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.

Targeting the FANCJ-BRCA1 interaction promotes a switch from recombination to poleta-dependent bypass.

BRCA1 and the DNA helicase FANCJ (also known as BACH1 or BRIP1) have common functions in breast cancer suppression and DNA repair. However, the functional significance of the direct interaction between BRCA1 and FANCJ remains unclear. Here, we have discovered that BRCA1 binding to FANCJ regulates DNA damage repair choice. Thus, when FANCJ binding to BRCA1 is ablated, the molecular mechanism chosen for the repair of damaged DNA is dramatically altered. Specifically, a FANCJ protein that cannot be phosphorylated at serine 990 or bind BRCA1 inhibits DNA repair via homologous recombination and promotes poleta-dependent bypass. Furthermore, the poleta-dependent bypass promoted by FANCJ requires the direct binding to the mismatch repair (MMR) protein, MLH1. Together, our findings implicate that in human cells BRCA1 binding to FANCJ is critical to regulate DNA repair choice and promote genomic stability. Moreover, unregulated FANCJ function could be associated with cancer and/or chemoresistance.

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.

A pilot study for a screening trial of cervical fluorescence spectroscopy.

Fluorescence spectroscopy is a promising technology for detection of epithelial precancers and cancers. In preparation for a multicenter phase II screening trial, a pilot trial was conducted to test data collection and patient examination procedures, use data forms, time procedures, and identify problems with preliminary data analysis. Women 18 years of age and older underwent a questionnaire, a complete history, and a physical examination, including a pan-colposcopy of the lower genital tract. A fiber-optic probe measured fluorescence excitation-emission matrices at 1-3 cervical sites for 58 women. The data collection procedures, data forms, and procedure times worked well, although collection times for all the clinical data take an average of 28 min. The clinical team followed procedures well, and the data could be retrieved from the database at all sites. The multivariate analysis algorithm correctly identified squamous normal tissue 99% of the time and columnar normal tissue only 7%. The assessment of ploidy from monolayer samples was not accurate in this small sample. The study was successful as a pilot trial. We learned who participated, who withdrew, how often abnormalities were present, and that algorithms that have worked extremely well in previous studies do not work as well when a few study parameters are changed. The current algorithm for diagnosis identified squamous normal tissue very accurately and did less well for columnar normal tissue. Inflammation may be an explanation for this phenomenon. Fluorescence spectroscopy is a promising technology for the detection of epithelial precancers and cancers. The screening trial of fluorescence and reflectance spectroscopy was successful.

Clinical and economic impact of multiple gated acquisition scan monitoring during anthracycline therapy.

The clinical and economic impacts of monitoring cardiac function in patients given doxorubicin have yet to be determined, especially in relation to patient age, cumulative doxorubicin dose, and the relative efficacies of doxorubicin-based vs alternative regimens. We developed a decision analysis model that includes these factors to estimate the incremental survival benefit and cost-effectiveness of using multiple gated acquisition scans to measure left-ventricular ejection fraction before and during doxorubicin chemotherapy. Probability distributions for the incidences of abnormal left-ventricular ejection fraction findings and congestive heart failure were derived from a retrospective review of 227 consecutive cases at The University of Michigan Medical Center and published findings. Multiple gated acquisition-scan monitoring minimally improved the probability of 5-year survival (<1.5% in the base--case scenario). For patients who received up to 350 mg m(-2) of doxorubicin, multiple gated acquisition-scan screening had an incremental cost of $425 402 per life saved for patients between the ages of 15--39. This incremental cost markedly decreased to $138 191, for patients between the ages of 40--59, and to $86 829 for patients older than 60 years. The small gain in 5-year survival probability secondary to multiple gated acquisition scan monitoring doubled for all age groups when the average cumulative dose for doxorubicin reached 500 mg m(-2). Variations in the cure rate differences between the doxorubicin and alternative regimens had insignificant effects on the improvement in 5-year survival rates from multiple gated acquisition-scan screening. The use of multiple gated acquisition scans for pretreatment screening appears to be more cost-effective for patients who are 40 years or older, when cumulative doxorubicin dose is 350 mg m(-2) or less.

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.

Utility of chest computed tomography for staging in patients with T1 extremity soft tissue sarcomas.

BACKGROUND: National Cancer Center Network (NCCN) and Society of Surgical Oncology (SSO) practice guidelines recommend chest computed tomography (CT) as part of the staging evaluation of patients with extremity soft tissue sarcoma (STS). In the current study, the authors evaluated the use and yield of chest roentgenography (CXR) and selective chest CT to screen for pulmonary metastases in patients with T1 STS. METHODS: The utility of these staging studies was evaluated retrospectively in a cohort of 125 consecutive patients who presented to a tertiary care cancer center with T1 primary (nonrecurrent) extremity STS. Two diagnostic strategies (CXR alone vs. CXR plus chest CT) were evaluated using an incremental cost-effectiveness ratio. RESULTS: The majority of tumors (70%) were high grade. The median sarcoma size was 3.0 cm; 64 of the tumors (51%) were located deep to the investing fascia of the extremity. All patients underwent staging CXR; 1 CXR (< 1%) was suspicious for metastatic disease. Fifty-one patients (41%) also underwent chest CT; 1 chest CT, performed in the patient with a suspicious CXR, revealed metastatic disease. With a median follow-up of 76 months, 19 patients (15%) developed metachronous pulmonary metastases. The relatively low yield resulted in an incremental cost-effectiveness ratio of $59,772 per case of synchronous pulmonary metastasis detected by CXR plus chest CT. CONCLUSIONS: Less than 1% of patients with T1 primary extremity STS were found to have pulmonary metastases that were detectable using a staging algorithm that employs routine CXR with the selective use of chest CT. The findings of the current study do not support current NCCN or SSO practice guidelines for patients with high-grade T1 STS.

BACH1, a novel helicase-like protein, interacts directly with BRCA1 and contributes to its DNA repair function.

BRCA1 interacts in vivo with a novel protein, BACH1, a member of the DEAH helicase family. BACH1 binds directly to the BRCT repeats of BRCA1. A BACH1 derivative, bearing a mutation in a residue that was essential for catalytic function in other helicases, interfered with normal double-strand break repair in a manner that was dependent on its BRCA1 binding function. Thus, BACH1/BRCA1 complex formation contributes to a key BRCA1 activity. In addition, germline BACH1 mutations affecting the helicase domain were detected in two early-onset breast cancer patients and not in 200 matched controls. Thus, it is conceivable that, like BRCA1, BACH1 is a target of germline cancer-inducing mutations.

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.

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

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.

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.

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.

Quality of life and cost effectiveness analysis of therapy for locally recurrent rectal cancer.

PURPOSE: This study was performed to determine the quality of life and cost-effectiveness of therapeutic options for patients with locally recurrent rectal carcinoma, determined from the perspectives of patients and health care providers. METHODS: We reviewed the records of patients (N = 68) with locally recurrent rectal carcinoma evaluated from 1992 through 1995. We constructed a decision-analytic model incorporating outcomes, survival, and costs. Utilities were elicited from convenience samples of health care providers and patients using the standard gamble technique. RESULTS: The median survival for patients undergoing surgical resection (n = 40) was 42 months, compared with 16.8 months for patients undergoing diagnostic or palliative surgery (n = 16) and 18.3 months for patients treated nonoperatively (n = 12; P < 0.005). The mean cost of treatment per patient was $19,283 for the nonoperative group, $45,647 for the diagnostic or palliative surgery group, and $70,878 for the surgical resection group. The diagnostic or palliative surgical strategy was dominated by the nonoperative strategy because the former had greater costs with fewer health benefits. The incremental cost-utility ratio of surgical resection compared with nonoperative management using health care provider utilities was $109,777 per quality-adjusted life year gained; it was reduced to $56,698 using per quality-adjusted life year using mean patient utilities. CONCLUSIONS: Patients with recurrent rectal carcinoma view surgery and morbidity to be less severe than health care providers. Diagnostic or palliative surgery is expensive and affects quality-adjusted survival adversely compared with nonoperative therapy. Surgical resection may be a cost-effective use of resources, particularly when cost-effectiveness is calculated using patient preferences.

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.

Telephone interviews vs. workstation sessions for acquiring quality of life data.

Patient quality of life data can be acquired in a variety of ways, including over the telephone and through computerized questionnaires. However, if the method of collection produces different results, medical decisions regarding appropriate and cost-effective care may be influenced by collection method. We conducted an experiment where subjects had two quality of life measures, the time trade-off and rating scale utilities, assessed both in telephone interivews and via computer touchscreens. The order of telephone and touchscreen was randomized. We found that rating scale utilities were similar whether obtained via the telephone or via touchscreen regardless of which was done first. However, patients who had their time trade-off utilities assessed over the telephone first did not provide as consistent responses as those elicited first via touchscreen (p = 0.01). Caution is suggested when considering eliciting time trade-off over the telephone with subjects who have not had time trade-off elicited previously.

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.

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.

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.

Influence of data display formats on physician investigators' decisions to stop clinical trials: prospective trial with repeated measures.

OBJECTIVE: To examine the effect of the method of data display on physician investigators' decisions to stop hypothetical clinical trials for an unplanned statistical analysis. DESIGN: Prospective, mixed model design with variables between subjects and within subjects (repeated measures). SETTING: Comprehensive cancer centre. PARTICIPANTS: 34 physicians, stratified by academic rank, who were conducting clinical trials. INTERVENTIONS: PARTICIPANTS were shown tables, pie charts, bar graphs, and icon displays containing hypothetical data from a clinical trial and were asked to decide whether to continue the trial or stop for an unplanned statistical analysis. MAIN OUTCOME MEASURE: Percentage of accurate decisions with each type of display. RESULTS: Accuracy of decisions was affected by the type of data display and positive or negative framing of the data. More correct decisions were made with icon displays than with tables, pie charts, and bar graphs (82% v 68%, 56%, and 43%, respectively; P=0.03) and when data were negatively framed rather than positively framed in tables (93% v 47%; P=0.004). CONCLUSIONS: Clinical investigators' decisions can be affected by factors unrelated to the actual data. In the design of clinical trials information systems, careful consideration should be given to the method by which data are framed and displayed in order to reduce the impact of these extraneous factors.