Tim Lustberg

Radiomics: the bridge between medical imaging and personalized medicine

Radiomics, the high-throughput mining of quantitative image features from standard-of-care medical imaging that enables data to be extracted and applied within clinical-decision support systems to improve diagnostic, prognostic, and predictive accuracy, is gaining importance in cancer research. Radiomic analysis exploits sophisticated image analysis tools and the rapid development and validation of medical imaging data that uses image-based signatures for precision diagnosis and treatment, providing a powerful tool in modern medicine. Herein, we describe the process of radiomics, its pitfalls, challenges, opportunities, and its capacity to improve clinical decision making, emphasizing the utility for patients with cancer. Currently, the field of radiomics lacks standardized evaluation of both the scientific integrity and the clinical relevance of the numerous published radiomics investigations resulting from the rapid growth of this area. Rigorous evaluation criteria and reporting guidelines need to be established in order for radiomics to mature as a discipline. Herein, we provide guidance for investigations to meet this urgent need in the field of radiomics.

Decision support systems for personalized and participative radiation oncology.

Abstract A paradigm shift from current population based medicine to personalized and participative medicine is underway. This transition is being supported by the development of clinical decision support systems based on prediction models of treatment outcome. In radiation oncology, these models ‘learn’ using advanced and innovative information technologies (ideally in a distributed fashion — please watch the animation: http://youtu.be/ZDJFOxpwqEA) from all available/appropriate medical data (clinical, treatment, imaging, biological/genetic, etc.) to achieve the highest possible accuracy with respect to prediction of tumor response and normal tissue toxicity. In this position paper, we deliver an overview of the factors that are associated with outcome in radiation oncology and discuss the methodology behind the development of accurate prediction models, which is a multi‐faceted process. Subsequent to initial development/validation and clinical introduction, decision support systems should be constantly re‐evaluated (through quality assurance procedures) in different patient datasets in order to refine and re‐optimize the models, ensuring the continuous utility of the models. In the reasonably near future, decision support systems will be fully integrated within the clinic, with data and knowledge being shared in a standardized, dynamic, and potentially global manner enabling truly personalized and participative medicine. Graphical abstract Figure. No caption available.

Development and evaluation of an online three-level proton vs photon decision support prototype for head and neck cancer – Comparison of dose, toxicity and cost-effectiveness

To quantitatively assess the effectiveness of proton therapy for individual patients, we developed a prototype for an online platform for proton decision support (PRODECIS) comparing photon and proton treatments on dose metric, toxicity and cost-effectiveness levels. An evaluation was performed with 23 head and neck cancer datasets.

Interfractional trend analysis of dose differences based on 2D transit portal dosimetry

Dose delivery of a radiotherapy treatment can be influenced by a number of factors. It has been demonstrated that the electronic portal imaging device (EPID) is valuable for transit portal dosimetry verification. Patient related dose differences can emerge at any time during treatment and can be categorized in two types: (1) systematic-appearing repeatedly, (2) random-appearing sporadically during treatment. The aim of this study is to investigate how systematic and random information appears in 2D transit dose distributions measured in the EPID plane over the entire course of a treatment and how this information can be used to examine interfractional trends, building toward a methodology to support adaptive radiotherapy. To create a trend overview of the interfractional changes in transit dose, the predicted portal dose for the different beams is compared to a measured portal dose using a γ evaluation. For each beam of the delivered fraction, information is extracted from the γ images to differentiate systematic from random dose delivery errors. From the systematic differences of a fraction for a projected anatomical structures, several metrics are extracted like percentage pixels with |γ| > 1. We demonstrate for four example cases the trends and dose difference causes which can be detected with this method. Two sample prostate cases show the occurrence of a random and systematic difference and identify the organ that causes the difference. In a lung cancer case a trend is shown of a rapidly diminishing atelectasis (lung fluid) during the course of treatment, which was detected with this trend analysis method. The final example is a breast cancer case where we show the influence of set-up differences on the 2D transit dose. A method is presented based on 2D portal transit dosimetry to record dose changes throughout the course of treatment, and to allow trend analysis of dose discrepancies. We show in example cases that this method can identify the causes of dose delivery differences and that treatment adaptation can be triggered as a result. It provides an important element toward informed decision-making for adaptive radiotherapy.

Measured vs simulated portal images for low MU fields on three accelerator types: Possible consequences for 2D portal dosimetry

PURPOSE As external beam treatment plans become more dynamic and the dose to normal tissue is further constrained, treatments may consist of a larger number of beams, each delivering smaller doses (or monitor units, MU), in, e.g., volumetric modulated arc therapy (VMAT). Electronic portal imaging devices (EPID) may be used to verify external beam treatments on integrated fractions as well as in a more time dependent manner such as field by field. For treatment verification performed during a fraction (e.g., individual fields or VMAT control points), the lower limit of EPID measurement capability becomes important. The authors quantified the signal and timing accuracy of EPID images for low MU intensity modulated radiotherapy (IMRT) and conformal fields. METHODS EPID images were collected from three different vendors accelerators for low MU fields and compared to expected images. Simulations were performed to replicate the EPID acquisition pattern and to enhance the understanding of EPID readout schemes. RESULTS Large discrepancies between observed and predicted images were noted due to an under-response to single low MU fields. It is shown that a variability of up to 37% can be observed for low MU fields in clinically used EPID acquisition modes and that the majority of this variability can be accounted for by the readout scheme, integration, and timing of EPID acquisitions. Simulations have confirmed the causes of the discrepancies. The occurrence and extent of the variation has been estimated for clinical settings. CONCLUSIONS Incorrect absolute EPID signals collected for low MU fields in external beam treatments will negatively affect quantitative applications such as individual field based EPID dosimetry, typically appearing as an underdose, unless corrections to currently employed EPID readout schemes are made.

Clinical evaluation of atlas and deep learning based automatic contouring for lung cancer

BACKGROUND AND PURPOSE Contouring of organs at risk (OARs) is an important but time consuming part of radiotherapy treatment planning. The aim of this study was to investigate whether using institutional created software-generated contouring will save time if used as a starting point for manual OAR contouring for lung cancer patients. MATERIAL AND METHODS Twenty CT scans of stage I-III NSCLC patients were used to compare user adjusted contours after an atlas-based and deep learning contour, against manual delineation. The lungs, esophagus, spinal cord, heart and mediastinum were contoured for this study. The time to perform the manual tasks was recorded. RESULTS With a median time of 20 min for manual contouring, the total median time saved was 7.8 min when using atlas-based contouring and 10 min for deep learning contouring. Both atlas based and deep learning adjustment times were significantly lower than manual contouring time for all OARs except for the left lung and esophagus of the atlas based contouring. CONCLUSIONS User adjustment of software generated contours is a viable strategy to reduce contouring time of OARs for lung radiotherapy while conforming to local clinical standards. In addition, deep learning contouring shows promising results compared to existing solutions.

Machine learning algorithms for outcome prediction in (chemo)radiotherapy: An empirical comparison of classifiers

Purpose Machine learning classification algorithms (classifiers) for prediction of treatment response are becoming more popular in radiotherapy literature. General Machine learning literature provides evidence in favor of some classifier families (random forest, support vector machine, gradient boosting) in terms of classification performance. The purpose of this study is to compare such classifiers specifically for (chemo)radiotherapy datasets and to estimate their average discriminative performance for radiation treatment outcome prediction. Methods We collected 12 datasets (3496 patients) from prior studies on post‐(chemo)radiotherapy toxicity, survival, or tumor control with clinical, dosimetric, or blood biomarker features from multiple institutions and for different tumor sites, that is, (non‐)small‐cell lung cancer, head and neck cancer, and meningioma. Six common classification algorithms with built‐in feature selection (decision tree, random forest, neural network, support vector machine, elastic net logistic regression, LogitBoost) were applied on each dataset using the popular open‐source R package caret. The R code and documentation for the analysis are available online (https://github.com/timodeist/classifier_selection_code). All classifiers were run on each dataset in a 100‐repeated nested fivefold cross‐validation with hyperparameter tuning. Performance metrics (AUC, calibration slope and intercept, accuracy, Cohens kappa, and Brier score) were computed. We ranked classifiers by AUC to determine which classifier is likely to also perform well in future studies. We simulated the benefit for potential investigators to select a certain classifier for a new dataset based on our study (pre‐selection based on other datasets) or estimating the best classifier for a dataset (set‐specific selection based on information from the new dataset) compared with uninformed classifier selection (random selection). Results Random forest (best in 6/12 datasets) and elastic net logistic regression (best in 4/12 datasets) showed the overall best discrimination, but there was no single best classifier across datasets. Both classifiers had a median AUC rank of 2. Preselection and set‐specific selection yielded a significant average AUC improvement of 0.02 and 0.02 over random selection with an average AUC rank improvement of 0.42 and 0.66, respectively. Conclusion Random forest and elastic net logistic regression yield higher discriminative performance in (chemo)radiotherapy outcome and toxicity prediction than other studied classifiers. Thus, one of these two classifiers should be the first choice for investigators when building classification models or to benchmark ones own modeling results against. Our results also show that an informed preselection of classifiers based on existing datasets can improve discrimination over random selection.

Big Data in radiation therapy: challenges and opportunities

Data collected and generated by radiation oncology can be classified by the Volume, Variety, Velocity and Veracity (4Vs) of Big Data because they are spread across different care providers and not easily shared owing to patient privacy protection. The magnitude of the 4Vs is substantial in oncology, especially owing to imaging modalities and unclear data definitions. To create useful models ideally all data of all care providers are understood and learned from; however, this presents challenges in the guise of poor data quality, patient privacy concerns, geographical spread, interoperability and large volume. In radiation oncology, there are many efforts to collect data for research and innovation purposes. Clinical trials are the gold standard when proving any hypothesis that directly affects the patient. Collecting data in registries with strict predefined rules is also a common approach to find answers. A third approach is to develop data stores that can be used by modern machine learning techniques to provide new insights or answer hypotheses. We believe all three approaches have their strengths and weaknesses, but they should all strive to create Findable, Accessible, Interoperable, Reusable (FAIR) data. To learn from these data, we need distributed learning techniques, sending machine learning algorithms to FAIR data stores around the world, learning from trial data, registries and routine clinical data rather than trying to centralize all data. To improve and personalize medicine, rapid learning platforms must be able to process FAIR “Big Data” to evaluate current clinical practice and to guide further innovation.

Implementation of a rapid learning platform: Predicting 2-year survival in laryngeal carcinoma patients in a clinical setting

Background and Purpose To improve quality and personalization of oncology health care, decision aid tools are needed to advise physicians and patients. The aim of this work is to demonstrate the clinical relevance of a survival prediction model as a first step to multi institutional rapid learning and compare this to a clinical trial dataset. Materials and Methods Data extraction and mining tools were used to collect uncurated input parameters from Illawarra Cancer Care Centres (clinical cohort) oncology information system. Prognosis categories previously established from the Maastricht Radiation Oncology (training cohort) dataset, were applied to the clinical cohort and the radiotherapy only arm of the RTOG-9111 (trial cohort). Results Data mining identified 125 laryngeal carcinoma patients, ending up with 52 patients in the clinical cohort who were eligible to be evaluated by the model to predict 2-year survival and 177 for the trial cohort. The model was able to classify patients and predict survival in the clinical cohort, but for the trial cohort it failed to do so. Conclusions The technical infrastructure and model is able to support the prognosis prediction of laryngeal carcinoma patients in a clinical cohort. The model does not perform well for the highly selective patient population in the trial cohort.

Towards a semantic PACS : Using Semantic Web technology to represent imaging data

The DICOM standard is ubiquitous within medicine. However, improved DICOM semantics would significantly enhance search operations. Furthermore, databases of current PACS systems are not flexible enough for the demands within image analysis research. In this paper, we investigated if we can use Semantic Web technology, to store and represent metadata of DICOM image files, as well as linking additional computational results to image metadata. Therefore, we developed a proof of concept containing two applications: one to store commonly used DICOM metadata in an RDF repository, and one to calculate imaging biomarkers based on DICOM images, and store the biomarker values in an RDF repository. This enabled us to search for all patients with a gross tumor volume calculated to be larger than 50 cc. We have shown that we can successfully store the DICOM metadata in an RDF repository and are refining our proof of concept with regards to volume naming, value representation, and the applications themselves.