Reply: Timeliness, risk communication and patient preferences for investigations or referral

This is the final version. Available from the publisher via the DOI in this record.Letter to the Edito

Measures of promptness of cancer diagnosis in primary care: Secondary analysis of national audit data on patients with 18 common and rarer cancers

This is the final version. Available on open access from Springer Nature via the DOI in this recordBackground: Evidence is needed about the promptness of cancer diagnosis and associations between its measures. Methods: We analysed data from the National Audit of Cancer Diagnosis in Primary Care 2009-10 exploring the association between the interval from first symptomatic presentation to specialist referral (the primary care interval, or 'interval' hereafter) and the number of pre-referral consultations. Results: Among 13 035 patients with any of 18 different cancers, most (82%) were referred after 1 (58%) or 2 (25%) consultations (median intervals 0 and 15 days, respectively) while 9%, 4% and 5% patients required 3, 4 or 5+ consultations (median intervals 34, 47 and 97 days, respectively) (Spearman's r=0.70). The association was at least moderate for any cancer (Spearman's r range: 0.55 (prostate)-0.77 (brain)). Patients with cancers with a higher proportion of three or more pre-referral consultations typically also had longer median intervals (e.g., multiple myeloma) and vice versa (e.g., breast cancer). Conclusion: The number of pre-referral consultations has construct validity as a measure of the primary care interval. Developing interventions to reduce the number of pre-referral consultations can help improve the timeliness of cancer diagnosis, and constitutes a priority for early diagnosis initiatives and research. © 2013 Cancer Research UK. All rights reserved.National Institute for Health Research (NIHR

Gender inequalities in the promptness of diagnosis of bladder and renal cancer after symptomatic presentation: Evidence from secondary analysis of an English primary care audit survey

This is the final published version. Available from BMJ Publishing group via the DOI in this record.Data sharing statement: Please contact the corresponding author.Objectives: To explore whether women experience greater delays in the diagnosis of bladder and renal cancer when first presenting to a general practitioner with symptoms caused by those cancers and potential reasons for such gender inequalities. Design: Prospective national audit survey of cancer diagnosis. Setting: English primary care (2009-2010). Participants: 920 patients with bladder and 398 patients with renal cancer (252 (27%) and 165 (42%), respectively, were women). Primary and secondary outcome measures: Proportion of patients with three or more pre-referral consultations; number of days from first presentation to referral; proportion of patients who presented with haematuria and proportion of patients investigated in primary care. Results: Women required three or more prereferral consultations more often than men (27% (95% CI 21% to 33%) vs 11% (9% to 14%) for bladder (p<0.001); and 30% (22% to 39%) vs 18% (13% to 25%) for renal cancer (p=0.025)) and had a greater number of days from presentation to referral. In multivariable analysis (adjusting for age, haematuria status and use of primary care-led investigations), being a woman was independently associated with higher odds of three or more pre-referral consultations (OR=3.29 (2.06 to 5.25, p<0.001) for bladder cancer; and OR=1.90 (1.06 to 3.42, p=0.031) for renal cancer). Although presentation with haematuria was associated with more timely diagnosis of bladder cancer, gender inequalities did not vary by haematuria status for either cancer (p=0.18 for bladder and p=0.27 for renal). Each year in the UK, approximately 700 women with either bladder or renal cancer experience a delayed diagnosis because of their gender, of whom more than a quarter (197, or 28%) present with haematuria. Conclusions: There are notable gender inequalities in the timeliness of diagnosis of urological cancers. There is a need to both reinforce existing guidelines on haematuria investigation and develop new diagnostic decision aids and tests for patients who present without haematuria. Copyright © 2013 BMJ Publishing Group. All rights reserved.National Institute for Health Research (NIHR

Methane storms as a driver of Titan's dune orientation

Titan's equatorial regions are covered by eastward propagating linear dunes. This direction is opposite to mean surface winds simulated by Global Climate Models (GCMs), which are oriented westward at these latitudes, similar to trade winds on Earth. Different hypotheses have been proposed to address this apparent contradiction, involving Saturn's gravitational tides, large scale topography or wind statistics, but none of them can explain a global eastward dune propagation in the equatorial band. Here we analyse the impact of equinoctial tropical methane storms developing in the superrotating atmosphere (i.e. the eastward winds at high altitude) on Titan's dune orientation. Using mesoscale simulations of convective methane clouds with a GCM wind profile featuring superrotation, we show that Titan's storms should produce fast eastward gust fronts above the surface. Such gusts dominate the aeolian transport, allowing dunes to extend eastward. This analysis therefore suggests a coupling between superrotation, tropical methane storms and dune formation on Titan. Furthermore, together with GCM predictions and analogies to some terrestrial dune fields, this work provides a general framework explaining several major features of Titan's dunes: linear shape, eastward propagation and poleward divergence, and implies an equatorial origin of Titan's dune sand.Comment: Published online on Nature Geoscience on 13 April 201

Impact of investigations in general practice on timeliness of referral for patients subsequently diagnosed with cancer: Analysis of national primary care audit data

This is the final published version. Available from Springer Nature via the DOI in this record.Background:For patients with symptoms of possible cancer who do not fulfil the criteria for urgent referral, initial investigation in primary care has been advocated in the United Kingdom and supported by additional resources. The consequence of this strategy for the timeliness of diagnosis is unknown.Methods:We analysed data from the English National Audit of Cancer Diagnosis in Primary Care on patients with lung (1494), colorectal (2111), stomach (246), oesophagus (513), pancreas (327), and ovarian (345) cancer relating to the ordering of investigations by the General Practitioner and their nature. Presenting symptoms were categorised according to National Institute for Health and Care Excellence (NICE) guidance on referral for suspected cancer. We used linear regression to estimate the mean difference in primary-care interval by cancer, after adjustment for age, gender, and the symptomatic presentation category.Results:Primary-care investigations were undertaken in 3198/5036 (64%) of cases. The median primary-care interval was 16 days (IQR 5-45) for patients undergoing investigation and 0 days (IQR 0-10) for those not investigated. Among patients whose symptoms mandated urgent referral to secondary care according to NICE guidelines, between 37% (oesophagus) and 75% (pancreas) were first investigated in primary care. In multivariable linear regression analyses stratified by cancer site, adjustment for age, sex, and NICE referral category explained little of the observed prolongation associated with investigation.Interpretation:For six specified cancers, investigation in primary care was associated with later referral for specialist assessment. This effect was independent of the nature of symptoms. Some patients for whom urgent referral is mandated by NICE guidance are nevertheless investigated before referral. Reducing the intervals between test order, test performance, and reporting can help reduce the prolongation of primary-care intervals associated with investigation use. Alternative models of assessment should be considered.National Institute for Health Research (NIHR

Meaningful characterisation of perturbative theoretical uncertainties

We consider the problem of assigning a meaningful degree of belief to uncertainty estimates of perturbative series. We analyse the assumptions which are implicit in the conventional estimates made using renormalisation scale variations. We then formulate a Bayesian model that, given equivalent initial hypotheses, allows one to characterise a perturbative theoretical uncertainty in a rigorous way in terms of a credibility interval for the remainder of the series. We compare its outcome to the conventional uncertainty estimates in the simple case of the calculation of QCD corrections to the e+e- -> hadrons process. We find comparable results, but with important conceptual differences. This work represents a first step in the direction of a more comprehensive and rigorous handling of theoretical uncertainties in perturbative calculations used in high energy phenomenology.Comment: 28 pages, 5 figures. Language modified in order to make it more 'bayesian'. No change in results. Version published in JHE

Comparison of cancer diagnostic intervals before and after implementation of NICE guidelines: analysis of data from the UK General Practice Research Database

This is the final version of the article. Available from Nature Publishing Group via the DOI in this record.BACKGROUND: The primary aim was to use routine data to compare cancer diagnostic intervals before and after implementation of the 2005 NICE Referral Guidelines for Suspected Cancer. The secondary aim was to compare change in diagnostic intervals across different categories of presenting symptoms. METHODS: Using data from the General Practice Research Database, we analysed patients with one of 15 cancers diagnosed in either 2001-2002 or 2007-2008. Putative symptom lists for each cancer were classified into whether or not they qualified for urgent referral under NICE guidelines. Diagnostic interval (duration from first presented symptom to date of diagnosis in primary care records) was compared between the two cohorts. RESULTS: In total, 37,588 patients had a new diagnosis of cancer and of these 20,535 (54.6%) had a recorded symptom in the year prior to diagnosis and were included in the analysis. The overall mean diagnostic interval fell by 5.4 days (95% CI: 2.4-8.5; P<0.001) between 2001-2002 and 2007-2008. There was evidence of significant reductions for the following cancers: (mean, 95% confidence interval) kidney (20.4 days, -0.5 to 41.5; P=0.05), head and neck (21.2 days, 0.2-41.6; P=0.04), bladder (16.4 days, 6.6-26.5; P≤0.001), colorectal (9.0 days, 3.2-14.8; P=0.002), oesophageal (13.1 days, 3.0-24.1; P=0.006) and pancreatic (12.6 days, 0.2-24.6; P=0.04). Patients who presented with NICE-qualifying symptoms had shorter diagnostic intervals than those who did not (all cancers in both cohorts). For the 2007-2008 cohort, the cancers with the shortest median diagnostic intervals were breast (26 days) and testicular (44 days); the highest were myeloma (156 days) and lung (112 days). The values for the 90th centiles of the distributions remain very high for some cancers. Tests of interaction provided little evidence of differences in change in mean diagnostic intervals between those who did and did not present with symptoms specifically cited in the NICE Guideline as requiring urgent referral. CONCLUSION: We suggest that the implementation of the 2005 NICE Guidelines may have contributed to this reduction in diagnostic intervals between 2001-2002 and 2007-2008. There remains considerable scope to achieve more timely cancer diagnosis, with the ultimate aim of improving cancer outcomes.This research was funded by the National Cancer Action Team and the Department of Health Cancer Policy Team. The views contained in it are those of the authors and do not represent Department of Health policy. We can confirm that the corresponding author has had full access to the data and final responsibility for the decision to submit for publication. We would like to thank Rosemary Tate for early input into the protocol, staff of the GPRD for help in understanding the data. OCU is supported by the Peninsula Collaboration for Leadership in Applied Health Research and Care. Ethical approval: Independent Scientific Advisory Committee, numbers 09_0110 and 09_0111

The relative length of the patient and the primary care interval in patients with 28 common and rarer cancers

This is the final version. Available from the publisher via the DOI in this record.BACKGROUND: Appreciating variation in the length of pre- or post-presentation diagnostic intervals can help prioritise early diagnosis interventions with either a community or a primary care focus.METHODS: We analysed data from the first English National Audit of Cancer Diagnosis in Primary Care on 10 953 patients with any of 28 cancers. We calculated summary statistics for the length of the patient and the primary care interval and their ratio, by cancer site.RESULTS: Interval lengths varied greatly by cancer. Laryngeal and oropharyngeal cancers had the longest median patient intervals, whereas renal and bladder cancer had the shortest (34.5 and 30 compared with 3 and 2 days, respectively). Multiple myeloma and gallbladder cancer had the longest median primary care intervals, and melanoma and breast cancer had the shortest (20.5 and 20 compared with 0 and 0 days, respectively). Mean patient intervals were longer than primary care intervals for most (18 of 28) cancers, and notably so (two- to five-fold greater) for 10 cancers (breast, melanoma, testicular, vulval, cervical, endometrial, oropharyngeal, laryngeal, ovarian and thyroid).CONCLUSIONS: The findings support the continuing development and evaluation of public health interventions aimed at shortening patient intervals, particularly for cancers with long patient interval and/or high patient interval over primary care interval ratio.National Institute for Health Research (NIHR)Cancer Research UKPublic Health WalesBetsi Cadwaladr University Health Boar

A first principles approach to differential expression in microarray data analysis

<p>Abstract</p> <p>Background</p> <p>The disparate results from the methods commonly used to determine differential expression in Affymetrix microarray experiments may well result from the wide variety of probe set and probe level models employed. Here we take the approach of making the fewest assumptions about the structure of the microarray data. Specifically, we only require that, under the null hypothesis that a gene is not differentially expressed for specified conditions, for any probe position in the gene's probe set: a) the probe amplitudes are independent and identically distributed over the conditions, and b) the distributions of the replicated probe amplitudes are amenable to classical analysis of variance (ANOVA). Log-amplitudes that have been standardized within-chip meet these conditions well enough for our approach, which is to perform ANOVA across conditions for each probe position, and then take the median of the resulting (1 - p) values as a gene-level measure of differential expression.</p> <p>Results</p> <p>We applied the technique to the HGU-133A, HG-U95A, and "Golden Spike" spike-in data sets. The resulting receiver operating characteristic (ROC) curves compared favorably with other published results. This procedure is quite sensitive, so much so that it has revealed the presence of probe sets that might properly be called "unanticipated positives" rather than "false positives", because plots of these probe sets strongly suggest that they are differentially expressed.</p> <p>Conclusion</p> <p>The median ANOVA (1-p) approach presented here is a very simple methodology that does not depend on any specific probe level or probe models, and does not require any pre-processing other than within-chip standardization of probe level log amplitudes. Its performance is comparable to other published methods on the standard spike-in data sets, and has revealed the presence of new categories of probe sets that might properly be referred to as "unanticipated positives" and "unanticipated negatives" that need to be taken into account when using spiked-in data sets at "truthed" test beds.</p

Variation in promptness of presentation among 10,297 patients subsequently diagnosed with one of 18 cancers: Evidence from a National Audit of Cancer Diagnosis in Primary Care

This is the final published version. Available from Wiley via the DOI in this record.Cancer awareness public campaigns aim to shorten the interval between symptom onset and presentation to a doctor (the 'patient interval'). Appreciating variation in promptness of presentation can help to better target awareness campaigns. We explored variation in patient intervals recorded in consultations with general practitioners among 10,297 English patients subsequently diagnosed with one of 18 cancers (bladder, brain, breast, colorectal, endometrial, leukaemia, lung, lymphoma, melanoma, multiple myeloma, oesophageal, oro-pharyngeal, ovarian, pancreatic, prostate, renal, stomach, and unknown primary) using data from of the National Audit of Cancer Diagnosis in Primary Care (2009-2010). Proportions of patients with 'prompt'/'non-prompt' presentation (0-14 or 15+ days from symptom onset, respectively) were described and respective odds ratios were calculated by multivariable logistic regression. The overall median recorded patient interval was 10 days (IQR 0-38). Of all patients, 56% presented promptly. Prompt presentation was more frequent among older or housebound patients (p < 0.001). Prompt presentation was most frequent for bladder and renal cancer (74% and 70%, respectively); and least frequent for oro-pharyngeal and oesophageal cancer (34% and 39%, respectively, p <.001). Using lung cancer as reference, the adjusted odds ratios of non-prompt presentation were 2.26 (95% confidence interval 1.57-3.25) and 0.42 (0.34-0.52) for oro-pharyngeal and bladder cancer, respectively. Sensitivity analyses produced similar findings. Routinely recorded patient interval data reveal considerable variation in the promptness of presentation. These findings can help to prioritise public awareness initiatives and research focusing on symptoms of cancers associated with greater risk of non-prompt presentation, such as oro-pharyngeal and oesophageal cancer. What's new? A critical aspect of cancer diagnosis is how promptly patients consult a doctor after they first notice initial symptoms. Here, the authors examine differences in this so-called patient interval in English patients subsequently diagnosed with one of 18 cancers. On average, patients with bladder and renal cancer as well as older and housebound patients consulted a doctor relatively promptly while patients with oro-pharyngeal and oesophageal cancer took the longest until first presenting to a general practitioner. The authors point out that cancer awareness campaigns should encompass symptoms of oro-pharyngeal and oesophageal cancer aiming to shorten the patient interval for these cancers. © 2014 The Authors. Published by Wiley Periodicals, Inc. on behalf of UICC.National Institute for Health Research (NIHR)NHS Public Health Training Schem