Early detection and treatment strategies for breast cancer in low-income and upper middle-income countries: a modelling study.

BACKGROUND: Poor breast cancer survival in low-income and middle-income countries (LMICs) can be attributed to advanced-stage presentation and poor access to systemic therapy. We aimed to estimate the outcomes of different early detection strategies in combination with systemic chemotherapy and endocrine therapy in LMICs. METHODS: We adapted a microsimulation model to project outcomes of three early detection strategies alone or in combination with three systemic treatment programmes beyond standard of care (programme A): programme B was endocrine therapy for all oestrogen-receptor (ER)-positive cases; programme C was programme B plus chemotherapy for ER-negative cases; programme D was programme C plus chemotherapy for advanced ER-positive cases. The main outcomes were reductions in breast cancer-related mortality and lives saved per 100 000 women relative to the standard of care for women aged 30-49 years in a low-income setting (East Africa; using incidence data and life tables from Uganda and data on tumour characteristics from various East African countries) and for women aged 50-69 years in a middle-income setting (Colombia). FINDINGS: In the East African setting, relative mortality reductions were 8-41%, corresponding to 23 (95% uncertainty interval -12 to 49) to 114 (80 to 138) lives saved per 100 000 women over 10 years. In Colombia, mortality reductions were 7-25%, corresponding to 32 (-29 to 70) to 105 (61 to 141) lives saved per 100 000 women over 10 years. INTERPRETATION: The best projected outcomes were in settings where access to both early detection and adjuvant therapy is improved. Even in the absence of mammographic screening, improvements in detection can provide substantial benefit in settings where advanced-stage presentation is common. FUNDING: Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium Cancer Center Support Grant of the US National Institutes of Health.

Correction: A New Method for Estimating the Number of Undiagnosed HIV Infected Based on HIV Testing History, with an Application to Men Who Have Sex with Men in Seattle/King County, WA.

[This corrects the article DOI: 10.1371/journal.pone.0129551.].

Comparative Effectiveness of Biomarkers to Target Cancer Treatment: Modeling Implications for Survival and Costs.

BACKGROUND: Biomarkers used at the time of diagnosis to tailor treatment decisions may diffuse into clinical practice before data become available on whether biomarker testing reduces cancer mortality. In the interim, quantitative estimates of the mortality impact of testing are needed to assess the value of these diagnostic biomarkers. These estimates are typically generated by customized models that are resource intensive to build and apply. METHODS: We developed a user-friendly system of models for Cancer Translation of Comparative Effectiveness Research (CANTRANce) to model the mortality impact of cancer interventions. The Diagnostic Biomarker module of this system projects the mortality impact of testing for a diagnostic biomarker, given data on how testing affects treatment recommendations. Costs and quality-of-life outcomes may also be modeled. We applied the Diagnostic Biomarker module to 2 case studies to demonstrate its capabilities. RESULTS: The user interface (http://www.fhcrc.org/cantrance) allows comparative effectiveness researchers to use the Diagnostic Biomarker module of CANTRANce. Our case studies indicate that the model produces estimates on par with those generated by customized models and is a strong tool for quickly generating novel projections. LIMITATIONS: The simple structure that makes CANTRANce user-friendly also constrains the complexity with which cancer progression can be modeled. The quality of the results rests on the quality of the input data, which may pertain to small or dissimilar populations or suffer from informative censoring. CONCLUSIONS: The Diagnostic Biomarker module of CANTRANce is a novel public resource that can provide timely insights into the expected mortality impact of testing for diagnostic biomarkers. The model projections should be useful for understanding the long-term potential of emerging diagnostic biomarkers.

A New Method for Estimating the Number of Undiagnosed HIV Infected Based on HIV Testing History, with an Application to Men Who Have Sex with Men in Seattle/King County, WA.

We develop a new approach for estimating the undiagnosed fraction of HIV cases, the first step in the HIV Care Cascade. The goal is to address a critical blindspot in HIV prevention and treatment planning, with an approach that simplifies data requirements and can be implemented with open-source software. The primary data required is HIV testing history information on newly diagnosed cases. Two methods are presented and compared. The first is a general methodology based on simplified back-calculation that can be used to assess changes in the undiagnosed fraction over time. The second makes an assumption of constant incidence, allowing the estimate to be expressed as a simple closed formula calculation. We demonstrate the methods with an application to HIV diagnoses among men who have sex with men (MSM) from Seattle/King County. The estimates suggest that 6% of HIV-infected MSM in King County are undiagnosed, about one-third of the comparable national estimate. A sensitivity analysis on the key distributional assumption gives an upper bound of 11%. The undiagnosed fraction varies by race/ethnicity, with estimates of 4.9% among white, 8.6% of African American, and 9.3% of Hispanic HIV-infected MSM being undiagnosed.

Projecting Benefits and Harms of Novel Cancer Screening Biomarkers: A Study of PCA3 and Prostate Cancer.

BACKGROUND: New biomarkers for early detection of cancer must pass through several phases of development. Early phases provide information on diagnostic properties but not on population benefits and harms. Prostate cancer antigen 3 (PCA3) is a promising prostate cancer biomarker still in early development. We use simulation modeling to project the impact of adding PCA3 to prostate-specific antigen (PSA) screening on prostate cancer detection and mortality in the United States. METHODS: We used data from a recent study of PCA3 in men referred for prostate biopsy to extend an existing simulation model of PSA growth, disease progression, and survival. We specified several PSA-PCA3 strategies designed to improve specificity and reduce overdiagnosis. Using these strategies to screen a cohort of men biennially between ages 50 and 74, we projected true- and false-positive tests, overdiagnoses, and lives saved relative to a PSA-based strategy with a cutoff of 4.0 ng/mL for biopsy referral. RESULTS: We identified several PSA-PCA3 strategies that substantially reduced false-positive tests and overdiagnoses while preserving the majority of lives saved. PCA3>35 for biopsy referral in men with PSA between 4.0 and 10.0 ng/mL retained 85% of lives saved while approximately halving false positives and reducing overdiagnoses by 25%. CONCLUSIONS: Adding PCA3 to PSA screening can significantly reduce adverse screening outcomes. Strategies can be identified that preserve most of the lives saved relative to PSA-based screening. IMPACT: Simulation modeling provides advance projections of population outcomes of new screening biomarkers and may help guide early detection research.

Direct estimation of cause-specific mortality fractions from verbal autopsies: multisite validation study using clinical diagnostic gold standards.

BACKGROUND: Verbal autopsy (VA) is used to estimate the causes of death in areas with incomplete vital registration systems. The King and Lu method (KL) for direct estimation of cause-specific mortality fractions (CSMFs) from VA studies is an analysis technique that estimates CSMFs in a population without predicting individual-level cause of death as an intermediate step. In previous studies, KL has shown promise as an alternative to physician-certified verbal autopsy (PCVA). However, it has previously been impossible to validate KL with a large dataset of VAs for which the underlying cause of death is known to meet rigorous clinical diagnostic criteria. METHODS: We applied the KL method to adult, child, and neonatal VA datasets from the Population Health Metrics Research Consortium gold standard verbal autopsy validation study, a multisite sample of 12,542 VAs where gold standard cause of death was established using strict clinical diagnostic criteria. To emulate real-world populations with varying CSMFs, we evaluated the KL estimations for 500 different test datasets of varying cause distribution. We assessed the quality of these estimates in terms of CSMF accuracy as well as linear regression and compared this with the results of PCVA. RESULTS: KL performance is similar to PCVA in terms of CSMF accuracy, attaining values of 0.669, 0.698, and 0.795 for adult, child, and neonatal age groups, respectively, when health care experience (HCE) items were included. We found that the length of the cause list has a dramatic effect on KL estimation quality, with CSMF accuracy decreasing substantially as the length of the cause list increases. We found that KL is not reliant on HCE the way PCVA is, and without HCE, KL outperforms PCVA for all age groups. CONCLUSIONS: Like all computer methods for VA analysis, KL is faster and cheaper than PCVA. Since it is a direct estimation technique, though, it does not produce individual-level predictions. KL estimates are of similar quality to PCVA and slightly better in most cases. Compared to other recently developed methods, however, KL would only be the preferred technique when the cause list is short and individual-level predictions are not needed.

Simplified Symptom Pattern Method for verbal autopsy analysis: multisite validation study using clinical diagnostic gold standards.

BACKGROUND: Verbal autopsy can be a useful tool for generating cause of death data in data-sparse regions around the world. The Symptom Pattern (SP) Method is one promising approach to analyzing verbal autopsy data, but it has not been tested rigorously with gold standard diagnostic criteria. We propose a simplified version of SP and evaluate its performance using verbal autopsy data with accompanying true cause of death. METHODS: We investigated specific parameters in SP's Bayesian framework that allow for its optimal performance in both assigning individual cause of death and in determining cause-specific mortality fractions. We evaluated these outcomes of the method separately for adult, child, and neonatal verbal autopsies in 500 different population constructs of verbal autopsy data to analyze its ability in various settings. RESULTS: We determined that a modified, simpler version of Symptom Pattern (termed Simplified Symptom Pattern, or SSP) performs better than the previously-developed approach. Across 500 samples of verbal autopsy testing data, SSP achieves a median cause-specific mortality fraction accuracy of 0.710 for adults, 0.739 for children, and 0.751 for neonates. In individual cause of death assignment in the same testing environment, SSP achieves 45.8% chance-corrected concordance for adults, 51.5% for children, and 32.5% for neonates. CONCLUSIONS: The Simplified Symptom Pattern Method for verbal autopsy can yield reliable and reasonably accurate results for both individual cause of death assignment and for determining cause-specific mortality fractions. The method demonstrates that verbal autopsies coupled with SSP can be a useful tool for analyzing mortality patterns and determining individual cause of death from verbal autopsy data.