The American Society of Pediatric Hematology/Oncology workforce assessment: Part 2-Implications for fellowship training.

The American Society of Pediatric Hematology/Oncology (ASPHO) solicited information from division directors and fellowship training program directors to capture pediatric hematology/oncology (PHO) specific workforce data of 6 years (2010-2015), in response to an increase in graduating fellows during that time. Observations included a stable number of physicians and advanced practice providers (APPs) in clinical PHO, an increased proportion of APPs hired compared to physicians, and an increase in training-level first career positions. Rapid changes in the models of PHO care have significant implications to current and future trainees and require continued analysis to understand the evolving discipline of PHO.

Excess congenital non-synonymous variation in leukemia-associated genes in MLL- infant leukemia: a Children's Oncology Group report.

Infant leukemia (IL) is a rare sporadic cancer with a grim prognosis. Although most cases are accompanied by MLL rearrangements and harbor very few somatic mutations, less is known about the genetics of the cases without MLL translocations. We performed the largest exome-sequencing study to date on matched non-cancer DNA from pairs of mothers and IL patients to characterize congenital variation that may contribute to early leukemogenesis. Using the COSMIC database to define acute leukemia-associated candidate genes, we find a significant enrichment of rare, potentially functional congenital variation in IL patients compared with randomly selected genes within the same patients and unaffected pediatric controls. IL acute myeloid leukemia (AML) patients had more overall variation than IL acute lymphocytic leukemia (ALL) patients, but less of that variation was inherited from mothers. Of our candidate genes, we found that MLL3 was a compound heterozygote in every infant who developed AML and 50% of infants who developed ALL. These data suggest a model by which known genetic mechanisms for leukemogenesis could be disrupted without an abundance of somatic mutation or chromosomal rearrangements. This model would be consistent with existing models for the establishment of leukemia clones in utero and the high rate of IL concordance in monozygotic twins.

Maternal vitamin and iron supplementation and risk of infant leukaemia: a report from the Children's Oncology Group.

BACKGROUND: Prenatal supplementation has been inversely associated with childhood, but not with infant, leukaemia. METHODS: Mothers of 443 cases of infant leukaemia diagnosed during 1996-2006 and 324 frequency-matched controls completed interviews. Associations were evaluated by unconditional logistic regression. RESULTS: We observed no associations between prenatal vitamin (odds ratio (OR)=0.79, 95% confidence interval (CI): 0.44-1.42) or iron supplementation (OR=1.07, 95% CI: 0.75-1.52) and infant leukaemia after adjustment for race/ethnicity and income. Similar results were observed for leukaemia subtypes analysed separately. CONCLUSION: The observed null associations may be attributable to high supplementation rates and/or national fortification programmes.

Compliance with and short-term adverse events from clarithromycin versus placebo in patients with stable coronary heart disease: the CLARICOR trial.

BACKGROUND: The randomized placebo-controlled double-blind CLARICOR trial investigated the influence of clarithromycin versus placebo on cardiovascular events and mortality in patients with chronic coronary artery disease (ClinicalTrials.gov NCT 00121550). The trial randomized 2172 patients to 500 mg of clarithromycin daily versus 2200 patients to matching placebo for 14 days. This paper presents protocol-specified analysis of the patient-reported information regarding their compliance and non-serious adverse events during the 14 days of treatment as well as serious adverse events (mortality and hospitalizations) during the first 30 days after randomization. METHODS: Randomized clinical trial focusing on patient-reported information regarding their compliance and adverse events. RESULTS: Of the randomized patients, 99% reported information regarding their compliance and adverse events. A 100% tablet intake was reported by 90% of the clarithromycin group and by 93.7% of the placebo group. Of the clarithromycin patients, 39.5% reported at least one non-serious adverse event versus 25.1% of the placebo patients (P < 0.001). Gastrointestinal adverse reactions were reported 950 times by 697 patients (32.3%) in the clarithromycin group and 485 times by 390 patients (17.9%) in the placebo group (P < 0.001). No significant differences were seen in other non-serious or serious adverse events during the first month after inclusion. Short-term non-serious adverse events did not explain the previously reported long-term significantly increased mortality associated with clarithromycin. CONCLUSIONS: Gastrointestinal adverse reactions are common during clarithromycin administration, but at least half are also seen with a placebo.

The Osteoporosis Self-Assessment Tool versus alternative tests for selecting postmenopausal women for bone mineral density assessment: a comparative systematic review of accuracy.

SUMMARY: We performed a systematic review of studies comparing the Osteoporosis Self-Assessment Tool (OST) and other tests used to select women for bone mineral density (BMD) assessment. In comparative meta-analyses, we found that the accuracy of OST was similar to other tests that are based on information from the medical history. By contrast, assessment by quantitative ultrasonography at the heel was more accurate than OST in discriminating between women with high and low BMD. The methodological quality of the included studies was generally low. INTRODUCTION: Numerous tests are suggested for triaging postmenopausal women for bone mineral density (BMD) assessment by dual-energy X-ray absorptiometry. Previous studies suggest that OST, based on age and weight only, may be as accurate as more complex triage tests. We systematically compare the accuracy of OST and alternative triage tests in postmenopausal women. METHODS: We searched PubMed, Embase, Web of Science, citation lists, and conference proceedings. Our main measure of accuracy was the diagnostic odds ratio (DOR). We compared summary estimates of DOR (sDOR) for OST and alternative tests in pairwise meta-analyses by using the Moses-Littenberg approach. RESULTS: Summary estimates of DOR for OST and the clinical decision rules Simple Calculated Osteoporosis Risk Estimation (SCORE) and Osteoporosis Risk Assessment Instrument (ORAI) did not differ significantly in white women (relative sDOR: 0.57-1.17, all p >or= 0.11). By contrast, sDOR was higher for Stiffness Index assessed by calcaneal quantitative ultrasonography than for OST (relative sDOR: 1.9, p = 0.005). Studies were few in Asian and black women. Methodological quality, assessed with the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) checklist, was generally low. CONCLUSIONS: In white women, the accuracy of OST and alternative clinical decision rules was similar, whereas Stiffness Index was more accurate than OST. Low study quality renders transferability to clinical settings uncertain.

Impact of allocation concealment on conclusions drawn from meta-analyses of randomized trials.

BACKGROUND: Randomized trials without reported adequate allocation concealment have been shown to overestimate the benefit of experimental interventions. We investigated the robustness of conclusions drawn from meta-analyses to exclusion of such trials. MATERIAL: Random sample of 38 reviews from The Cochrane Library 2003, issue 2 and 32 other reviews from PubMed accessed in 2002. Eligible reviews presented a binary effect estimate from a meta-analysis of randomized controlled trials as the first statistically significant result that supported a conclusion in favour of one of the interventions. METHODS: We assessed the methods sections of the trials in each included meta-analysis for adequacy of allocation concealment. We replicated each meta-analysis using the authors' methods but included only trials that had adequate allocation concealment. Conclusions were defined as not supported if our result was not statistically significant. RESULTS: Thirty-four of the 70 meta-analyses contained a mixture of trials with unclear or inadequate concealment as well as trials with adequate allocation concealment. Four meta-analyses only contained trials with adequate concealment, and 32, only trials with unclear or inadequate concealment. When only trials with adequate concealment were included, 48 of 70 conclusions (69%; 95% confidence interval: 56-79%) lost support. The loss of support mainly reflected loss of power (the total number of patients was reduced by 49%) but also a shift in the point estimate towards a less beneficial effect. CONCLUSION: Two-thirds of conclusions in favour of one of the interventions were no longer supported if only trials with adequate allocation concealment were included.

Performance of the Osteoporosis Self-Assessment Tool in ruling out low bone mineral density in postmenopausal women: a systematic review.

UNLABELLED: The Osteoporosis Self-Assessment Tool (OST) is a simple test that may be of clinical value to rule-out low bone mineral density. We performed a systematic review to assess its performance in postmenopausal women. We included 36 studies. OST performed moderately in ruling-out femoral neck T-score or=0.28). Methodological study quality was generally low. CONCLUSIONS: The clinical usefulness of OST is uncertain. OST could be useful for ruling-out femoral neck T-score

Multivariable modelling for meta-epidemiological assessment of the association between trial quality and treatment effects estimated in randomized clinical trials.

Methodological deficiencies are known to affect the results of randomized trials. There are several components of trial quality, which, when inadequately attended to, may bias the treatment effect under study. The extent of this bias, so far only vaguely known, is currently being investigated by 'meta-epidemiological' re-analysis of data collected as part of systematic reviews. As inadequate quality components often co-occur, we maintain that the suspected biases must be evaluated simultaneously. Furthermore, the biases cannot safely be assumed to be homogeneous across systematic reviews. Therefore, a stable multivariable method that allows for heterogeneity is needed for assessing the 'bias coefficients'. We present two general statistical models for analysis of a study of 523 randomized trials from 48 meta-analyses in a random sample of Cochrane reviews: a logistic regression model uses the design of the trials as such to give estimates; a weighted regression model incorporates between-trial variation and thus gives wider confidence intervals, but is computationally lighter and can be used with trials of more general design. In both models, heterogeneity in the bias coefficients can be incorporated in two ways. A stratification approach pools the estimates from models estimated on subgroups of the data. We explore stratification by reviews and by broad trial types, the latter of which gives larger subgroups of the data, circumventing instabilities. A multilevel approach also avoids instabilities and addresses the more fundamental problem of interpretation of the pooled multivariable effect in the presence of heterogeneity.

Performance of four clinical screening tools to select peri- and early postmenopausal women for dual X-ray absorptiometry.

Several methods to select postmenopausal women for dual X-ray absorptiometry (DXA) have been proposed. We decided to compare the performance of three clinical decision rules (SCORE, ORAI, OST) with the usual case-finding strategy based on the presence of a major risk factor for future fracture (CFMRF). The study subjects were 2009 healthy, white, peri- or early postmenopausal women participating in the Danish Osteoporosis Prevention Study (DOPS). DXA results expressed as T-scores and scores on SCORE, ORAI, OST and CFMRF were extracted from the DOPS database. First, we evaluated the screening tools as originally described by the developers. The resulting sensitivities and specificities ranged from 18% to 92% and from 66% to 85%, respectively. Only OST achieved a high sensitivity (92%) with respect to femoral neck T-score < or = -2.5; however, the sensitivity with respect to lumbar spine T-score < or = -2.5 was only 51%. Next, the performance of the screening tools was evaluated against T-score < or = -2.0 (and T-score < or = -2.5) in at least one of the regions: femoral neck, total hip or lumbar spine. Using ROC curve analysis, we determined cut-offs yielding sensitivities as close as possible to 90%. The CFMRF and the ORAI tool were too coarse to yield 90% sensitivity. The performances of OST and SCORE were equal from a clinical perspective in that the sensitivities and the specificities varied from 89% to 94% and from 23% to 28%, respectively. The performance of CFMRF was no better than could be expected by chance, yielding a sensitivity of 19% and a specificity of 85%. Applying SCORE or OST 75% of the women would have to be referred for densitometry to identify 90% of the women with T-score < or = -2.0 (or T-score < or = -2.5) in at least one region. In conclusion, our results question the utility of all the evaluated tools for screening peri- and early postmenopausal women for low BMD. However, if a decision on referral has to be made, it may be based on the simple OST rule, which performed as well as or better than any of the other tools.

CLL family 'Pedigree 14' revisited: 1947-2004.

The notion that inherited predisposition contributes to the development of haematological malignancies is generally thought of as being a relatively new idea. However, Videbaek made a clear enunciation of such a hypothesis in 1947, from a study of tumour incidence in relatives of patients with different leukaemias. To gain further insight into inherited susceptibility to chronic lymphocytic leukaemia (CLL), we followed up the descendants of Videbaek's 'Pedigree 14' series of families. Using the Danish medical and pedigree databases, complete tracing of 222 descendants of the original 57 family members was achieved. To date, 10 family members have been diagnosed with CLL, one with T-cell lymphoma and 17 with nonhaematological cancers, including five with breast cancer. The detailed follow up of this family provides further support for inherited predisposition to CLL and illustrates the value of follow-up studies of previously published family material for genetic analyses.

Sensitive quantitative predictions of peptide-MHC binding by a 'Query by Committee' artificial neural network approach.

We have generated Artificial Neural Networks (ANN) capable of performing sensitive, quantitative predictions of peptide binding to the MHC class I molecule, HLA-A*0204. We have shown that such quantitative ANN are superior to conventional classification ANN, that have been trained to predict binding vs non-binding peptides. Furthermore, quantitative ANN allowed a straightforward application of a 'Query by Committee' (QBC) principle whereby particularly information-rich peptides could be identified and subsequently tested experimentally. Iterative training based on QBC-selected peptides considerably increased the sensitivity without compromising the efficiency of the prediction. This suggests a general, rational and unbiased approach to the development of high quality predictions of epitopes restricted to this and other HLA molecules. Due to their quantitative nature, such predictions will cover a wide range of MHC-binding affinities of immunological interest, and they can be readily integrated with predictions of other events involved in generating immunogenic epitopes. These predictions have the capacity to perform rapid proteome-wide searches for epitopes. Finally, it is an example of an iterative feedback loop whereby advanced, computational bioinformatics optimize experimental strategy, and vice versa.

Survival differences between heart failure in general practices and in hospitals.

OBJECTIVES: To compare the survival of patients thought to have heart failure in general practice (GP-HF) with that of patients with heart failure in hospital (hospital-HF), patients with heart disease but without heart failure (non-HF), and a control group without heart disease. DESIGN AND SETTING: Cross sectional study from general practice with a prospective follow up from 5.3 to 7.4 years. PARTICIPANTS: 2157 community participants, 1999 of whom lived outside nursing homes, were selected because they were registered with four general practitioners at entry. Study participants were divided into the four groups after a review of general practice case notes, questionnaires, and interviews. MAIN OUTCOME MEASURES: Five year survival and multivariate predictors of all cause mortality. RESULTS: Five year survival was 76% in the control group (n = 571, mean age at entry 74.1 years), 71% in non-HF patients (n = 218, 74.4 years), 61% in GP-HF patients (n = 67, 75.8 years), and 39% in hospital-HF patients (n = 33, 76.7 years). The median survival times were 6.8 years for GP-HF patients and 3.9 years for hospital-HF patients. Significant predictors of mortality in the multivariate Cox model of 1979 patients living outside nursing homes were hospital-HF (hazard ratio (HR) 2.1, p = 0.002), GP-HF (HR 1.7, p = 0.004), non-HF heart disease (HR 1.4, p = 0.03), previous myocardial infarction (HR 1.6, p = 0.04), no response to questionnaire (HR 2.0, p < 0.0001), higher age (for every 10 years, HR 2.4, p < 0.0001), and male sex (HR 2.1, p < 0.0001). Other factors such as atrial fibrillation, hypertension, and diabetes were not significant. CONCLUSION: Heart failure in general practice is associated with a worse survival than that seen in the control group but is better than for patients who have been treated at least once for heart failure in a hospital.

Numerical analysis of capillarity in packed spheres: planar hexagonal-packed spheres.

General solutions of the capillary pressure for liquids as a function of contact angle and volume in planar close-packed spheres have been calculated numerically using Surface Evolver software. Applied pressure differences between liquid and vapor result in undulating (puckered) menisci exhibiting anticlastic curvature in the narrower spaces near particle contacts. The corresponding capillary pressures exhibit maxima with infiltration volume (minima with drainage), corresponding to critical pressures for engulfment of the spheres by the liquid (vapor). The analysis also reveals the formation of residual pendular rings of the wetting phase around particle contacts. Pendular ring formation is explored further by analyzing hexagonally packed spheres separated by 1/10 their radius. The results are discussed relative to the wide range of approximate solutions available in the literature.

Wastewater exposure and health--a comparative study of two occupational groups.

AIMS: To investigate whether wastewater workers are at increased risk of developing cancer. METHODS: Two cohorts of workers employed by the City of Copenhagen, 591 wastewater workers and 1545 water supply workers (controls), were followed from 1965 until 1998. These two cohorts were compared in terms of cause specific mortality and cancer incidence. RESULTS: The wastewater workers' mortality exceeded that of the controls (relative risk (RR) = 1.25, 95% CI: 1.03 to 1.51). A similar small excess was seen for cancer incidence (RR = 1.27, 95% CI: 0.97 to 1.67). Though rare, there was a strongly increased incidence of primary liver cancer among the wastewater workers (RR = 8.9, 95% CI: 1.5 to 51.5). CONCLUSION: The excess mortality seen among the wastewater workers was smaller than originally feared. It may partly have been due to their occupational exposure, and for preventive purposes, exposure to wastewater and sludge should be minimised. The possibility that sewage exposure confers an increased risk of primary liver cancer deserves further investigation.

Premature stopping and informed consent in AMI trials.

Clinical trials give rise to ethical dilemmas, especially in the acutely ill, but we take issue with two points raised in a recent comment on a specific acute myocardial infarction (AMI) trial. The commentators judged that the trial most likely could, and therefore should, have been terminated much earlier. By analysing the problem statistically we arrive at results that go against their intuitive judgment-they also see it as mandatory to update the patient Information sheet as trial results accrue and trends begin to emerge. In our view, interpreting subtle trends and borderline p-values must rest with data monitoring boards, not patients. Moreover, patients with AMI or in other medical emergencies need very simple instructions. Empirical studies of the consent process confirm that the idea of a genuinely informed consent is problematic in such cases.

[Evidence-based use of clinical biochemistry]. / Evidensbaseret anvendelse af klinisk biokemi.

Evidence-based use of clinical biochemistry integrates into clinical decision-making the best research evidence with the clinical expertise of the physician and the expectations and concerns of the patient. The best research evidence for the clinical use of a biochemical test should be appraised in close collaboration between clinicians and specialists in clinical biochemistry, as familiarity with both the clinical problem and the analytical performance of the test is necessary. At present, it is difficult to ensure an evidence-based use of biochemical tests. More and methodologically better studies of the clinical value of biochemical tests are needed, and methods should be developed that make it possible to assess the results of such studies by systematic reviews and meta-analyses. Clinical biochemistry is an interdisciplinary specialty, and papers on the clinical value of biochemical tests are published in a vast number of journals of different clinical specialties as well as those of clinical biochemistry. It is thus almost impossible to keep abreast of the subject. The establishment of a system for literature surveillance focusing on methodologically sound studies of the clinical value of biochemical tests would be advantageous. Lastly, training and education on how to find and assess the existing evidence for the clinical use of biochemical tests are needed.

Quantitative predictions of peptide binding to MHC class I molecules using specificity matrices and anchor-stratified calibrations.

Peptides are key immune targets. They are generated by fragmentation of antigenic proteins, selected by major histocompatibility complex (MHC) molecules and subsequently presented to T cells. One of the most selective requirements is that of peptide binding to MHC. Accurate descriptions and predictions of peptide-MHC interactions are therefore important. Quantitative matrices representing MHC class I specificity can be used to search any query protein for the presence of MHC binding peptides. Assuming that each peptide residue contributes to binding in an additive and sequence independent manner, such "crude" matrix-driven predictions can be expressed as a quantitative estimates of binding strength. Crude matrix-driven predictions are reasonably uniform (i.e. precise), however, there is a general tendency towards overestimating binding (i.e. being inaccurate). To evaluate and possibly improve predictions, we have measured the MHC class I binding of a large number of peptides. In an attempt to further improve predictions and to include sequence dependency, we subdivided the panel of peptides according to whether the peptides had zero, one or two primary anchor residues. This allowed us to define unique anchor-stratified calibrations, which led to predictions of improved precision and accuracy.

Cross sectional study estimating prevalence of heart failure and left ventricular systolic dysfunction in community patients at risk.

OBJECTIVE: To examine a general practice population to measure the prevalence of signs and symptoms of heart failure (SSHF) and left ventricular systolic dysfunction (LVSD). DESIGN: Cross sectional screening study in three general practices followed by echocardiography. SETTING AND PATIENTS: All patients >/= 50 years in two general practices and >/= 40 years in one general practice were screened by case record reviews and questionnaires (n = 2158), to identify subjects with some evidence of heart disease. Among these, subjects were sought who had SSHF (n = 115). Of 357 subjects with evidence of heart disease, 252 were eligible for examination, and 126 underwent further cardiological assessment, including 43 with SSHF. MAIN OUTCOME MEASURES: Prevalence of SSHF as defined by a modified Boston index, LVSD defined as an indirectly measured left ventricular ejection fraction /= 50 years of age 6.4% had SSHF, 2.9% had LVSD, and 1.9% (95% confidence interval 1.3% to 2.5%) had both. To detect one case with LVSD in primary care, 14 patients with evidence of heart disease without SSHF and 5.5 patients with SSHF had to be examined. CONCLUSION: SSHF is extremely prevalent in the community, especially in primary care, but more than two thirds do not have LVSD. The number of subjects with some evidence of heart disease needing an echocardiogram to detect one case of LVSD is 14.