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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Failure to regulate TNF-induced NF-kappaB and cell death responses in A20-deficient mice.

A20 is a cytoplasmic zinc finger protein that inhibits nuclear factor kappaB (NF-kappaB) activity and tumor necrosis factor (TNF)-mediated programmed cell death (PCD). TNF dramatically increases A20 messenger RNA expression in all tissues. Mice deficient for A20 develop severe inflammation and cachexia, are hypersensitive to both lipopolysaccharide and TNF, and die prematurely. A20-deficient cells fail to terminate TNF-induced NF-kappaB responses. These cells are also more susceptible than control cells to undergo TNF-mediated PCD. Thus, A20 is critical for limiting inflammation by terminating TNF-induced NF-kappaB responses in vivo.

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.

Phylogenetic characterization of bacteria in the subsurface microbial culture collection.

The Subsurface Microbial Culture Collection (SMCC) was established by the U.S. Dept. of Energy (DOE) and contains nearly 10,000 strains of microorganisms (mostly bacteria) isolated from terrestrial subsurface environments. Selected groups of bacterial isolates from three sample sites situated above geochemically and hydrologically different subsurface environments have been characterized by phylogenetic analysis of 16S ribosomal RNA (rRNA) gene nucleotide sequences. Among these isolates were members of six major phylogenetic groups of bacteria: the high-G+C and low-G+C Gram-positive bacteria; the alpha-, beta-, and gamma-subdivisions of the Proteobacteria; and the Flexibacter/Cytophaga/Bacteroides group. A small number of the SMCC strains may be members of new bacterial genera, but most of them could be placed with reasonable confidence into more than 35 previously described genera. The majority of the Gram-positive isolates were species of Arthrobacter, Bacillus, or Streptococcus, whereas Acinetobacter, Comamonas, Pseudomonas, Sphingomonas, and Variovorax were among the most frequently encountered Gram-negative genera. A high proportion of the strains were placed in fewer than 10 genera, implying that there is substantial duplication within the SMCC at the genus level. When groups of isolates assigned to Acinetobacter, Arthrobacter, or Sphingomonas were analyzed in more detail, however, it was found that each group consisted of subgroups of strains that probably differed at the species level. Restriction endonuclease analysis (applied to the strains from one sample site) indicated that additional diversity was present at the strain level. Most of the SMCC isolates assigned to some genera (e.g., Acinetobacter) were very closely related to previously described species in those genera, but most of the isolates assigned to other genera (e.g., Arthrobacter and Sphingomonas) appeared (or were shown) to be new species, thereby indicating that a reasonable amount of novelty is present within the SMCC at the species level.

Immunophenotypic analysis of peripheral blood leukocytes at different stages of HIV infection. An analysis of asymptomatic, ARC, and AIDS populations.

Blood leukocytes from 51 patients with acquired immune deficiency syndrome (AIDS) or AIDS-related syndrome (ARC) were immunophenotyped with the use of monoclonal antibodies and flow cytometry. The patients were placed into four clinically defined groups: HIV-positive asymptomatic (HIV+/A, 8); persistent generalized adenopathy (14); Kaposi's sarcoma (12); and opportunistic infections (17). Immunophenotypes were compared between groups. Statistically significant differences were seen in absolute lymphocyte counts, total T-cells, helper/inducer T-cells, the helper inducer subset of CD4+ lymphocytes, the suppressor inducer subset of CD4+ lymphocytes, activated helper T-cells, and natural killer cells. CD8+ cells and subsets were not statistically different between groups, possibly obscured by large ranges, but median values suggested differences. Results indicate a pattern of increasing or decreasing numbers of certain subpopulations as HIV infection progresses.

Temperature dependence of ethanol depression in rats.

The relationship between ambient temperature, body temperature, and brain sensitivity to ethanol was investigated in rats. Drug naive male Long Evans rats were injected IP with a hypnotic dose of ethanol (2.75 g/kg, 20% w/v). Immediately after injection, separate groups were exposed to one of five ambient temperatures from 12 to 34 degrees C. Ambient temperature significantly affected wake-up rectal temperature, sleep-time, and wake-up brain ethanol concentration. Sleep-times in individual rats increased 387% (from 24.0 min at 12 degrees C to 116.8 min at 34 degrees C) and wake-up brain ethanol concentrations decreased 79% (from 3.6 mg/g at 12 degrees C to 2.3 mg/g at 34 degrees C) as body temperatures increased from 35 to 41 degrees C. In addition, wake-up rectal temperatures were significantly, positively correlated with sleep-times (r = 0.32, P less than 0.05) and significantly, negatively correlated with wake-up brain ethanol concentrations (r = -0.49, P less than 0.01), further suggesting that brain sensitivity to ethanol increases as body temperature increases. These results are consistent with previous findings in mice, fit membrane perturbation theories of anesthesia, and indicate that temperature dependence of ethanol sensitivity is a general phenomenon extending across species. In conjunction with previous findings, the results also suggest that body temperature during intoxication may participate in mediating species differences in ethanol sensitivity.

Morphometric analysis of dysplasia in cervical cone biopsy specimens in cases with false-negative cytology.

Conization specimens with a histologic diagnosis of cervical intraepithelial neoplasia III were reviewed with respect to cytology findings in the three months preceding conization. In 29% of the cases, one or more false-negative cytology reports preceded conization. No dysplastic cells were found on review of the false-negative cytology slides from these cases. Morphometric analysis of surface dysplasia in the conization specimens was performed to explain these findings. A statistically significantly greater surface area of dysplasia and greater spread of dysplastic cells in the endocervical canal was found in the positive cytology when compared to the false-negative cytology cases. No difference in vaginal spread of dysplasia existed between the two groups. The endocervical canal was sampled with a moist cotton swab in all of the cases. The results suggest that small numbers of dysplastic cells high in the endocervical canal may not be effectively sampled by cotton swabs in cases of false-negative cervical cytology, lowering screening sensitivity.

Arachidonic acid and cell signalling in the ovary and placenta.

Arachidonic acid (AA) and its metabolites make up a diverse group of signalling molecules important to mediation of metabolic and endocrine function of ovarian and placental cell membranes. This paper reviews recent literature examining AA and eicosanoid involvement in the functional dynamics of follicular development, ovulation and corpus luteum function. The putative roles of AA metabolites in establishment and maintenance of pregnancy are reviewed with reference to decidualization, trophoblast invasion and implantation, maintenance of perfusion of the feto-placental unit and lipid transfer. Finally, recent evidence implicating AA metabolism in mediation of enzyme activity following hormone-receptor coupling within various cells types comprising the placental membranes is reviewed.

The surface density of glial fibrillary acidic protein immunopositive astrocytic processes in the rat supraoptic nucleus is reversibly altered by dehydration and rehydration.

Ultrastructural and immunohistochemical studies of the supraoptic nucleus (SON) have provided evidence that retraction and extension of astrocytic processes from between magnocellular neuroendocrine cells (MNCs) likely plays a role in the release of oxytocin, and/or vasopressin, that accompanies parturition, lactation and dehydration. The present study estimates the surface density (Sv) of glial fibrillary acidic protein (GFAP)-immunoreactivity, predominantly in astrocytic processes, in the SON of normally hydrated, dehydrated and rehydrated rats. The Sv of GFAP processes in dehydrated rats was significantly reduced compared with control levels. Rehydration returned Sv to control levels. The reversible reduction in Sv indicates that the previously observed reduction in optical density is due to a rearrangement of astrocyte processes in the SON which occurs at the same time as the selective functional activation of MNCs.