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Additional file1 Supplemental Fig. S1 Diagram of the proposed methodology for the detection and BI-RADS classification of breast microcalcifications using temporal subtraction of sequential mammograms. Supplemental Table S1 Features selected for the 1st and 2nd round of BI-RADS classification using temporal subtraction and only the most recent mammograms. Supplemental Fig. S2 Results of the classification of the radiologically true microcalcifications as BI-RADS benign or suspicious in the most recent mammographic view of a woman (BI-RADS breast density class b). (a) Most recent mammographic view, with green circles around the BI-RADS benign microcalcifications, and a red circle around the BI-RADS suspicious microcalcifications. (b) Zoomed view of the red square in a with BI-RADS suspicious microcalcifications. (c) Zoomed view of the green square in a with BI-RADS benign microcalcifications. Supplemental Table S2 Comparison of accuracy and AUC of different state-of-the-art techniques for the classification of benign versus malignant microcalcifications [36–40].

In Optical Coherence tomography (OCT), dispersion mismatches cause degradation of the image resolution and are, thus, compensated accordingly. However, dispersion is specific to the material that is causing the effect and can, therefore, carry useful information regarding the composition of the samples. In this summary, we propose a novel technique for estimating tissue dispersion by calculating the cross-correlation of images acquired at different center wavelengths to estimate the shift between their features, also known as walk-off, and use that to calculate the dispersion. Since a distinct reflector is not required, this method is applicable to any sample and can even be implemented in vivo and in situ in human tissues. The proposed technique was verified ex vivo resulting in Group Velocity Dispersion (GVD) values comparable to those obtained from estimating the walk-off from a mirror, as described in the literature. The applicability to cancer diagnosis was evaluated on a small set of gastrointestinal normal and cancer OCT images. Using the statistics of the GVD estimates, tissue classification resulted in 100% sensitivity and 81% specificity (92% correct classification rate). The success of these preliminary results indicates the potential of the proposed method, which should be further investigated to elucidate its advantages and limitations. 10867

Precision medicine promises better healthcare delivery by improving clinical practice. Using evidence-based substratification of patients, the objective is to achieve better prognosis, diagnosis, and treatment that will transform existing clinical pathways toward optimizing care for the specific needs of each patient. The wealth of today's healthcare data, often characterized as big data, provides invaluable resources toward new knowledge discovery that has the potential to advance precision medicine. The latter requires interdisciplinary efforts that will capitalize the information, know-how, and medical data of newly formed groups fusing different backgrounds and expertise. The objective of this paper is to provide insights with respect to the state-of-the-art research in precision medicine. More specifically, our goal is to highlight the fundamental challenges in emerging fields of radiomics and radiogenomics by reviewing the case studies of Cancer and Alzheimer's disease, describe the computational challenges from a big data analytics perspective, and discuss standardization and open data initiatives that will facilitate the adoption of precision medicine methods and practices. 23 5 2063 2079

The epidermal growth factor receptor (EGFR) is a key target in anticancer research, whose aberrant function in malignancies has been linked to severe irregularities in critical cellular processes, including cell cycle progression, proliferation, differentiation, and survival. EGFR mutant variants, either transmembrane or translocated to the mitochondria and/or the nucleus, often exhibit resistance to EGFR inhibitors. The ability to noninvasively image and quantify EGFR provides novel approaches in the detection, monitoring, and treatment of EGFR-related malignancies. The current study aimed to deliver a new theranostic agent that combines fluorescence imaging properties with EGFR inhibition. This was achieved via conjugation of an in-house-developed ((4-bromophenyl)amino)quinazoline inhibitor of mutant EGFR-TK, selected from a focused aminoquinazoline library, with a [Ru(bipyridine)3]2+ fluorophore. A triethyleneglycol-derived diamino linker featuring (+)-ionizable sites was employed to link the two functional moieties, affording two unprecedented Ru conjugates with 1:1 and 2:1 stoichiometry of aminoquinazoline to the Ru complex (mono-quinazoline-Ru-conjugate and bis-quinazoline-Ru-conjugate, respectively). The bis-quinazoline-Ru-conjugate, which retains an essential inhibitory activity, was found by fluorescence imaging to be effectively uptaken by Uppsala 87 malignant glioma (grade IV malignant glioma) cells. The fluorescence imaging study and a time-resolved fluorescence resonance energy transfer study indicated a specific subcellular distribution of the conjugate that coincides with that of a mitochondria-targeted dye, suggesting mitochondrial localization of the conjugate and potential association with mitochondria-translocated forms of EGFR. Mitochondrial localization was further documented by the specific concentration of the bis-quinazoline-Ru-conjugate in a mitochondrial isolation assay. 16 10 4260 4273

Catheter-based Optical Coherence Tomography (OCT) devices allow real-time and comprehensive imaging of the human esophagus. Hence, they provide the potential to overcome some of the limitations of endoscopy and biopsy, allowing earlier diagnosis and better prognosis for esophageal adenocarcinoma patients. However, the large number of images produced during every scan makes manual evaluation of the data exceedingly difficult. In this study, we propose a fully automated tissue characterization algorithm, capable of discriminating normal tissue from Barrett’s Esophagus (BE) and dysplasia through entire three-dimensional (3D) data sets, acquired in vivo. The method is based on both the estimation of the scatterer size of the esophageal epithelial cells, using the bandwidth of the correlation of the derivative (COD) method, as well as intensity-based characteristics. The COD method can effectively estimate the scatterer size of the esophageal epithelium cells in good agreement with the literature. As expected, both the mean scatterer size and its standard deviation increase with increasing severity of disease (i.e. from normal to BE to dysplasia). The differences in the distribution of scatterer size for each tissue type are statistically significant, with a p value of &lt 0.0001. However, the scatterer size by itself cannot be used to accurately classify the various tissues. With the addition of intensity-based statistics the correct classification rates for all three tissue types range from 83 to 100% depending on the lesion size. 10483

Dispersion mismatch between the two arms of an Optical Coherence Tomography (OCT) interferometer causes degradation of the image resolution. However, dispersion in tissue is specific to the chemical constituents of the cells and can therefore carry diagnostically useful information. Unfortunately, dispersion measurement techniques, presented so far in the literature, require the presence of strong distinct reflections in the OCT image which are rarely present when imaging tissues in vivo. The novel method presented here relies on the image speckle to calculate the PSF degradation and is therefore applicable to any tissue and can be implemented in vivo and in situ. The resolution degradation is estimated using a Wiener-type deconvolution and was verified ex vivo resulting in Group Velocity Dispersion (GVD) values comparable to the standard techniques. This technique has also been applied to normal and malignant samples of human colon to evaluate its applicability for cancer diagnosis. Using the statistics of the GVD estimate, the tissue classification resulted in 93% sensitivity and 100% specificity (96% correct classification rate). The success of these preliminary results indicates the potential of the proposed method which should be further.

Dispersion, a result of wavelength-dependent index of refraction variations, causes pulse-width broadening with detrimental effects in many pulsed-laser applications. It is also considered to be one of the major causes of resolution degradation in Optical Coherence Tomography (OCT). However, dispersion is material dependent and, in tissue, Group Velocity Dispersion (GVD) could be used, for example, to detect changes associated with early cancer and result in more accurate disease diagnosis. In this summary we compare different techniques for estimating the GVD from OCT images, in order to evaluate their accuracy and applicability in highly scattering samples such as muscle and adipose tissue. The methods investigated included estimation of the GVD from (i) the point spread function (PSF) degradation, (ii) the shift (walk-off) between images taken at different center wavelengths and (iii) the second derivative of the spectral phase. The measurements were degraded by the presence of strong Mie scattering and speckle noise with the most robust being the PSF degradation and the least robust the phase derivative method. If the GVD is to be used to provide sensitive diagnostic information from highly scattering human tissues, it would be preferable to use the resolution degradation as an estimator of GVD.

Dispersion, resulting from wavelength-dependent index of refraction variations, could be used to detect changes associated with cancer for early and accurate diagnosis. Different techniques for estimating the dispersion from Optical Coherence Tomography (OCT) images were investigated to evaluate their accuracy and applicability to samples such as muscle and adipose tissue. The dispersion was estimated from (i) the point spread function (PSF) degradation, (ii) the shift (walk-off) between images taken at different center wavelengths and (iii) the second derivative of the spectral phase. A novel technique, which uses a Wiener-type deconvolution algorithm to calculate the PSF degradation from the image speckle and is, therefore, applicable in vivo and in situ is also presented. This method was applied to a set of normal and cancer gastrointestinal OCT images resulting in 93% sensitivity and 73% specificity. The success of these preliminary results indicates the potential of using dispersion measurements for disease diagnosis.

In Optical Coherence tomography (OCT), dispersion mismatches cause degradation of the image resolution. However, dispersion is specific to the material that is causing the effect and can therefore carry useful information regarding the composition of the samples. In this summary, we propose a novel technique for estimating the dispersion in tissue which uses the image speckle to calculate the PSF degradation and is therefore applicable to any tissue and can be implemented in vivo and in situ. A Wiener-type deconvolution algorithm was used to estimate the image PSF degradation from the speckle. The proposed method was verified ex vivo resulting in comparable values of the Group Velocity Dispersion (GVD) as obtained by a standard estimation technique described in the literature. The applicability to cancer diagnosis was evaluated on a small set of gastrointestinal normal and cancer OCT images. Using the statistics of the GVD estimate, the tissue classification resulted in 93% sensitivity and 73% specificity (84% correct classification rate). The success of these preliminary results indicates the potential of the proposed method which should be further investigated to elucidate its advantages and limitations.

Urinary Tract Infections (UTIs) are some of the most common bacterial diseases, especially in women, resulting in millions of hospital visits and a cost of 1.6 billion dollars every year in the US alone. Currently, diagnosis is performed with two sequential urine cultures, for species identification and antibiotic susceptibility testing, which require a total of 48 hrs. The limitations of the current scheme can be overcome by the development of a Surface Enhanced Raman Spectroscopy (SERS) based diagnostic. The proposed technology can: (i) identify the presence of bacteria (correctly quantifies the concentration and specifies the bacteurimic samples), (ii) classify the causative bacteria (∼94% correct classification), and (iii) determine the sensitivity of the bacteria to various antibiotics (81–100% correct classification depending on the antibiotic). These results demonstrate that SERS can be used for complete, fast, accurate, and inexpensive POCT for urinary tract and other bacterial infections.

The index of refraction (n) of materials and/or tissues depends on their physical properties and serves as a source of optical contrast in imaging. The variations of the index of refraction have also been investigated for diagnostic purposes in various fields, such as hematology, oncology, etc., since they can signify disease and cell dynamic changes. Optical coherence tomography (OCT) has been used in the past to measure the index ex vivo. However, most methodologies described in the literature are not appropriate for in vivo imaging since they require either a mirror below the sample or a complicated imaging setup and algorithms. We describe a technique that uses two images, obtained at different angles, to estimate the index of refraction and can, thus, also be applied in vivo. The index of refraction is calculated from the path-length difference observed by the OCT beam at the two different angles. When a reflector is not available, the path-length difference can be estimated using image registration and the cross-correlation of adjacent A-scans. The proposed technique was validated experimentally using both clear and scattering samples. The resulting values of the index of refraction were within ∼1% of the expected. The main limitation of this technique is the effect of misalignment on the results, requiring the precision provided by an angular-resolved OCT system. These very promising results provide evidence that the dual-angle method should be further investigated and validated on human tissues so that it can be developed into a clinically useful diagnostic tool in the future.