/p[D], where p[D] is the disease prevalence and C/B is the ratio of net costs of treating nondiseased individuals to net benefits of treating diseased individuals. We conducted a structured review of the medical literature to examine C/B ratios found in ROC curve analysis. Only two studies were found in which a C/B ratio was explicitly calculated; in another 11 studies, a C/B ratio was based on a so-called holistic estimate, an all-encompassing educated estimate of the relative costs and benefits relevant to the clinical situation. The C/B ratios ranged from 0.0025 (tuberculosis screening) to 2.7 (teeth restoration for carious lesions). Clinical scenarios that are directly life threatening but curable had C/B ratios of less than 0.05. This analysis led us to construct a table of ordered C/B ratios that may be used by investigators to approximate C/B ratios for other clinical situations in order to establish cutpoints for new diagnostic tests.

Optimal treatment strategy in patients with papillary thyroid cancer: a decision analysis.

BACKGROUND: The management of patients with papillary thyroid carcinoma (PTC) remains controversial. We used decision analysis to identify the optimal treatment strategy for patients with PTC, stratified by risk-group classification. METHODS: We designed a Markov model to compare thyroid lobectomy and total thyroidectomy (with adjuvant radioiodine therapy) in low- and high-risk patients with PTC. Morbidity, recurrence, and mortality estimates were obtained from the literature. Outcomes were quality-adjusted by using health state preferences. RESULTS: In low-risk patients, lobectomy and total thyroidectomy resulted in 31.7 and 32.9 quality-adjusted life years (QALYs). Total thyroidectomy was the optimal strategy as long as the relative risk of recurrence after lobectomy was greater than 1.3. Lobectomy became the preferred strategy if subjects were willing to give up 1.5 years of life to avoid thyroid hormone dependency and a remote risk of radioiodine-induced malignancy. In high-risk patients, lobectomy and total thyroidectomy resulted in 11.2 and 16.5 QALYs. Model results were robust to varying the permanent complication rates of initial or completion thyroidectomy, the efficacy of adjuvant radioiodine therapy, and the impact of complications and cancer recurrence on quality of life, irrespective of risk-group classification. CONCLUSIONS: Total thyroidectomy maximized quality-adjusted life expectancy in low- and high-risk patients with PTC.

Fluorescence spectroscopy for diagnosis of squamous intraepithelial lesions of the cervix.

OBJECTIVE: To calculate receiver operating characteristic (ROC) curves for fluorescence spectroscopy in order to measure its performance in the diagnosis of squamous intraepithelial lesions (SILs) and to compare these curves with those for other diagnostic methods: colposcopy, cervicography, speculoscopy, Papanicolaou smear screening, and human papillomavirus (HPV) testing. DATA SOURCES: Data from our previous clinical study were used to calculate ROC curves for fluorescence spectroscopy. Curves for other techniques were calculated from other investigators' reports. To identify these, a MEDLINE search for articles published from 1966 to 1996 was carried out, using the search terms "colposcopy," "cervicoscopy," "cervicography," "speculoscopy," "Papanicolaou smear," "HPV testing," "fluorescence spectroscopy," and "polar probe" in conjunction with the terms "diagnosis," "positive predictive value," "negative predictive value," and "receiver operating characteristic curve." METHODS OF STUDY SELECTION: We found 270 articles, from which articles were selected if they reported results of studies involving high-disease-prevalence populations, reported findings of studies in which colposcopically directed biopsy was the criterion standard, and included sufficient data for recalculation of the reported sensitivities and specificities. TABULATION, INTEGRATION, AND RESULTS: We calculated ROC curves for fluorescence spectroscopy using Bayesian and neural net algorithms. A meta-analytic approach was used to calculate ROC curves for the other techniques. Areas under the curves were calculated. Fluorescence spectroscopy using the neural net algorithm had the highest area under the ROC curve, followed by fluorescence spectroscopy using the Bayesian algorithm, followed by colposcopy, the standard diagnostic technique. Cervicography, Papanicolaou smear screening, and HPV testing performed comparably with each other but not as well as fluorescence spectroscopy and colposcopy. CONCLUSION: Fluorescence spectroscopy performs better than colposcopy and other techniques in the diagnosis of SILs. Because it also permits real-time diagnosis and has the potential of being used by inexperienced health care personnel, this technology holds bright promise.

Colposcopy for the diagnosis of squamous intraepithelial lesions: a meta-analysis.

OBJECTIVE: To quantify by meta-analysis the performance of colposcopy to set a standard against which new technologies can be compared. DATA SOURCES: MEDLINE was searched for articles on colposcopy for diagnosis of squamous intraepithelial lesions (SIL). The search selected articles from 1960 to 1996 combining the key word "colposcopy" with key words "diagnosis," "positive predictive value," "negative predictive value," "likelihood ratio," and "receiver operating characteristic (ROC) curve." METHODS OF STUDY SELECTION: Articles were selected if the authors studied a population of patients with abnormal screening Papanicolaou smears and presented raw data showing for each cervical lesion type the number of patients judged positive and negative by colposcopic impression versus the standard of colposcopic biopsy results. Nine of 86 studies met these criteria. TABULATION, INTEGRATION, AND RESULTS: Biopsies had been categorized as normal, atypia, cervical intraepithelial neoplasia (CIN) I, CIN II, CIN III, carcinoma in situ, and invasive cancer; we recalculated performance measures using the Bethesda system. Overall sensitivity, specificity, likelihood ratios, ROC curves, and the corresponding areas under the curves were calculated. The average weighted sensitivity of diagnostic colposcopy for the threshold normal compared with all cervix abnormalities (atypia, low-grade SIL, high-grade SIL, cancer) was 96% and the average weighted specificity 48%. For the threshold normal cervix and low-grade SIL compared with high-grade SIL and cancer, average weighted sensitivity was 85% and average weighted specificity 69%. Likelihood ratios generated small but important changes in probability for distinguishing normal cervix and low-grade SIL from high-grade SIL and cancer. Areas under the ROC curve were 0.80 for the threshold normal cervix compared with all abnormalities and 0.82 for the threshold normal cervix and low-grade SIL compared with high-grade SIL and cancer. CONCLUSION: Colposcopy compares favorably with other medical diagnostic tests in terms of sensitivity, specificity, and area under the ROC curve. New diagnostic methods for the cervix can be compared with colposcopy using these quantified values.

Screening for squamous intraepithelial lesions with fluorescence spectroscopy.

OBJECTIVE: To evaluate the accuracy of fluorescence spectroscopy in screening for squamous intraepithelial lesions (SILs) and to compare its performance with that of Papanicolaou smear screening, colposcopy, cervicoscopy, cervicography, and human papillomavirus (HPV) testing. DATA SOURCES: Receiver operating characteristic (ROC) curve analysis was used to analyze performance by fluorescence spectroscopy (primary data) and other methods (secondary data). METHODS OF STUDY SELECTION: In our search, 275 articles were identified in MEDLINE (1966-1996). Articles were included if the investigators had studied a population in whom low disease prevalence was expected; used either Papanicolaou smear screening and colposcopy or colposcopically directed biopsy as a standard against which the screening technique was measured, and included enough data for recalculation of reported sensitivities and specificities. TABULATION, INTEGRATION, AND RESULTS: Receiver operating characteristic curves for fluorescence spectroscopy were calculated using a Bayesian algorithm, and ROC curves for the other screening methods were constructed using metaanalytic techniques. Areas under the ROC curves and Q points were calculated. Screening colposcopy had the highest area under the curve (0.95), followed by screening cervicography (0.90), HPV testing (0.88), cervicoscopy (0.85), fluorescence spectroscopy (0.76), and Papanicolaou smear screening (0.70). CONCLUSION: In terms of screening for SILs, fluorescence spectroscopy performed better than the standard technique, Papanicolaou smear screening, and less well than screening colposcopy, cervicography, HPV testing, and cervicoscopy. The promise of this research technique warrants further investigation.

Cost-effectiveness analysis of diagnosis and management of cervical squamous intraepithelial lesions.

OBJECTIVE: To compare five strategies for the diagnosis and treatment of cervical squamous intraepithelial lesions (SILs), including those that incorporate colposcopy and a new technology, fluorescence spectroscopy. METHODS: On the basis of a health care perspective, we performed a cost-effectiveness analysis using a decision-analytic model for the diagnosis and management of SILs. We compared the five strategies based on the expected costs and number of cases that were treated appropriately, missed, treated inappropriately, and appropriately not treated in a hypothetical cohort of 100 patients referred after an abnormal Papanicolaou smear. Data on prevalence and operating characteristics were derived from the medical literature. Costs were adjusted from hospital charge data. RESULTS: A see-and-treat strategy based on fluorescence spectroscopy was the least expensive but least effective strategy, costing $160,479 to detect 31.55 cases of cervical precancer accurately in 100 patients. The most expensive strategy was colposcopically directed biopsy, at $311,808 to find 45.78 cases; however, when both tests were used in a see-and-treat modality, slightly more cases were found (46.05) at a lower cost ($285,133). Other strategies were dominated in the base case. The incremental cost-effectiveness of the joint strategy compared with the spectroscopy-only strategy was $8596 per case of cervical precancer detected. Sensitivity analysis showed that the analysis was sensitive to the cost of the new technology of fluorescence spectroscopy. CONCLUSION: Fluorescence spectroscopy should be considered an important innovation in the diagnosis of SILs as demonstrated by its efficacy and economic advantages.

The Alcohol Use Disorders Identification Test (AUDIT) as a screen for at-risk drinking in primary care patients of different racial/ethnic backgrounds.

This study examined the operating characteristics of the Alcohol Use Disorders Identification Test (AUDIT) as a screen for "at-risk" drinking in a multi-ethnic sample of primary care patients, from a family practice center located in the southwestern United States. A probability sample of 1,333 family medicine patients, stratified by gender and racial/ethnic background (white, African-American and Mexican-American) completed the AUDIT, followed by the Alcohol Use Disorders and Associated Disabilities Interview Schedule (AUDADIS) to determine ICD-10 diagnoses. Indicators of hazardous alcohol use and alcohol-related problems were included as measures of "at-risk" drinking. Despite differences in the spectrum of alcohol problems across patient subgroups, there was no evidence of gender or racial/ethnic bias in the AUDIT as indicated by Receiver Operating Characteristic Curve analysis. Excluding abstainers from the analysis and little impact on screening efficacy. In this population, the AUDIT appears to be an unbiased measure of "at-risk" drinking.

Identifying risk factors for imminent death in cancer patients with acute dyspnea.

A substantial proportion of cancer patients presenting to an emergency center (EC) or clinic with acute dyspnea survives fewer than 2 weeks. If these patients could be identified at the time of admission, physicians and patients would have additional information on which to base decisions to continue therapy to extend life or to refocus treatment efforts on palliation and/or hospice care alone. The purpose of this study was to identify risk factors for imminent death (survival

A cost-effectiveness analysis of epoetin usage for patients with AIDS.

Epoetin (recombinant human erythropoietin) therapy for patients with AIDS may reduce the need for blood transfusion; however, it is expensive. We conducted a cost-effectiveness analysis of the use of epoetin for AIDS patients from a healthcare system perspective. We constructed a decision analysis model using probability, outcome and cost data from the literature and hospital sources. The incremental cost-effectiveness ratio was measured in dollars per unit of blood saved. In AIDS patients undergoing transfusion with serum epoetin concentrations less than or equal to 500 U/L treatment with epoetin cost $US1007 per unit of blood saved compared with treatment without epoetin. One-way sensitivity analysis revealed that the incremental cost-effectiveness ratio was sensitive to the efficacy and unit price of epoetin, but less sensitive to the current price cap determined by the distributor.

Cost-effectiveness analysis, extended dominance, and ethics: a quantitative assessment.

The principle of extended dominance is applied in incremental cost-effectiveness analysis to eliminate from consideration strategies whose costs and benefits are improved by a mixed strategy of two other alternatives. Ethical considerations arise, however, in that equal care is not provided to all of the population. To explore these concerns, the authors establish a theoretical health care example with three diagnostic strategies. They demonstrate, both algebraically and geometrically, how to calculate the set of all possible mixed strategies that dominate the strategy eliminated by extended dominance. With the consideration of budget constraints, they define the "coefficient of inequity" as the minimum proportion of the population that would receive an inferior health care strategy if a mixed strategy were to be used instead of the dominated strategy. The implications of cost-effectiveness analysis are made explicit, revealing classic economic concerns about the tradeoff of equity and efficiency.

Determining the area under the ROC curve for a binary diagnostic test.

The authors provide a simple calculation for the unbiased estimation of the area under the ROC curve for a binary diagnostic test or a continuously valued test result that is effectively used in a binary way. The formula described can be used to interpret the discriminative ability of a diagnostic test.

Population-based time preferences for future health outcomes.

CONTEXT: Time preference (how preference for an outcome changes depending on when the outcome occurs) affects clinical decisions, but little is known about determinants of time preferences in clinical settings. OBJECTIVES: To determine whether information about mean population time preferences for specific health states can be easily assessed, whether mean time preferences are constant across different diseases, and whether under certain circumstances substantial fractions of the patient population make choices that are consistent with a negative time preference. DESIGN: Self-administered survey. SETTING: Family physician waiting rooms in four states. PATIENTS: A convenience sample of 169 adults. INTERVENTION: Subjects were presented five clinical vignettes. For each vignette the subject chose between interventions maximizing a present and a future health outcome. The options for individual vignettes varied among the patients so that a distribution of responses was obtained across the population of patients. MAIN OUTCOME MEASURE: Logistic regression was used to estimate the mean preference for each vignette, which was translated into an implicit discount rate for this group of patients. RESULTS: There were marked differences in time preferences for future health outcomes based on the five vignettes, ranging from a negative to a high positive (116%) discount rate. CONCLUSIONS: The study provides empirical evidence that time preferences for future health outcomes may vary substantially among disease conditions. This is likely because the vignettes evoked different rationales for time preferences. Time preference is a critical element in patient decision making and cost-effectiveness research, and more work is necessary to improve our understanding of patient preferences for future health outcomes.

Performance estimation of diagnostic tests for cervical precancer based on fluorescence spectroscopy: effects of tissue type, sample size, population, and signal-to-noise ratio.

Fluorescence spectroscopy may provide a cost-effective tool to improve precancer detection. We describe a method to estimate the diagnostic performance of classifiers based on optical spectra, and to explore the sensitivity of these estimations to factors affecting spectrometer cost. Fluorescence spectra were obtained at three excitation wavelengths in 92 patients with an abnormal Papanicolaou smear and 51 patients with no history of an abnormal smear. Bayesian classification rules were developed and evaluated at multiple misclassification costs. We explored the sensitivity of classifier performance to variations in tissue type, sample size, tested population, signal to noise ratio (SNR), and number of excitation and emission wavelengths. Sensitivity and specificity could be evaluated within +/- 7%. Minimal decrease in diagnostic performance is observed as SNR is reduced to 15, the number of excitation-emission wavelength combinations is reduced to 15 or the number of excitation wavelengths is reduced to one. Diagnostic performance is compromised when ultraviolet excitation is not included. Significant spectrometer cost reduction is possible without compromising diagnostic ability. Decision-analytic methods can be used to rate designs based on incremental cost-effectiveness.