Background Even though we have established a few risk factors for metastatic breast cancer ( MBC ) through epidemiologic studies, these risk factors have not proven to be effective in predicting an individual’s risk of developing metastasis. Therefore, identifying critical risk factors for MBC continues to be a major research imperative, and one which can lead to advances in breast cancer clinical care. The objective of this research is to leverage Bayesian Networks (BN) and information theory to identify key risk factors for breast cancer metastasis from data. Methods We develop the Markov Blanket and Interactive risk factor Learner ( MBIL ) algorithm, which learns single and interactive risk factors having a direct influence on a patient’s outcome. We evaluate the effectiveness of MBIL using simulated datasets, and compare MBIL with the BN learning algorithms Fast Greedy Search ( FGS ), PC algorithm ( PC ), and CPC algorithm ( CPC ). We apply MBIL to learn risk factors for 5 year breast cancer metastasis using a clinical dataset we curated. We evaluate the learned risk factors by consulting with breast cancer experts and literature. We further evaluate the effectiveness of MBIL at learning risk factors for breast cancer metastasis by comparing it to the BN learning algorithms Necessary Path Conditio n ( NPC ) and Greedy Equivalent Search ( GES ). Results The averages of the Jaccard index for the simulated datasets containing 2000 records were 0.705, 0.272, 0.228, and 0.147 for MBIL, FGS, PC, and CPC respectively. MBIL, NPC, and GES all learned that grade and lymph_nodes_positive are direct risk factors for 5 year metastasis. Only MBIL and NPC found that surgical_margins is a direct risk factor. Only NPC found that invasive is a direct risk factor. MBIL learned that HER2 and ER interact to directly affect 5 year metastasis. Neither GES nor NPC learned that HER2 and ER are direct risk factors. Discussion The results involving simulated datasets indicated that MBIL can learn direct risk factors substantially better than standard Bayesian network learning algorithms. An application of MBIL to a real breast cancer dataset identified both single and interactive risk factors that directly influence breast cancer metastasis, which can be investigated further.

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The work of Valentina Palazzi, Paolo Mezzanotte, and Luca Roselli was supported by the Italian Ministry of University and Research (MUR) through the PRIN Project "Development and promotion of the Levulinic acid and Carboxylate platforms by the formulation of novel and advanced PHA-based biomaterials and their exploitation for 3D printed green-electronics applications" under Grant 2017FWC3WC 003. This work did not involve human subjects or animals in its research.

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This paper presents a curvature-compensated sub-1V voltage reference (VR) and a shared-resistive nanoampere current reference (CR) in a 130 nm CMOS process. The CR is used to generate a bipolar junction transistor complementaryto-absolute-temperature voltage, which is summed up with a proportional-to-absolute-temperature voltage generated using a summing network of PMOS gate-coupled pairs. The measured output voltage and current references from 10 chips (V REF and I REF ) at room temperature are 469 mV and 1.86 nA, respectively. The measured average temperature coefficient of V REF and I REF are 29 ppm/ • C and 822 ppm/ • C over a temperature range from −40 • C to 120 • C. The minimum supply voltage of the voltage-current reference is 0.95 V, and the total power consumption is 30 nW.

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