Background Radiomic features may quantify characteristics present in medical imaging. However, the lack of standardized definitions and validated reference values have hampered clinical use. Purpose To standardize a set of 174 radiomic features. Materials and Methods Radiomic features were assessed in three phases. In phase I, 487 features were derived from the basic set of 174 features. Twenty-five research teams with unique radiomics software implementations computed feature values directly from a digital phantom, without any additional image processing. In phase II, 15 teams computed values for 1347 derived features using a CT image of a patient with lung cancer and predefined image processing configurations. In both phases, consensus among the teams on the validity of tentative reference values was measured through the frequency of the modal value and classified as follows: less than three matches, weak; three to five matches, moderate; six to nine matches, strong; 10 or more matches, very strong. In the final phase (phase III), a public data set of multimodality images (CT, fluorine 18 fluorodeoxyglucose PET, and T1-weighted MRI) from 51 patients with soft-tissue sarcoma was used to prospectively assess reproducibility of standardized features. Results Consensus on reference values was initially weak for 232 of 302 features (76.8%) at phase I and 703 of 1075 features (65.4%) at phase II. At the final iteration, weak consensus remained for only two of 487 features (0.4%) at phase I and 19 of 1347 features (1.4%) at phase II. Strong or better consensus was achieved for 463 of 487 features (95.1%) at phase I and 1220 of 1347 features (90.6%) at phase II. Overall, 169 of 174 features were standardized in the first two phases. In the final validation phase (phase III), most of the 169 standardized features could be excellently reproduced (166 with CT; 164 with PET; and 164 with MRI). Conclusion A set of 169 radiomics features was standardized, which enabled verification and calibration of different radiomics software. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Kuhl and Truhn in this issue.

https://pubs.rsna.org/doi/pdf/10.1148/radiol.2020191145

The Image Biomarker Standardization Initiative: Standardized Quantitative Radiomics for High-Throughput Image-based Phenotyping

A large data set containing coincident in situ chlorophyll and remote sensing reflectance measurements was used to evaluate the accuracy, precision, and suitability of a wide variety of ocean color chlorophyll algorithms for use by SeaWiFS (Sea-viewing Wide Field-of-view Sensor). The radiance-chlorophyll data were assembled from various sources during the SeaWiFS Bio-optical Algorithm Mini-Workshop (SeaBAM) and is composed of 919 stations encompassing chlorophyll concentrations between 0.019 and 32.79 μg L−1. Most of the observations are from Case I nonpolar waters, and ∼20 observations are from more turbid coastal waters. A variety of statistical and graphical criteria were used to evaluate the performances of 2 semianalytic and 15 empirical chlorophyll/pigment algorithms subjected to the SeaBAM data. The empirical algorithms generally performed better than the semianalytic. Cubic polynomial formulations were generally superior to other kinds of equations. Empirical algorithms with increasing complexity (number of coefficients and wavebands), were calibrated to the SeaBAM data, and evaluated to illustrate the relative merits of different formulations. The ocean chlorophyll 2 algorithm (OC2), a modified cubic polynomial (MCP) function which uses Rrs490/Rrs555, well simulates the sigmoidal pattern evident between log-transformed radiance ratios and chlorophyll, and has been chosen as the at-launch SeaWiFS operational chlorophyll a algorithm. Improved performance was obtained using the ocean chlorophyll 4 algorithm (OC4), a four-band (443, 490, 510, 555 nm), maximum band ratio formulation. This maximum band ratio (MBR) is a new approach in empirical ocean color algorithms and has the potential advantage of maintaining the highest possible satellite sensor signal: noise ratio over a 3-orders-of-magnitude range in chlorophyll concentration.

/pdf/ocean-color-chlorophyll-algorithms-for-seawifs-68regm2asj.pdf

Ocean Color Chlorophyll Algorithms for SEAWIFS

Purpose
This article provides working definitions and a conceptual framework to understand the roles of biomarkers in clinical research.

What are biomarkers

During the past decade, a conceptual shift occurred in the field of Alzheimer's disease (AD) considering the disease as a continuum. Thanks to evolving biomarker research and substantial discoveries, it is now possible to identify the disease even at the preclinical stage before the occurrence of the first clinical symptoms. This preclinical stage of AD has become a major research focus as the field postulates that early intervention may offer the best chance of therapeutic success. To date, very little evidence is established on this "silent" stage of the disease. A clarification is needed about the definitions and lexicon, the limits, the natural history, the markers of progression, and the ethical consequence of detecting the disease at this asymptomatic stage. This article is aimed at addressing all the different issues by providing for each of them an updated review of the literature and evidence, with practical recommendations.

/pdf/preclinical-alzheimer-s-disease-definition-natural-history-1op128x94m.pdf

Preclinical Alzheimer's disease: Definition, natural history, and diagnostic criteria.

According to Genome Sequencing Project statistics (http://www.ncbi.nlm.nih.gov/genomes/static/gpstat.html), as of Feb 16, 2012, complete gene sequences have become available for 2816 viruses, 1117 prokaryotes, and 36 eukaryotes.1–2 The availability of full genome sequences has greatly facilitated biological research in many fields, and has greatly contributed to the growth of proteomics.

Proteins are important because they are the direct bio-functional molecules in the living organisms. The term “proteomics” was coined from merging “protein” and “genomics” in the 1990s.3–4 As a post-genomic discipline, proteomics encompasses efforts to identify and quantify all the proteins of a proteome, including expression, cellular localization, interactions, post-translational modifications (PTMs), and turnover as a function of time, space and cell type, thus making the full investigation of a proteome more challenging than sequencing a genome. There are possibly 100,000 protein forms encoded by the approximate 20,235 genes of the human genome,5 and determining the explicit function of each form will be a challenge.

The progress of proteomics has been driven by the development of new technologies for peptide/protein separation, mass spectrometry analysis, isotope labeling for quantification, and bioinformatics data analysis. Mass spectrometry has emerged as a core tool for large-scale protein analysis. In the past decade, there has been a rapid advance in the resolution, mass accuracy, sensitivity and scan rate of mass spectrometers used to analyze proteins. In addition, hybrid mass analyzers have been introduced recently (e.g. Linear Ion Trap-Orbitrap series6–7) which have significantly improved proteomic analysis.

“Bottom-up” protein analysis refers to the characterization of proteins by analysis of peptides released from the protein through proteolysis. When bottom-up is performed on a mixture of proteins it is called shotgun proteomics,8–10 a name coined by the Yates lab because of its analogy to shotgun genomic sequencing.11 Shotgun proteomics provides an indirect measurement of proteins through peptides derived from proteolytic digestion of intact proteins. In a typical shotgun proteomics experiment, the peptide mixture is fractionated and subjected to LC-MS/MS analysis. Peptide identification is achieved by comparing the tandem mass spectra derived from peptide fragmentation with theoretical tandem mass spectra generated from in silico digestion of a protein database. Protein inference is accomplished by assigning peptide sequences to proteins. Because peptides can be either uniquely assigned to a single protein or shared by more than one protein, the identified proteins may be further scored and grouped based on their peptides. In contrast, another strategy, termed ‘top-down’ proteomics, is used to characterize intact proteins (Figure 1). The top-down approach has some potential advantages for PTM and protein isoform determination and has achieved notable success. Intact proteins have been measured up to 200 kDa,12 and a large scale study has identified more than 1,000 proteins by multi-dimensional separations from complex samples.13 However, the top-down method has significant limitations compared with shotgun proteomics due to difficulties with protein fractionation, protein ionization and fragmentation in the gas phase. By relying on the analysis of peptides, which are more easily fractionated, ionized and fragmented, shotgun proteomics can be more universally adopted for protein analysis. In fact, a hybrid of bottom-up and top-down methodologies and instrumentation has been introduced as middle-down proteomics.14 Essentially, middle-down proteomics analyzes larger peptide fragments than bottom-up proteomics, minimizing peptide redundancy between proteins. Additionally the large peptide fragments yield similar advantages as top-down proteomics, such as gaining further insight into post-translational modifications, without the analytical challenges of analyzing intact proteins. Shotgun proteomics has become a workhorse for the analysis of proteins and their modifications and will be increasingly combined with top-down methods in the future.



Figure 1

Proteomic strategies: bottom-up vs. top-down vs. middle-down. The bottom-up approach analyzes proteolytic peptides. The top-down method measures the intact proteins. The middle-down strategy analyzes larger peptides resulted from limited digestion or ...



In the past decade shotgun proteomics has been widely used by biologists for many different research experiments, advancing biological discoveries. Some applications include, but are not limited to, proteome profiling, protein quantification, protein modification, and protein-protein interaction. There have been several reviews nicely summarizing mass spectrometry history,15 protein quantification with mass spectrometry,16 its biological applications,5,17–26 and many recent advances in methodology.27–32 In this review, we try to provide a full and updated survey of shotgun proteomics, including the fundamental techniques and applications that laid the foundation along with those developed and greatly improved in the past several years.

Protein Analysis by Shotgun/Bottom-up Proteomics

genome are dramatically reshaping the research and development pathways for drugs, vaccines, and diagnostics. The growth in the number of molecular entities entering the drug development pipeline has accelerated as a consequence of powerful discovery and screening technologies such as combinatorial chemistry, mass spectrometry, high throughput screening, celland tissue-based DNA microarrays, and proteomic approaches.1 As a consequence, there is an escalating number of therapeutic candidates, which has caused the need for new technologies and strategies to streamline the process to make safe and effective therapies available to patients. One approach to the achievement of more expeditious and informative therapeutic research is the use of precise clinical measurement tools to determine disease progression and the effects of interventions (drugs, surgery, and vaccines). For example, gene-based approaches such as single nucleotide polymorphism maps are now being developed to distinguish the molecular and cellular basis for variations in clinical response to therapy.2 Another approach is the use of a wide array of analytical tools to assess biological parameters, which are referred to as biomarkers. Biomarker measurements can help explain empirical results of clinical trials by relating the effects of interventions on molecular and cellular pathways to clinical responses. In doing so, biomarkers provide an avenue for researchers to gain a mechanistic understanding of the differences in clinical response that may be influenced by uncontrolled variables (for example, drug metabolism). There are a variety of ways that biomarker measurements can aid in the development and evaluation of COMMENTARY

Biomarkers and surrogate endpoints: Preferred definitions and conceptual framework*

Pharmacokinetics of multiple oral doses of selected polychlorinated biphenyls in mice.

A computer method has been investigated to differentiate the prenephrotoxic patient from the nontoxic patient by routine monitoring of serum gentamicin concentrations duringtherapy, without the need to discontinue medication. The method deliberately assumes an incorreect pharmacokinetic model and uses a nonlinear regression program to analyze data collected during continuous dosing. In principle, it appears that the prenephrotoxic patients may be identified on the basis of a decreasing “apparent” elimination rate constant of gentamicin during continuous therapy.

A model for the prospective identification of the prenephrotoxic state during gentamicin therapy

Pharmacokinetics in the interpretation of chronic toxicity tests: the last-in, first-out phenomenon.

Absorption of saccharin from rat urinary bladder.

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