High-dimensional randomization-based inference capitalizing on classical design and modern computing.

A common complication that can arise with analyses of high-dimensional data is the repeated use of hypothesis tests. A second complication, especially with small samples, is the reliance on asymptotic p-values. Our proposed approach for addressing both complications uses a scientifically motivated scalar summary statistic, and although not entirely novel, seems rarely used. The method is illustrated using a crossover study of seventeen participants examining the effect of exposure to ozone versus clean air on the DNA methylome, where the multivariate outcome involved 484,531 genomic locations. Our proposed test yields a single null randomization distribution, and thus a single Fisher-exact p-value that is statistically valid whatever the structure of the data. However, the relevance and power of the resultant test requires the careful a priori selection of a single test statistic. The common practice using asymptotic p-values or meaningless thresholds for "significance" is inapposite in general.

Laser produced soft x-ray source diagnostics with temporal, spectral, and spatial resolution.

We demonstrate the use of three diagnostic tools which simultaneously view the target from nearly the same direction, and their results are combined to provide temporally, spectrally, and spatially resolved absolutely calibrated target emission information. To demonstrate this capability, Au targets were irradiated by 1.8 kJ, 3 ns laser pulses to produce broadband soft x-ray emission in the 0.1-3.5 keV spectral range. Target diagnostics included a time-resolved x-ray diode array, each measured a partial spectral band, time-integrated spectrally resolved absolutely calibrated transmission grating spectrometer, and static and time-resolved soft x-ray imagers coupled to a charge-coupled device camera and to a streak camera, respectively, measuring spatially and temporally resolved radiation at the main Au target emission bands. The combined temporally, spectrally, and spatially resolved absolutely calibrated target emission result can be compared to simulations and be used to design and analyze experiments in which the source emission is used as a drive for various physical processes.

The importance of having a conceptual stage when reporting non-randomized studies.

Formal guidelines for statistical reporting of non-randomized studies are important for journals that publish results of such studies. Although it is gratifying to see some journals providing guidelines for statistical reporting, we feel that the current guidelines that we have seen are not entirely adequate when the study is used to draw causal conclusions. We therefore offer some comments on ways to improve these studies. In particular, we discuss and illustrate what we regard as the need for an essential initial stage of any such statistical analysis, the conceptual stage, which formally describes the embedding of a non-randomized study within a hypothetical randomized experiment.

Time-dependent soft and hard x-ray measurements using streak and x-ray diode array diagnostic systems.

High-temperature, high-density experiments require a simultaneous understanding of temporal and spectral regions. The spectral x-ray streak camera (SXSC) is a new high-temporal-resolution spectral x-ray diagnostic system that allows researchers to differentiate between soft and hard x-ray regions. The diagnostic offers three spectral channels with a wide spectral range, one direct channel that includes a filter and two indirect channels that include both mirrors and filters. The opto-mechanical design positions the filtered radiation at three different locations along the streak photo-cathode (PC) slit to provide time-dependent spectral channels with pico-second temporal resolution. A moderate spatial resolution (150-700 µm) is achieved using slits perpendicular to the PC slit, while the slit width is optimized according to the central channel wavelength (for each channel). The diagnostic system covers a spectral range of 30-500 eV for the mirror channels and >1300 eV for the direct channel. The temporal and spatial axes of the streak camera are calibrated with respect to a sequence of x-ray pulses. The SXSC diagnostic system is tested and analyzed using Marshak-wave emission from an SiO2 foam that was heated by a laser-beam irradiated halfraum. The SXSC results are compared to measurements from an x-ray diode array with similar spectral channels.

Challenges and opportunities for artificial intelligence in oncological imaging.

Imaging plays a key role in oncology, including the diagnosis and detection of cancer, determining clinical management, assessing treatment response, and complications of treatment or disease. The current use of clinical oncology is predominantly qualitative in nature with some relatively crude size-based measurements of tumours for assessment of disease progression or treatment response; however, it is increasingly understood that there may be significantly more information about oncological disease that can be obtained from imaging that is not currently utilized. Artificial intelligence (AI) has the potential to harness quantitative techniques to improve oncological imaging. These may include improving the efficiency or accuracy of traditional roles of imaging such as diagnosis or detection. These may also include new roles for imaging such as risk-stratifying patients for different types of therapy or determining biological tumour subtypes. This review article outlines several major areas in oncological imaging where there may be opportunities for AI technology. These include (1) screening and detection of cancer, (2) diagnosis and risk stratification, (3) tumour segmentation, (4) precision oncology, and (5) predicting prognosis and assessing treatment response. This review will also address some of the potential barriers to AI research in oncological imaging.

Deep learning enables the automation of grading histological tissue engineered cartilage images for quality control standardization.

OBJECTIVE: To automate the grading of histological images of engineered cartilage tissues using deep learning. METHODS: Cartilaginous tissues were engineered from various cell sources. Safranin O and fast green stained histological images of the tissues were graded for chondrogenic quality according to the Modified Bern Score, which ranks images on a scale from zero to six according to the intensity of staining and cell morphology. The whole images were tiled, and the tiles were graded by two experts and grouped into four categories with the following grades: 0, 1-2, 3-4, and 5-6. Deep learning was used to train models to classify images into these histological score groups. Finally, the tile grades per donor were averaged. The root mean square errors (RMSEs) were calculated between each user and the model. RESULTS: Transfer learning using a pretrained DenseNet model was selected. The RMSEs of the model predictions and 95% confidence intervals were 0.49 (0.37, 0.61) and 0.78 (0.57, 0.99) for each user, which was in the same range as the inter-user RMSE of 0.71 (0.51, 0.93). CONCLUSION: Using supervised deep learning, we could automate the scoring of histological images of engineered cartilage and achieve results with errors comparable to inter-user error. Thus, the model could enable the automation and standardization of assessments currently used for experimental studies as well as release criteria that ensure the quality of manufactured clinical grafts and compliance with regulatory requirements.

Heterogeneous ozone effects on the DNA methylome of bronchial cells observed in a crossover study.

We used a randomized crossover experiment to estimate the effects of ozone (vs. clean air) exposure on genome-wide DNA methylation of target bronchial epithelial cells, using 17 volunteers, each randomly exposed on two separated occasions to clean air or 0.3-ppm ozone for two hours. Twenty-four hours after exposure, participants underwent bronchoscopy to collect epithelial cells whose DNA methylation was measured using the Illumina 450 K platform. We performed global and regional tests examining the ozone versus clean air effect on the DNA methylome and calculated Fisher-exact p-values for a series of univariate tests. We found little evidence of an overall effect of ozone on the DNA methylome but some suggestive changes in PLSCR1, HCAR1, and LINC00336 DNA methylation after ozone exposure relative to clean air. We observed some participant-to-participant heterogeneity in ozone responses.

When possible, report a Fisher-exact P value and display its underlying null randomization distribution.

In randomized experiments, Fisher-exact P values are available and should be used to help evaluate results rather than the more commonly reported asymptotic P values. One reason is that using the latter can effectively alter the question being addressed by including irrelevant distributional assumptions. The Fisherian statistical framework, proposed in 1925, calculates a P value in a randomized experiment by using the actual randomization procedure that led to the observed data. Here, we illustrate this Fisherian framework in a crossover randomized experiment. First, we consider the first period of the experiment and analyze its data as a completely randomized experiment, ignoring the second period; then, we consider both periods. For each analysis, we focus on 10 outcomes that illustrate important differences between the asymptotic and Fisher tests for the null hypothesis of no ozone effect. For some outcomes, the traditional P value based on the approximating asymptotic Student's t distribution substantially subceeded the minimum attainable Fisher-exact P value. For the other outcomes, the Fisher-exact null randomization distribution substantially differed from the bell-shaped one assumed by the asymptotic t test. Our conclusions: When researchers choose to report P values in randomized experiments, 1) Fisher-exact P values should be used, especially in studies with small sample sizes, and 2) the shape of the actual null randomization distribution should be examined for the recondite scientific insights it may reveal.

Chromatic confocal displacement sensing at oblique incidence angles.

A commercial chromatic confocal displacement sensor, designed for probing a target at normal incidence, is adapted to probe reflective targets at an oblique incidence angle. The sensor is modified by positioning two low-cost optical elements-a collimating lens and a retro-reflector-in the reflection plane.

Automatic Staging of Cancer Tumors Using AIM Image Annotations and Ontologies.

A second opinion about cancer stage is crucial when clinicians assess patient treatment progress. Staging is a process that takes into account description, location, characteristics, and possible metastasis of tumors in a patient. It should follow standards, such as the TNM Classification of Malignant Tumors. However, in clinical practice, the implementation of this process can be tedious and error prone. In order to alleviate these problems, we intend to assist radiologists by providing a second opinion in the evaluation of cancer stage. For doing this, we developed a TNM classifier based on semantic annotations, made by radiologists, using the ePAD tool. It transforms the annotations (stored using the AIM format), using axioms and rules, into AIM4-O ontology instances. From then, it automatically calculates the liver TNM cancer stage. The AIM4-O ontology was developed, as part of this work, to represent annotations in the Web Ontology Language (OWL). A dataset of 51 liver radiology reports with staging data, from NCI's Genomic Data Commons (GDC), were used to evaluate our classifier. When compared with the stages attributed by physicians, the classifier stages had a precision of 85.7% and recall of 81.0%. In addition, 3 radiologists from 2 different institutions manually reviewed a random sample of 4 of the 51 records and agreed with the tool staging. AIM4-O was also evaluated with good results. Our classifier can be integrated into AIM aware imaging tools, such as ePAD, to offer a second opinion about staging as part of the cancer treatment workflow.

Evidence for a Diagenetic Origin of Vera Rubin Ridge, Gale Crater, Mars: Summary and Synthesis of Curiosity's Exploration Campaign.

This paper provides an overview of the Curiosity rover's exploration at Vera Rubin ridge (VRR) and summarizes the science results. VRR is a distinct geomorphic feature on lower Aeolis Mons (informally known as Mount Sharp) that was identified in orbital data based on its distinct texture, topographic expression, and association with a hematite spectral signature. Curiosity conducted extensive remote sensing observations, acquired data on dozens of contact science targets, and drilled three outcrop samples from the ridge, as well as one outcrop sample immediately below the ridge. Our observations indicate that strata composing VRR were deposited in a predominantly lacustrine setting and are part of the Murray formation. The rocks within the ridge are chemically in family with underlying Murray formation strata. Red hematite is dispersed throughout much of the VRR bedrock, and this is the source of the orbital spectral detection. Gray hematite is also present in isolated, gray-colored patches concentrated toward the upper elevations of VRR, and these gray patches also contain small, dark Fe-rich nodules. We propose that VRR formed when diagenetic event(s) preferentially hardened rocks, which were subsequently eroded into a ridge by wind. Diagenesis also led to enhanced crystallization and/or cementation that deepened the ferric-related spectral absorptions on the ridge, which helped make them readily distinguishable from orbit. Results add to existing evidence of protracted aqueous environments at Gale crater and give new insight into how diagenesis shaped Mars' rock record.

An evaluation of the implementation of a parent-led, games-based physical activity intervention: the Active Play at Home quasi-randomized trial.

Trial Registration: NCT02058342. Registered 6 February 2014 retrospectively registered.

Obestatin and adropin in Prader-Willi syndrome and nonsyndromic obesity: Associations with weight, BMI-z, and HOMA-IR.

The roles of obestatin and adropin in paediatric obesity are poorly understood. We compared obestatin and adropin concentrations in younger (n = 21) and older children (n = 14) with Prader-Willi syndrome (PWS) and age and BMI-z-matched controls (n = 31). Fasting plasma obestatin and adropin were higher in younger children with PWS than controls; adropin was also higher in older children with PWS. Growth hormone treatment had no effects on obestatin or adropin in PWS. The ratio of ghrelin to obestatin declined from early to late childhood but was higher in older PWS than older controls. Adropin correlated with fasting glucose in the PWS group only. Changes in the ratio of ghrelin to obestatin may suggest changes in the processing of preproghrelin to ghrelin and obestatin during development and differential processing of preproghrelin in PWS.

Changes in cardiometabolic markers in children with Prader-Willi syndrome and nonsyndromic obesity following participation in a home-based physical activity intervention.

BACKGROUND: Physical activity is associated with improved cardiometabolic markers in children with nonsyndromic obesity (NSO). Prader-Willi Syndrome (PWS) is a neurodevelopmental disorder characterized by obesity. OBJECTIVE: To compare cardiometabolic changes in response to a home-based parent-facilitated physical activity intervention between children with PWS or with NSO. METHODS: Participants included 18 children with PWS (age = 10.5 ± 0.7y; body fat = 44.6 ± 2.0%) and 30 children with NSO (age = 9.7 ± 0.2y; body fat = 44.8 ± 1.2%). Active Play @ Home was a 24-week physical activity intervention curriculum containing playground-based and active video games completed 4 days per week. Pre- and post-intervention measurements included physical activity, body composition, blood samples analysed for glucose, insulin, lipids and cytokines, and insulin resistance computed using the homeostatic model of assessment for insulin resistance (HOMA-IR). RESULTS: All children (n = 48) showed a significant decrease in Interleukin-8 (3.64 ± 0.24 vs. 3.06 ± 0.22 pg/mL). Children with obesity who did not gain or who lost body fat percentage (n = 18) demonstrated a significant decrease in HOMA-IR (3.17 ± 0.39 vs. 2.72 ± 0.34) and an increase in high-density lipoprotein (44.30 ± 2.51 vs. 47.29 ± 2.59 mg/dL). All other measurements showed no significant changes. CONCLUSIONS: The most favourable changes in cardiometabolic factors were observed in children with nonsyndromic obesity who demonstrated no gain or a decrease in body fat percentage.

Correction to: A Mixed Methods Evaluation of Early Childhood Abuse Prevention Within Evidence-Based Home Visiting Programs.

The article "A Mixed Methods Evaluation of Early Childhood Abuse Prevention Within Evidence-Based Home Visiting Programs", written by M. Matone, K. Kellom, H. Griffis, W. Quarshie, J. Faerber, P. Gierlach, J. Whittaker, D. M. Rubin and P. F. Cronholm, was originally published electronically on the publisher's internet portal (currently SpringerLink) on 31 May 2018 without open access. With the author(s)' decision to opt for Open Choice the copyright of the article changed on 27 July 2018 to

A Mixed Methods Evaluation of Early Childhood Abuse Prevention Within Evidence-Based Home Visiting Programs.

Objectives In this large scale, mixed methods evaluation, we determined the impact and context of early childhood home visiting on rates of child abuse-related injury. Methods Entropy-balanced and propensity score matched retrospective cohort analysis comparing children of Pennsylvania Nurse-Family Partnership (NFP), Parents As Teachers (PAT), and Early Head Start (EHS) enrollees and children of Pennsylvania Medicaid eligible women from 2008 to 2014. Abuse-related injury episodes were identified in medical assistance claims with ICD-9 codes. Weighted frequencies and logistic regression odds of injury within 24 months are presented. In-depth interviews with staff and clients (n = 150) from 11 programs were analyzed using a modified grounded theory approach. Results The odds of a healthcare encounter for early childhood abuse among clients were significantly greater than comparison children (NFP: 1.32, 95% CI [1.08, 1.62]; PAT: 4.11, 95% CI [1.60, 10.55]; EHS: 3.15, 95% CI [1.41, 7.06]). Qualitative data illustrated the circumstances of and program response to client issues related to child maltreatment, highlighting the role of non-client caregivers. All stakeholders described curricular content aimed at prevention (e.g. positive parenting) with little time dedicated to addressing current or past abuse. Clients who reported a lack of abuse-related content supposed their home visitor's assumption of an absence of risk in their home, but were supportive of the introduction of abuse-related content. Approach, acceptance, and available resources were mediators of successfully addressing abuse. Conclusions for Practice Home visiting aims to prevent child abuse among high-risk families. Adequate home visitor capacity to proactively assess abuse risk, deliver effective preventive curriculum with fidelity to caregivers, and access appropriate resources is necessary.

Intravenous vitamin C in the supportive care of cancer patients: a review and rational approach.

This article reviews intravenous vitamin C (IV C) in cancer care and offers a rational approach to enable medical oncologists and integrative practitioners to safely provide IV C combined with oral vitamin C to patients. The use of IV C is a safe supportive intervention to decrease inflammation in the patient and to improve symptoms related to antioxidant deficiency, disease processes, and side effects of standard cancer treatments. A proposed rationale, together with relevant clinical safety considerations for the application of IV C in oncologic supportive care, is provided.