Doug Altman, medical statistician par excellence: What can radiologists learn from his legacy?

This narrative review describes our experience of working with Doug Altman, the most highly cited medical statistician in the world. Doug was particularly interested in diagnostics, and imaging studies in particular. We describe how his insights helped improve our own radiological research studies and we provide advice for other researchers hoping to improve their own research practice.

Initial results from the New Horizons exploration of 2014 MU69, a small Kuiper Belt object.

The Kuiper Belt is a distant region of the outer Solar System. On 1 January 2019, the New Horizons spacecraft flew close to (486958) 2014 MU69, a cold classical Kuiper Belt object approximately 30 kilometers in diameter. Such objects have never been substantially heated by the Sun and are therefore well preserved since their formation. We describe initial results from these encounter observations. MU69 is a bilobed contact binary with a flattened shape, discrete geological units, and noticeable albedo heterogeneity. However, there is little surface color or compositional heterogeneity. No evidence for satellites, rings or other dust structures, a gas coma, or solar wind interactions was detected. MU69's origin appears consistent with pebble cloud collapse followed by a low-velocity merger of its two lobes.

The JAK inhibitor ruxolitinib reduces inflammation in an ILC3-independent model of innate immune colitis.

Innate immunity contributes to the pathogenesis of inflammatory bowel disease (IBD). However, the mechanisms of IBD mediated by innate immunity are incompletely understood and there are limited models of spontaneous innate immune colitis to address this question. Here we describe a new robust model of colitis occurring in the absence of adaptive immunity. RAG1-deficient mice expressing TNFAIP3 in intestinal epithelial cells (TRAG mice) spontaneously developed 100% penetrant, early-onset colitis that was limited to the colon and dependent on intestinal microbes but was not transmissible to co-housed littermates. TRAG colitis was associated with increased mucosal numbers of innate lymphoid cells (ILCs) and depletion of ILC prevented colitis in TRAG mice. ILC depletion also therapeutically reversed established colitis in TRAG mice. The colitis in TRAG mice was not prevented by interbreeding to mice lacking group 3 ILC nor by depletion of TNF. Treatment with the JAK inhibitor ruxolitinib ameliorated colitis in TRAG mice. This new model of colitis, with its predictable onset and colon-specific inflammation, will have direct utility in developing a more complete understanding of innate immune mechanisms that can contribute to colitis and in pre-clinical studies for effects of therapeutic agents on innate immune-mediated IBD.

Magnetic resonance based texture parameters as potential imaging biomarkers for predicting long-term survival in locally advanced rectal cancer treated by chemoradiotherapy.

AIM: The study aimed to investigate whether textural features of rectal cancer on MRI can predict long-term survival in patients treated with long-course chemoradiotherapy. METHOD: Textural analysis (TA) using a filtration-histogram technique of T2-weighted pre- and 6-week post-chemoradiotherapy MRI was undertaken using TexRAD, a proprietary software algorithm. Regions of interest enclosing the largest cross-sectional area of the tumour were manually delineated on the axial images and the filtration step extracted features at different anatomical scales (fine, medium and coarse) followed by quantification of statistical features [mean intensity, standard deviation, entropy, skewness, kurtosis and mean of positive pixels (MPP)] using histogram analysis. Cox multiple regression analysis determined which univariate features including textural, radiological and histological independently predicted overall survival (OS), disease-free survival (DFS) and recurrence-free survival (RFS). RESULTS: MPP [fine texture, hazard ratio (HR) 6.9, 95% CI: 2.43-19.55, P < 0.001], mean (medium texture, HR 5.6, 95% CI: 1.4-21.7, P = 0.007) and extramural venous invasion (EMVI) on MRI (HR 2.96, 95% CI: 1.04-8.37, P = 0.041) independently predicted OS while mean (medium texture, HR 4.53, 95% CI: 1.58-12.94, P = 0.003), MPP (fine texture, HR 3.36, 95% CI: 1.36-8.31, P = 0.008) and threatened circumferential resection margin (CRM) on MRI (HR 3.1, 95% CI: 1.01-9.46, P = 0.046) predicted DFS. For OS, EMVI on MRI (HR 4.23, 95% CI: 1.41-12.69, P = 0.01) and for DFS kurtosis (medium texture, HR 3.97, 95% CI: 1.44-10.94, P = 0.007) and CRM involvement on MRI (HR 3.36, 95% CI: 1.21-9.32, P = 0.02) were the independent post-treatment factors. Only TA independently predicted RFS on pre- or post-treatment analyses. CONCLUSION: MR based TA of rectal cancers can predict outcome before undergoing surgery and could potentially select patients for individualized therapy.

Towards a framework for analysis of eye-tracking studies in the three dimensional environment: a study of visual search by experienced readers of endoluminal CT colonography.

OBJECTIVE: Eye tracking in three dimensions is novel, but established descriptors derived from two-dimensional (2D) studies are not transferable. We aimed to develop metrics suitable for statistical comparison of eye-tracking data obtained from readers of three-dimensional (3D) "virtual" medical imaging, using CT colonography (CTC) as a typical example. METHODS: Ten experienced radiologists were eye tracked while observing eight 3D endoluminal CTC videos. Subsequently, we developed metrics that described their visual search patterns based on concepts derived from 2D gaze studies. Statistical methods were developed to allow analysis of the metrics. RESULTS: Eye tracking was possible for all readers. Visual dwell on the moving region of interest (ROI) was defined as pursuit of the moving object across multiple frames. Using this concept of pursuit, five categories of metrics were defined that allowed characterization of reader gaze behaviour. These were time to first pursuit, identification and assessment time, pursuit duration, ROI size and pursuit frequency. Additional subcategories allowed us to further characterize visual search between readers in the test population. CONCLUSION: We propose metrics for the characterization of visual search of 3D moving medical images. These metrics can be used to compare readers' visual search patterns and provide a reproducible framework for the analysis of gaze tracking in the 3D environment. ADVANCES IN KNOWLEDGE: This article describes a novel set of metrics that can be used to describe gaze behaviour when eye tracking readers during interpretation of 3D medical images. These metrics build on those established for 2D eye tracking and are applicable to increasingly common 3D medical image displays.

Evaluating patients' preferences for type of bowel preparation prior to screening CT colonography: convenience and comfort versus sensitivity and specificity.

AIMS: To explore the relative value patients place on comfort and convenience versus test sensitivity and specificity in the context of computed tomographic colonography (CTC) screening. MATERIALS AND METHODS: Twenty semi-structured interviews were carried out with patients attending hospital for radiological tests unrelated to CTC. Preferences for CTC with different types of bowel preparation for CTC screening were examined and interviews were analysed thematically. The discussion guide included separate sections on CTC, bowel preparation methods (non-, reduced- and full-laxative), and sensitivity and specificity. Patients were given information on each topic in turn and asked about their views and preferences during each section. RESULTS: Following information about the test, patients' attitudes towards CTC were positive. Following information on bowel preparation, full-laxative purgation was anticipated to cause more adverse physical and lifestyle effects than using reduced- or non-laxative preparation. However, stated preferences were approximately equally divided, largely due to patients anticipating that non-laxative preparations would reduce test accuracy (because the bowel was not thoroughly cleansed). Following information on sensitivity and specificity (which supported patients' expectations), the predominant stated preference was for full-laxative preparation. CONCLUSIONS: Patients are likely to value test sensitivity and specificity over a more comfortable and convenient preparation. Future research should test this hypothesis on a larger sample.

Diffusion weighted MRI: overview and implications for rectal cancer management.

Diffusion weighted imaging (DWI) is an MRI technique that quantifies the movement of water molecules at a cellular level. As the diffusion properties of water vary in areas of necrosis, high cellularity, inflammation and fibrosis, this technique is inherently sensitive to different pathologies. Having become a well-established adjunct to standard sequences during neurological MRI, technological advances have enabled extrapolation to abdominopelvic imaging, including staging of rectal cancer. Scan acquisitions can be performed rapidly using widely available equipment and consequently there has been rapid dissemination into routine practice. However, while DWI shows promise for detecting, staging and monitoring rectal cancer response to therapy, the evidence base remains scant with no current consensus for technical protocols, interpretation or integration into rectal cancer management. Moreover, those studies available to date have a small sample size and few observers, and their results may not be generalizable to daily practice. This article outlines the physical principles of DWI, reviews the literature and suggests avenues for future research into this important technical development.

An interview study analysing patients' experiences and perceptions of non-laxative or full-laxative preparation with faecal tagging prior to CT colonography.

AIM: To compare patients' experiences of either non- or full-laxative bowel preparation with additional faecal tagging and subsequent computed tomographic (CT) colonography using in-depth interviews to elicit detailed responses. MATERIALS AND METHODS: Patients who received CT colonography after non- (n = 9) or full-laxative (n = 9) preparation participated in a semi-structured telephone interview at least 2 days after the investigation. Full-laxative preparation consisted of magnesium citrate and sodium picosulphate administered at home (or polyethylene glycol, if contraindicated), followed by hospital-based faecal tagging with iohexol. Non-laxative preparation was home-based barium sulphate for faecal tagging. Interviews were transcribed and thematically analysed to identify recurrent themes on patients' perceptions and experiences. RESULTS: Experiences of full-laxative preparation were usually negative and characterized by pre-test diarrhoea that caused significant interference with daily routine. Post-test flatus was common. Non-laxative preparation was well-tolerated; patients reported no or minimal changes to bowel habit and rapid return to daily routine. Patients reported worry and uncertainty about the purpose of faecal tagging. For iohexol, this also added burden from waiting before testing. CONCLUSION: Patients' responses supported previous findings that non-laxative preparation is more acceptable than full-laxative preparation but both can be improved. Faecal tagging used in combination with laxative preparation is poorly understood, adding burden and worry. Home-based non-laxative preparation is also poorly understood and patients require better information on the purpose and mechanism in order to give fully informed consent. This may also optimize adherence to instructions. Allowing home-based self-administration of all types of preparation would prevent waiting before testing.

WE-E-213CD-03: Inverse-Consistent Symmetric Registration of Inner Colon Surfaces Derived from Prone and Supine CT Colonography.

PURPOSE: Robust registration of prone and supine colonie surfaces acquired during CT colonography may lead to faster and more accurate detection of colorectal cancer and polyps. Any directional bias when registering one surface to the other could precipitate incorrect anatomical correspondence and engender reader error. Despite this, non-rigid registration methods are often implemented asymmetrically, which could negatively influence the registration. We aimed to reduce directional bias and so increase robustness by adapting a cylindrical registration algorithm to be both symmetric and inverse-consistent. METHODS: The registration task can be simplified by mapping both prone and supine colonie surfaces onto regular cylinders. Spatial correspondence can then be established in cylindrical space using the original surfaces' local shape indices. We implemented a symmetric formulation of the popular non-rigid B-spline image registration method in cylindrical space. A symmetric similarity measure computes the sum of squared differences between both cylindrical representations of prone-to-supine and supine-to-prone directions simultaneously. Inverse consistency of the transformation is enforced by adding an appropriately weighted penalty term to the optimisation function. RESULTS: We selected 8 CT colonography patient cases with marked variation in luminal distension and surface morphology. We randomly allocated 4 of these for tuning an optimal set of registration parameters and 4 for validation. The mean inverse-consistency error was reduced by 32% from 4.8mm to 3.2mm by the new symmetric formulation. The mean registration error improved from 8.2mm to 7.3mm for 330 manually chosen reference points on the 4 validation sets. CONCLUSIONS: A symmetric formulation of prone and supine surface registration improves the quality of registration. Information from both prone-to-supine and supine-to-prone directions helps enforce convergence towards a more accurate solution due to reduced directional bias. A more robust and accurate registration will facilitate interpretation of CT colonography and has the potential to improve existing computer-aided detection methods. The authors gratefully acknowledge financial support for this work from the NIHR program: â€Å“Imaging diagnosis of colorectal cancer: Interventions for efficient and acceptable diagnosis in symptomatic and screening populationsâ€.

CT colonography: who attends training? A survey of participants at educational workshops.

AIM: To obtain information regarding the demographics of attendees of computed tomography colonography (CTC) training workshops organized by the European Society of Gastrointestinal and Abdominal Radiology (ESGAR), in particular their prior expertise and current practice. MATERIALS AND METHODS: Attendees at five CTC training workshops conducted in Edinburgh (UK), Malmo (Sweden), Amsterdam (Netherlands), Pisa and Stresa (Italy) between February 2007 and April 2010 completed an online questionnaire. Responses were collated and descriptive statistics produced. RESULTS: Three hundred and forty-eight delegates responded; a response rate of 73%. There was wide geographical variability encompassing 20 European member-states and seven countries outside Europe. The overwhelming majority were radiologists (336; 97%). Of the respondents, 299 (86%) were already interpreting CTC in clinical practice but of these, 158 (54%) had no prior formal training in CTC whereas 21 (8%) had attended a previous workshop. Furthermore, of those reporting CTC, 227 (76%) had interpreted fewer than 50 cases. CONCLUSIONS: Despite political imperatives for other groups to interpret CTC, the vast majority of those attending training are radiologists. Worryingly, a significant proportion of these are apparently reporting CTC in clinical practice without adequate training.

Range of motion measurements: reference values and a database for comparison studies.

Many diseases and injuries can impair joint mobility. Normal reference values are needed to determine extent of impairment to assess and monitor joint motion. There is very little published data describing normal joint range of motion (ROM) for healthy men and women across a wide span of ages. We enrolled male and female subjects aged between 2 and 69 years who were free from conditions that could potentially limit joint mobility for the study. Nine licensed physical therapists used universal goniometers to determine passive joint motion bilaterally of elbow flexion, extension, supination and pronation, shoulder flexion, hip flexion and extension, knee flexion and extension, and ankle dorsiflexion and plantarflexion. Descriptive statistics were calculated for male and female subjects in four age groups: 2-8, 9-19, 20-44 and 45-69 years. Joint ROM measurements were obtained on a total of 674 (53.6% female) healthy, normal subjects aged 2-69 years. Female subjects had greater joint mobility in all age groups in nearly all joints and the gender difference was most obvious in measures of ankle plantarflexion, elbow pronation and supination. Range of motion average values for all joints decreased with advancing age for both men and women and, in most cases, were significantly different than most commonly used normative values. Our study of ROM measurements taken by trained physical therapists on a large sample of healthy individuals revealed significant gender- and age-related variation that may be an important consideration in patient assessment.

A novel Transformation Model© for personalized medicine laboratory systems.

The role of health system laboratories is critical to the appropriate clinical integration of personalized medicine. We conducted semistructured interviews with experts and opinion leaders representing laboratory medicine, health policy and the diagnostics industry, to examine what is known about the real-world effectiveness of health laboratories as organizations. We describe and encourage the wider use of an evidence-based, novel Transformation Model© to prepare for the future and set goals for a better health system. A collaborative approach appropriately integrates the efficiency and high-quality expertise of the health laboratory system with the transformative vision of the personalized medicine community.

Prophylactic total gastrectomy (PTG) for hereditary diffuse gastric cancer (HDGC): the Newfoundland experience with 23 patients.

BACKGROUND: Hereditary diffuse gastric cancer (HDGC) results from truncating mutations of the CDH1 (E-cadherin) gene. It is an autosomal dominant cancer susceptibility syndrome with a lifetime risk of diffuse gastric cancer (DGC) of 60-80%, with a mean age of onset of 37 years. There exists no adequate screening test for DGC. Early intramucosal diffuse/signet-ring cell carcinomas have been found in prophylactic total gastrectomy (PTG) specimens following normal preoperative endoscopy. Total gastrectomy has been advocated on a prophylactic basis. The aim of this study was to report our experience with PTG in 23 patients from the Canadian province of Newfoundland and Labrador. This is the largest series worldwide. METHODS: A retrospective study of consecutive patients undergoing PTG for HDGC was performed. All patients were confirmed to have a truncating mutation of the CDH1 gene. RESULTS: Twenty-three patients underwent PTG between February 2006 and November 2008. Major complications were found in 4/23 patients (17%), with no mortality. Two of 23 patients (9%) had positive mucosal biopsies on preoperative EGD. Twenty-two of 23 patients (96%) had evidence of diffuse/signet-ring carcinoma on final standardized pathological evaluation. Therefore, 21/23 (91%) were not picked up by preoperative EGD screening. CONCLUSIONS: PTG can be performed in patients with HDGC with a low rate of serious complications. Methods of reconstruction incorporating a pouch reservoir and preservation of the postgastric branches of the vagus nerves need to be explored. More refined penetrance estimates, effective screening protocols, and long-term psychological and functional outcomes following PTG require organized multicenter collaborative efforts.

How can we make laboratory testing safer?

BACKGROUND: Diagnostic errors occur in laboratory medicine resulting from an error or delay in diagnosis, a failure to employ indicated tests, and the use of outmoded tests. Since laboratory tests provide essential information used by physicians to make medical decisions, it is important to determine how often laboratory testing mistakes occur, whether they cause patient harm, where they are most likely to occur in the testing process, and how to prevent them from occurring. METHODS: The US Quality Institute Conference in 2003 and the Institute for Quality in Laboratory Medicine in 2005 brought together providers of, users of, and payers for laboratory services to explore how working together they could help to reduce laboratory testing errors and enhance patient safety. RESULTS AND CONCLUSIONS: Users of and payers for laboratory services must become partners in the laboratory's efforts to reduce laboratory testing errors and enhance patient safety. They must be linked to a laboratory information system that provides assistance in decisions on test ordering, patient preparation, and test interpretation. Laboratory quality assessment efforts need to be expanded to encompass the detection of non-analytical mistakes. Healthcare institutions need to adopt a culture of safety that is implemented at all levels of the organization.

Recommendations of the 2006 Human Variome Project meeting.

Lists of variations in genomic DNA and their effects have been kept for some time and have been used in diagnostics and research. Although these lists have been carefully gathered and curated, there has been little standardization and coordination, complicating their use. Given the myriad possible variations in the estimated 24,000 genes in the human genome, it would be useful to have standard criteria for databases of variation. Incomplete collection and ascertainment of variants demonstrates a need for a universally accessible system. These and other problems led to the World Heath Organization-cosponsored meeting on June 20-23, 2006 in Melbourne, Australia, which launched the Human Variome Project. This meeting addressed all areas of human genetics relevant to collection of information on variation and its effects. Members of each of eight sessions (the clinic and phenotype, the diagnostic laboratory, the research laboratory, curation and collection, informatics, relevance to the emerging world, integration and federation and funding and sustainability) developed a number of recommendations that were then organized into a total of 96 recommendations to act as a foundation for future work worldwide. Here we summarize the background of the project, the meeting and its recommendations.

Developing a sustainable process to provide quality control materials for genetic testing.

PURPOSE: To provide a summary of the outcomes of two working conferences organized by the Centers for Disease Control and Prevention (CDC), to develop recommendations for practical, sustainable mechanisms to make quality control (QC) materials available to the genetic testing community. METHODS: Participants were selected to include experts in genetic testing and molecular diagnostics from professional organizations, government agencies, industry, laboratories, academic institutions, cell repositories, and proficiency testing (PT)/external Quality Assessment (EQA) programs. Current efforts to develop QC materials for genetic tests were reviewed; key issues and areas of need were identified; and workgroups were formed to address each area of need and to formulate recommendations and next steps. RESULTS: Recommendations were developed toward establishing a sustainable process to improve the availability of appropriate QC materials for genetic testing, with an emphasis on molecular genetic testing as an initial step. CONCLUSIONS: Improving the availability of appropriate QC materials is of critical importance for assuring the quality of genetic testing, enhancing performance evaluation and PT/EQA programs, and facilitating new test development. To meet the needs of the rapidly expanding capacity of genetic testing in clinical and public health settings, a comprehensive, coordinated program should be developed. A Genetic Testing Quality Control Materials Program has therefore been established by CDC in March 2005 to serve these needs.

Effects of several inhibitors on pure cultures of ruminal methanogens.

AIMS: To examine the effects of five inhibitors of methanogenesis, 2-bromoethanesulphonate (BES), 3-bromopropanesulphonate (BPS), lumazine, propynoic acid and ethyl 2-butynoate, on CH4 production of the ruminal methanogens Methanobrevibacter ruminantium, Methanosarcina mazei and Methanomicrobium mobile. METHODS AND RESULTS: Methanogens were grown in MS medium including 25% (v/v) clarified ruminal fluid. Methane production was measured after 4 and 6 days of incubation. Methanobrevibacter ruminantium was the most sensitive species to BES, propynoic acid and ethyl 2-butynoate. Methanosarcina mazei was the least sensitive species to those chemical additives, and Mm. mobile was intermediate. BPS failed to inhibit any of the methanogens. All three species were almost completely inhibited by 50- and 100%-lumazine saturated media, but the inhibition was somewhat lower with a 25%-lumazine saturated media. CONCLUSIONS: There were important differences among species of methanogens regarding their sensitivity to the different inhibitors. In general, Ms. mazei was the most resistant to inhibitors, Mb. ruminantium the least resistant, and Mm. mobile was intermediate. SIGNIFICANCE AND IMPACT OF THE STUDY: Differences among methanogens regarding their resistance to chemical inhibitors should be considered when designing strategies of inhibition of ruminal methanogenesis, as selection of resistant species may result.

T cell-independent interleukin 15Ralpha signals are required for bystander proliferation.

Cytokine driven or "bystander" proliferation of T cells occurs in vivo independently of major histocompatibility complex-T cell receptor interactions. This process may be important for supporting T cell homeostasis and facilitating T cell responses to microbial antigens, and may involve the cytokine interleukin (IL)-15. In this study, we find that IL-15Ralpha-deficient (IL-15Ralpha(-/-)) mice fail to undergo poly I:C or IL-15 driven bystander proliferation of CD8(+) T cells. Surprisingly, IL-15Ralpha(-/-) CD8(+) T cells proliferate in response to poly I:C when adoptively transferred into normal mice, and normal CD8(+) T cells fail to proliferate in IL-15Ralpha(-/-) mice. Normal mice reconstituted with IL-15Ralpha(-/-) bone marrow cells also fail to exhibit bystander responses. Thus, CD8(+) T cell independent IL-15Ralpha signals from radiation sensitive hematopoietic cells are likely required for bystander responses. Moreover, normal CD8(+) T cells proliferate in IL-15Ralpha(-/-) mice after treatment with IL-15. Therefore, IL-15Ralpha signals may mediate a positive feedback loop involving the further physiological production of IL-15. These findings provide new insights into how IL-15Ralpha supports memory phenotype CD8(+) T cell proliferation, and suggest novel mechanisms by which memory CD8(+) T cells are maintained in vivo.