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1.  An ongoing case–control study to evaluate the NHS Bowel Cancer Screening Programme 
BMC Cancer  2014;14:945.
Colorectal cancer is the third most common cause of cancer death in both males and females in England. A national bowel cancer screening programme was rolled out in England between 2006 and 2010. In the post-randomised controlled trials epoch, assessment of the impact of the programme using observational studies is needed.
This study protocol was set up at the request of the UK Policy Research Unit in Cancer Awareness, Screening and Early Diagnosis to evaluate the effect of the current bowel cancer screening programme on incidence of advanced primary colorectal cancer.
All incident cases of primary colorectal cancer in England will be included. Cases will be matched to controls with respect to sex, age, area of registration and year of first invitation to screening. Each evaluation round will cover a 2-year period, starting from January 2012, and ongoing thereafter. In the first instance, a pilot will be carried out in a single region. Variables related to colorectal tumour pathology will be obtained to enable selection and matching of cases and controls, and to allow analyses stratification by anatomical subsite within the bowel. Cases at Duke’s stage B or worse will be considered as "advanced stage". The influence of sex will also be investigated. The incidence ratio observed in randomised controlled trials between controls (not invited) and non-attender invitees will be used to correct for self-selection bias overall. Screening participation at other national screening programmes (cervical, breast) will also be collected to derive a more contemporaneous adjustment factor for self-selection bias and assess consistency in self-selection correction in female patients.
Full ethical approval was obtained from the Health Research Authority.
The case–control design is potentially prone to a number of biases. The size of the planned study, the design specifications and the development of analytical strategies to cope with bias should enable us to obtain accurate estimates of reduction in incidence of advanced stage disease. The results of analyses by sex and anatomical subsite may highlight the potential need for sex-specific recommendations in the programme.
PMCID: PMC4320602  PMID: 25495609
Bowel cancer; Screening; Case–control; Incidence; Advanced stage
2.  Mammographic breast density refines Tyrer-Cuzick estimates of breast cancer risk in high-risk women: findings from the placebo arm of the International Breast Cancer Intervention Study I 
Mammographic density is well-established as a risk factor for breast cancer, however, adjustment for age and body mass index (BMI) is vital to its clinical interpretation when assessing individual risk. In this paper we develop a model to adjust mammographic density for age and BMI and show how this adjusted mammographic density measure might be used with existing risk prediction models to identify high-risk women more precisely.
We explored the association between age, BMI, visually assessed percent dense area and breast cancer risk in a nested case-control study of women from the placebo arm of the International Breast Cancer Intervention Study I (72 cases, 486 controls). Linear regression was used to adjust mammographic density for age and BMI. This adjusted measure was evaluated in a multivariable logistic regression model that included the Tyrer-Cuzick (TC) risk score, which is based on classical breast cancer risk factors.
Percent dense area adjusted for age and BMI (the density residual) was a stronger measure of breast cancer risk than unadjusted percent dense area (odds ratio per standard deviation 1.55 versus 1.38; area under the curve (AUC) 0.62 versus 0.59). Furthermore, in this population at increased risk of breast cancer, the density residual added information beyond that obtained from the TC model alone, with the AUC for the model containing both TC risk and density residual being 0.62 compared to 0.51 for the model containing TC risk alone (P =0.002).
Approximately 16% of controls and 19% of cases moved into the highest risk group (8% or more absolute risk of developing breast cancer within 10 years) when the density residual was taken into account. The net reclassification index was +15.7%.
In women at high risk of breast cancer, adjusting percent mammographic density for age and BMI provides additional predictive information to the TC risk score, which already incorporates BMI, age, family history and other classic breast cancer risk factors. Furthermore, simple selection criteria can be developed using mammographic density, age and BMI to identify women at increased risk in a clinical setting.
Clinical trial registration number (Registered: 1 June 2006).
PMCID: PMC4303130  PMID: 25292294
3.  Risk determination and prevention of breast cancer 
Breast cancer is an increasing public health problem. Substantial advances have been made in the treatment of breast cancer, but the introduction of methods to predict women at elevated risk and prevent the disease has been less successful. Here, we summarize recent data on newer approaches to risk prediction, available approaches to prevention, how new approaches may be made, and the difficult problem of using what we already know to prevent breast cancer in populations. During 2012, the Breast Cancer Campaign facilitated a series of workshops, each covering a specialty area of breast cancer to identify gaps in our knowledge. The risk-and-prevention panel involved in this exercise was asked to expand and update its report and review recent relevant peer-reviewed literature. The enlarged position paper presented here highlights the key gaps in risk-and-prevention research that were identified, together with recommendations for action. The panel estimated from the relevant literature that potentially 50% of breast cancer could be prevented in the subgroup of women at high and moderate risk of breast cancer by using current chemoprevention (tamoxifen, raloxifene, exemestane, and anastrozole) and that, in all women, lifestyle measures, including weight control, exercise, and moderating alcohol intake, could reduce breast cancer risk by about 30%. Risk may be estimated by standard models potentially with the addition of, for example, mammographic density and appropriate single-nucleotide polymorphisms. This review expands on four areas: (a) the prediction of breast cancer risk, (b) the evidence for the effectiveness of preventive therapy and lifestyle approaches to prevention, (c) how understanding the biology of the breast may lead to new targets for prevention, and (d) a summary of published guidelines for preventive approaches and measures required for their implementation. We hope that efforts to fill these and other gaps will lead to considerable advances in our efforts to predict risk and prevent breast cancer over the next 10 years.
PMCID: PMC4303126  PMID: 25467785
4.  Therapeutic Targeting of Integrin αvβ6 in Breast Cancer 
Integrin αvβ6 promotes migration, invasion, and survival of cancer cells; however, the relevance and role of αvβ6 has yet to be elucidated in breast cancer.
Protein expression of integrin subunit beta6 (β6) was measured in breast cancers by immunohistochemistry (n > 2000) and ITGB6 mRNA expression measured in the Molecular Taxonomy of Breast Cancer International Consortium dataset. Overall survival was assessed using Kaplan Meier curves, and bioinformatics statistical analyses were performed (Cox proportional hazards model, Wald test, and Chi-square test of association). Using antibody (264RAD) blockade and siRNA knockdown of β6 in breast cell lines, the role of αvβ6 in Human Epidermal Growth Factor Receptor 2 (HER2) biology (expression, proliferation, invasion, growth in vivo) was assessed by flow cytometry, MTT, Transwell invasion, proximity ligation assay, and xenografts (n ≥ 3), respectively. A student’s t-test was used for two variables; three-plus variables used one-way analysis of variance with Bonferroni’s Multiple Comparison Test. Xenograft growth was analyzed using linear mixed model analysis, followed by Wald testing and survival, analyzed using the Log-Rank test. All statistical tests were two sided.
High expression of either the mRNA or protein for the integrin subunit β6 was associated with very poor survival (HR = 1.60, 95% CI = 1.19 to 2.15, P = .002) and increased metastases to distant sites. Co-expression of β6 and HER2 was associated with worse prognosis (HR = 1.97, 95% CI = 1.16 to 3.35, P = .01). Monotherapy with 264RAD or trastuzumab slowed growth of MCF-7/HER2-18 and BT-474 xenografts similarly (P < .001), but combining 264RAD with trastuzumab effectively stopped tumor growth, even in trastuzumab-resistant MCF-7/HER2-18 xenografts.
Targeting αvβ6 with 264RAD alone or in combination with trastuzumab may provide a novel therapy for treating high-risk and trastuzumab-resistant breast cancer patients.
PMCID: PMC4151855  PMID: 24974129
5.  Reduced UCP-1 Content in In Vitro Differentiated Beige/Brite Adipocytes Derived from Preadipocytes of Human Subcutaneous White Adipose Tissues in Obesity 
PLoS ONE  2014;9(3):e91997.
Brown adipose tissue (BAT) is a potential therapeutic target to reverse obesity. The purpose of this study was to determine whether primary precursor cells isolated from human adult subcutaneous white adipose tissue (WAT) can be induced to differentiate in-vitro into adipocytes that express key markers of brown or beige adipose, and whether the expression level of such markers differs between lean and obese young adult males.
Adipogenic precursor cells were isolated from lean and obese individuals from subcutaneous abdominal WAT biopsies. Cells were grown to confluence, differentiated for 2.5 weeks then harvested for measurement of gene expression and UCP1 protein.
There was no difference between groups with respect to differentiation into adipocytes, as indicated by oil red-O staining, rates of lipolysis, and expression of adipogenic genes (FABP4, PPARG). WAT genes (HOXC9, RB1) were expressed equally in the two groups. Post differentiation, the beige adipose specific genes CITED1 and CD137 were significantly increased in both groups, but classic BAT markers ZIC1 and LHX8 decreased significantly. Cell lines from both groups also equally increased post-differentiation expression of the thermogenic-responsive gene PPARGC1A (PGC-1α). UCP1 gene expression was undetectable prior to differentiation, however after differentiation both gene expression and protein content were increased in both groups and were significantly greater in cultures from lean compared with obese individuals (p<0.05).
Human subcutaneous WAT cells can be induced to attain BAT characteristics, but this capacity is reduced in WAT cells from obese individuals.
PMCID: PMC3958417  PMID: 24642703
6.  Percutaneous Mitral Annuloplasty for Functional Mitral Regurgitation 
Circulation  2009;120(4):326-333.
Functional mitral regurgitation (FMR), a well-recognized component of left ventricular remodeling, is associated with increased morbidity and mortality in heart failure patients. Percutaneous mitral annuloplasty has the potential to serve as a therapeutic adjunct to standard medical care.
Methods and Results
Patients with dilated cardiomyopathy, moderate to severe FMR, an ejection fraction <40%, and a 6-minute walk distance between 150 and 450 m were enrolled in the CARILLON Mitral Annuloplasty Device European Union Study (AMADEUS). Percutaneous mitral annuloplasty was achieved through the coronary sinus with the CARILLON Mitral Contour System. Echocardiographic FMR grade, exercise tolerance, New York Heart Association class, and quality of life were assessed at baseline and 1 and 6 months. Of the 48 patients enrolled in the trial, 30 received the CARILLON device. Eighteen patients did not receive a device because of access issues, insufficient acute FMR reduction, or coronary artery compromise. The major adverse event rate was 13% at 30 days. At 6 months, the degree of FMR reduction among 5 different quantitative echocardiographic measures ranged from 22% to 32%. Six-minute walk distance improved from 307±87 m at baseline to 403±137 m at 6 months (P<0.001). Quality of life, measured by the Kansas City Cardiomyopathy Questionnaire, improved from 47±16 points at baseline to 69±15 points at 6 months (P<0.001).
Percutaneous reduction in FMR with a novel coronary sinus–based mitral annuloplasty device is feasible in patients with heart failure, is associated with a low rate of major adverse events, and is associated with improvement in quality of life and exercise tolerance.
PMCID: PMC3954526  PMID: 19597051
heart failure; mitral valve; regurgitation
7.  Factors Associated With Delayed Diagnosis of Breast Cancer in Northeast Thailand 
Journal of Epidemiology  2014;24(2):102-108.
We identified factors associated with delayed first consultation for breast symptoms (patient delay), delayed diagnosis after first consultation (doctor delay), and advanced pathologic stage at presentation among 180 women with breast cancer in Thailand.
In this cross-sectional study 180 patients with invasive breast cancer were interviewed about potential risk factors and markers of delayed presentation. Patient delay was defined as time from onset of symptoms to first consultation with a health care provider, and doctor delay was defined as time from first consultation with a health care provider to diagnosis of breast cancer. Linear regression and logistic regression were used for the data analyses.
Among the 180 patients, 17% delayed seeking consultation for longer than 3 months, and 42% reported a doctor delay of longer than 3 months. In multivariate linear analysis, a significant increase in patient delay was associated with higher family income and smoking; factors associated with increased doctor delay were previous breast symptoms, self-treatment, and travel time to the hospital. In multiple logistic regression, doctor delay was related to age at first birth (P = 0.003), previous breast symptoms (P = 0.01), and number of consultations with a surgeon before diagnosis (P = 0.007). Regarding stage of breast cancer, there were significant associations with age at diagnosis (P for trend = 0.04), education (P for trend = 0.01), family income (P for trend = 0.02), time to referral (P = 0.01), and number of consultations with a surgeon before diagnosis (P < 0.01).
Hospital referral from a health care provider was a major contributor to delayed diagnosis. Breast cancer awareness campaigns in Thailand should target individuals in low- and high-income groups, as well as practitioners.
PMCID: PMC3983282  PMID: 24335087
delayed diagnosis; advanced stage; breast cancer; Thailand
8.  Correction: The K+ Channel KCa3.1 as a Novel Target for Idiopathic Pulmonary Fibrosis  
PLoS ONE  2014;9(1):10.1371/annotation/790e86f8-3506-49d6-b7d0-7dbbc580d808.
PMCID: PMC3897356
9.  The K+ Channel KCa3.1 as a Novel Target for Idiopathic Pulmonary Fibrosis  
PLoS ONE  2013;8(12):e85244.
Idiopathic pulmonary fibrosis (IPF) is a common, progressive and invariably lethal interstitial lung disease with no effective therapy. We hypothesised that KCa3.1 K+ channel-dependent cell processes contribute to IPF pathophysiology.
KCa3.1 expression in primary human lung myofibroblasts was examined using RT-PCR, western blot, immunofluorescence and patch-clamp electrophysiology. The role of KCa3.1 channels in myofibroblast proliferation, wound healing, collagen secretion and contraction was examined using two specific and distinct KCa3.1 blockers (TRAM-34 and ICA-17043 [Senicapoc]).
Both healthy non fibrotic control and IPF-derived human lung myofibroblasts expressed KCa3.1 channel mRNA and protein. KCa3.1 ion currents were elicited more frequently and were larger in IPF-derived myofibroblasts compared to controls. KCa3.1 currents were increased in myofibroblasts by TGFβ1 and basic FGF. KCa3.1 was expressed strongly in IPF tissue. KCa3.1 pharmacological blockade attenuated human myofibroblast proliferation, wound healing, collagen secretion and contractility in vitro, and this was associated with inhibition of TGFβ1-dependent increases in intracellular free Ca2+.
KCa3.1 activity promotes pro-fibrotic human lung myofibroblast function. Blocking KCa3.1 may offer a novel approach to treating IPF with the potential for rapid translation to the clinic.
PMCID: PMC3877378  PMID: 24392001
10.  An ongoing case-control study to evaluate the NHS breast screening programme 
BMC Cancer  2013;13:596.
In England, a national breast screening programme (NHSBSP) has been in place since 1988, and assessment of its impact on breast cancer incidence and mortality is essential to ensure that the programme is indeed doing more good than harm. This article describes large observation studies designed to estimate the effects of the current programme in terms of the benefits on breast cancer incidence and mortality and detrimental effect in terms of overdiagnosis. The case-control design of the cervical screening programme evaluation was highly effective in informing policy on screening intervals and age ranges. We propose innovative selection of cases and controls and gathering of additional variables to address new outcomes of interest and develop new methodologies to control for potential sources of bias.
Traditional case-control evaluation of breast screening uses women who have died from breast cancer as cases, and women known to be alive at the time of case death as controls. Breast screening histories prior to the cases’ date of first diagnosis are compared. If breast screening is preventing mortality from breast cancer, cases will be characterised by a lesser screening history than controls. All deaths and incident cases of primary breast cancer in England within each 2-year study period will be included in this ongoing evaluation. Cases will be age- and area-matched to controls and variables related to cancer treatment and breast tumour pathology will be obtained to investigate the interplay between screening and treatment, and the effect of screening on incidence of advanced stage disease. Screening attendance at other national screening programmes will also be collected to derive superior adjustment for self-selection bias.
The study is registered and has received full ethics approval.
PMCID: PMC3866937  PMID: 24330588
Breast cancer; Case–control; Incidence; Mortality; Overdiagnosis; Advanced stage; Bias
11.  Correction: Pro-Inflammatory Action of MIF in Acute Myocardial Infarction via Activation of Peripheral Blood Mononuclear Cells 
PLoS ONE  2013;8(11):10.1371/annotation/6e24b7bb-83c7-4887-9621-96b64acfb1c1.
PMCID: PMC3829978  PMID: 24250778
12.  Pro-Inflammatory Action of MIF in Acute Myocardial Infarction via Activation of Peripheral Blood Mononuclear Cells 
PLoS ONE  2013;8(10):e76206.
Macrophage migration inhibitory factor (MIF), a pro-inflammatory cytokine, has been implicated in the pathogenesis of multiple inflammatory disorders. We determined changes in circulating MIF levels, explored the cellular source of MIF, and studied the role of MIF in mediating inflammatory responses following acute myocardial infarction (MI).
Methods and Results
We recruited 15 patients with MI, 10 patients with stable angina and 10 healthy volunteers and measured temporal changes of MIF in plasma. Expression of MIF, matrix metalloproteinase-9 (MMP-9) and interleukin-6 (IL-6) in cultured peripheral blood mononuclear cells (PBMCs) and the media were measured by ELISA or real-time PCR. Compared to controls, plasma levels of MIF and IL-6 were significantly elevated at admission and 72 h post-MI. In contrast, expression of MIF, MMP-9 and IL-6 by PBMCs from MI patients was unchanged at admission, but significantly increased at 72 h. Addition of MIF activated cultured PBMCs by upregulating expression of inflammatory molecules and also synergistically enhanced stimulatory action of IL-1β which were inhibited by anti-MIF interventions. In a mouse MI model we observed similar changes in circulating MIF as seen in patients, with reciprocal significant increases in plasma MIF and reduction of MIF content in the infarct myocardium at 3 h after MI. MIF content in the infarct myocardium was restored at 72 h post-MI and was associated with robust macrophage infiltration. Further, anti-MIF intervention significantly reduced inflammatory cell infiltration and expression of monocyte chemoattractant protein-1 at 24 h and incidence of cardiac rupture in mice post-MI.
MI leads to a rapid release of MIF from the myocardium into circulation. Subsequently MIF facilitates PBMC production of pro-inflammatory mediators and myocardial inflammatory infiltration. Attenuation of these events, and post-MI cardiac rupture, by anti-MIF interventions suggests that MIF could be a potential therapeutic target following MI.
PMCID: PMC3788072  PMID: 24098445
13.  Macrophage Migration Inhibitory Factor for the Early Prediction of Infarct Size 
Early diagnosis and knowledge of infarct size is critical for the management of acute myocardial infarction (MI). We evaluated whether early elevated plasma level of macrophage migration inhibitory factor (MIF) is useful for these purposes in patients with ST‐elevation MI (STEMI).
Methods and Results
We first studied MIF level in plasma and the myocardium in mice and determined infarct size. MI for 15 or 60 minutes resulted in 2.5‐fold increase over control values in plasma MIF levels while MIF content in the ischemic myocardium reduced by 50% and plasma MIF levels correlated with myocardium‐at‐risk and infarct size at both time‐points (P<0.01). In patients with STEMI, we obtained admission plasma samples and measured MIF, conventional troponins (TnI, TnT), high sensitive TnI (hsTnI), creatine kinase (CK), CK‐MB, and myoglobin. Infarct size was assessed by cardiac magnetic resonance (CMR) imaging. Patients with chronic stable angina and healthy volunteers were studied as controls. Of 374 STEMI patients, 68% had elevated admission MIF levels above the highest value in healthy controls (>41.6 ng/mL), a proportion similar to hsTnI (75%) and TnI (50%), but greater than other biomarkers studied (20% to 31%, all P<0.05 versus MIF). Only admission MIF levels correlated with CMR‐derived infarct size, ventricular volumes and ejection fraction (n=42, r=0.46 to 0.77, all P<0.01) at 3 day and 3 months post‐MI.
Plasma MIF levels are elevated in a high proportion of STEMI patients at the first obtainable sample and these levels are predictive of final infarct size and the extent of cardiac remodeling.
PMCID: PMC3835222  PMID: 24096574
infarct size; macrophage migration inhibitory factor; myocardial infarction
14.  Critical research gaps and translational priorities for the successful prevention and treatment of breast cancer 
Eccles, Suzanne A | Aboagye, Eric O | Ali, Simak | Anderson, Annie S | Armes, Jo | Berditchevski, Fedor | Blaydes, Jeremy P | Brennan, Keith | Brown, Nicola J | Bryant, Helen E | Bundred, Nigel J | Burchell, Joy M | Campbell, Anna M | Carroll, Jason S | Clarke, Robert B | Coles, Charlotte E | Cook, Gary JR | Cox, Angela | Curtin, Nicola J | Dekker, Lodewijk V | dos Santos Silva, Isabel | Duffy, Stephen W | Easton, Douglas F | Eccles, Diana M | Edwards, Dylan R | Edwards, Joanne | Evans, D Gareth | Fenlon, Deborah F | Flanagan, James M | Foster, Claire | Gallagher, William M | Garcia-Closas, Montserrat | Gee, Julia M W | Gescher, Andy J | Goh, Vicky | Groves, Ashley M | Harvey, Amanda J | Harvie, Michelle | Hennessy, Bryan T | Hiscox, Stephen | Holen, Ingunn | Howell, Sacha J | Howell, Anthony | Hubbard, Gill | Hulbert-Williams, Nick | Hunter, Myra S | Jasani, Bharat | Jones, Louise J | Key, Timothy J | Kirwan, Cliona C | Kong, Anthony | Kunkler, Ian H | Langdon, Simon P | Leach, Martin O | Mann, David J | Marshall, John F | Martin, Lesley Ann | Martin, Stewart G | Macdougall, Jennifer E | Miles, David W | Miller, William R | Morris, Joanna R | Moss, Sue M | Mullan, Paul | Natrajan, Rachel | O’Connor, James PB | O’Connor, Rosemary | Palmieri, Carlo | Pharoah, Paul D P | Rakha, Emad A | Reed, Elizabeth | Robinson, Simon P | Sahai, Erik | Saxton, John M | Schmid, Peter | Smalley, Matthew J | Speirs, Valerie | Stein, Robert | Stingl, John | Streuli, Charles H | Tutt, Andrew N J | Velikova, Galina | Walker, Rosemary A | Watson, Christine J | Williams, Kaye J | Young, Leonie S | Thompson, Alastair M
Breast cancer remains a significant scientific, clinical and societal challenge. This gap analysis has reviewed and critically assessed enduring issues and new challenges emerging from recent research, and proposes strategies for translating solutions into practice.
More than 100 internationally recognised specialist breast cancer scientists, clinicians and healthcare professionals collaborated to address nine thematic areas: genetics, epigenetics and epidemiology; molecular pathology and cell biology; hormonal influences and endocrine therapy; imaging, detection and screening; current/novel therapies and biomarkers; drug resistance; metastasis, angiogenesis, circulating tumour cells, cancer ‘stem’ cells; risk and prevention; living with and managing breast cancer and its treatment. The groups developed summary papers through an iterative process which, following further appraisal from experts and patients, were melded into this summary account.
The 10 major gaps identified were: (1) understanding the functions and contextual interactions of genetic and epigenetic changes in normal breast development and during malignant transformation; (2) how to implement sustainable lifestyle changes (diet, exercise and weight) and chemopreventive strategies; (3) the need for tailored screening approaches including clinically actionable tests; (4) enhancing knowledge of molecular drivers behind breast cancer subtypes, progression and metastasis; (5) understanding the molecular mechanisms of tumour heterogeneity, dormancy, de novo or acquired resistance and how to target key nodes in these dynamic processes; (6) developing validated markers for chemosensitivity and radiosensitivity; (7) understanding the optimal duration, sequencing and rational combinations of treatment for improved personalised therapy; (8) validating multimodality imaging biomarkers for minimally invasive diagnosis and monitoring of responses in primary and metastatic disease; (9) developing interventions and support to improve the survivorship experience; (10) a continuing need for clinical material for translational research derived from normal breast, blood, primary, relapsed, metastatic and drug-resistant cancers with expert bioinformatics support to maximise its utility. The proposed infrastructural enablers include enhanced resources to support clinically relevant in vitro and in vivo tumour models; improved access to appropriate, fully annotated clinical samples; extended biomarker discovery, validation and standardisation; and facilitated cross-discipline working.
With resources to conduct further high-quality targeted research focusing on the gaps identified, increased knowledge translating into improved clinical care should be achievable within five years.
PMCID: PMC3907091  PMID: 24286369
15.  The inguinal and femoral canals: A practical step-by-step approach to accurate sonographic assessment 
Ultrasonography (USG) is an accepted and reliable tool for the assessment of groin hernias. However, USG of the groin is operator dependent and challenging. The anatomy of this region is complex and the normal sonographic findings can be difficult to interpret. We describe the relevant normal anatomy of the groin relating to inguinal and femoral hernias, and describe a straightforward, reliable technique for identifying and assessing the integrity of the inguinal and femoral canals. The inferior epigastric vessels are a critical landmark for assessment of the inguinal canal and deep inguinal ring.
PMCID: PMC3932585  PMID: 24604947
Inguinal; technique; ultrasound
16.  Predictive Accuracy of the Liverpool Lung Project Risk Model for Stratifying Patients for Computed Tomography Screening for Lung Cancer 
Annals of internal medicine  2012;157(4):242-250.
External validation of existing lung cancer risk prediction models is limited. Using such models in clinical practice to guide the referral of patients for computed tomography (CT) screening for lung cancer depends on external validation and evidence of predicted clinical benefit.
To evaluate the discrimination of the Liverpool Lung Project (LLP) risk model and demonstrate its predicted benefit for stratifying patients for CT screening by using data from 3 independent studies from Europe and North America.
Case–control and prospective cohort study.
Europe and North America.
Participants in the European Early Lung Cancer (EUELC) and Harvard case–control studies and the LLP population-based prospective cohort (LLPC) study.
5-year absolute risks for lung cancer predicted by the LLP model.
The LLP risk model had good discrimination in both the Harvard (area under the receiver-operating characteristic curve [AUC], 0.76 [95% CI, 0.75 to 0.78]) and the LLPC (AUC, 0.82 [CI, 0.80 to 0.85]) studies and modest discrimination in the EUELC (AUC, 0.67 [CI, 0.64 to 0.69]) study. The decision utility analysis, which incorporates the harms and benefit of using a risk model to make clinical decisions, indicates that the LLP risk model performed better than smoking duration or family history alone in stratifying high-risk patients for lung cancer CT screening.
The model cannot assess whether including other risk factors, such as lung function or genetic markers, would improve accuracy. Lack of information on asbestos exposure in the LLPC limited the ability to validate the complete LLP risk model.
Validation of the LLP risk model in 3 independent external data sets demonstrated good discrimination and evidence of predicted benefits for stratifying patients for lung cancer CT screening. Further studies are needed to prospectively evaluate model performance and evaluate the optimal population risk thresholds for initiating lung cancer screening.
Primary Funding Source
Roy Castle Lung Cancer Foundation.
PMCID: PMC3723683  PMID: 22910935
17.  Overdiagnosis in breast cancer screening: the importance of length of observation period and lead time 
Overdiagnosis in breast cancer screening is a controversial topic. One difficulty in estimation of overdiagnosis is the separation of overdiagnosis from lead time that is the advance in the time of diagnosis of cancers, which confers an artificial increase in incidence when a screening programme is introduced.
We postulated a female population aged 50-79 with a similar age structure and age-specific breast cancer incidence as in England and Wales before the screening programme. We then imposed a two-yearly screening programme; screening women aged 50-69, to run for twenty years, with exponentially distributed lead time with an average of 40 months in screen-detected cancers. We imposed no effect of the screening on incidence other than lead time.
Comparison of age- and time-specific incidence between the screened and unscreened populations showed a major effect of lead time, which could only be adjusted for by follow-up for more than two decades and including ten years after the last screen. From lead time alone, twenty-year observation at ages 50-69 would confer an observed excess incidence of 37%. The excess would only fall below 10% with 25 years or more follow-up. For the excess to be nullified, we would require 30 year follow-up including observation up to 10 years above the upper age limit for screening.
Studies using shorter observation periods will overestimate overdiagnosis by inclusion of cancers diagnosed early due to lead time among the nominally overdiagnosed tumours.
PMCID: PMC3706885  PMID: 23680223
18.  Assessing risk of breast cancer in an ethnically South-East Asia population (results of a multiple ethnic groups study) 
BMC Cancer  2012;12:529.
Gail and others developed a model (GAIL) using age-at-menarche, age-at-birth of first live child, number of previous benign breast biopsy examinations, and number of first-degree-relatives with breast cancer as well as baseline age-specific breast cancer risks for predicting the 5-year risk of invasive breast cancer for Caucasian women. However, the validity of the model for projecting risk in South-East Asian women is uncertain. We evaluated GAIL and attempted to improve its performance for Singapore women of Chinese, Malay and Indian origins.
Data from the Singapore Breast Screening Programme (SBSP) are used. Motivated by lower breast cancer incidence in many Asian countries, we utilised race-specific invasive breast cancer and other cause mortality rates for Singapore women to produce GAIL-SBSP. By using risk factor information from a nested case-control study within SBSP, alternative models incorporating fewer then additional risk factors were determined. Their accuracy was assessed by comparing the expected cases (E) with the observed (O) by the ratio (E/O) and 95% confidence interval (CI) and the respective concordance statistics estimated.
From 28,883 women, GAIL-SBSP predicted 241.83 cases during the 5-year follow-up while 241 were reported (E/O=1.00, CI=0.88 to 1.14). Except for women who had two or more first-degree-relatives with breast cancer, satisfactory prediction was present in almost all risk categories. This agreement was reflected in Chinese and Malay, but not in Indian women. We also found that a simplified model (S-GAIL-SBSP) including only age-at-menarche, age-at-birth of first live child and number of first-degree-relatives performed similarly with associated concordance statistics of 0.5997. Taking account of body mass index and parity did not improve the calibration of S-GAIL-SBSP.
GAIL can be refined by using national race-specific invasive breast cancer rates and mortality rates for causes other than breast cancer. A revised model containing only three variables (S-GAIL-SBSP) provides a simpler approach for projecting absolute risk of invasive breast cancer in South-East Asia women. Nevertheless its role in counseling the individual women regarding their risk of breast cancer remains problematical and needs to be validated in independent data.
PMCID: PMC3529190  PMID: 23164155
19.  The number of women who would need to be screened regularly by mammography to prevent one death from breast cancer 
Journal of Medical Screening  2011;18(4):210-212.
The number of women who would need to be screened regularly by mammography to prevent one death from breast cancer depends strongly on several factors, including the age at which regular screening starts, the period over which it continues, and the duration of follow-up after screening. Furthermore, more women would need to be INVITED for screening than would need to be SCREENED to prevent one death, since not all women invited attend for screening or are screened regularly. Failure to consider these important factors accounts for many of the major discrepancies between different published estimates. The randomised evidence indicates that, in high income countries, around one breast cancer death would be prevented in the long term for every 400 women aged 50–70 years regularly screened over a ten-year period.
PMCID: PMC3266234  PMID: 22184734
20.  Polygenic susceptibility to prostate and breast cancer: implications for personalised screening 
British journal of cancer  2011;104(10):1656-1663.
We modelled the efficiency of a personalised approach to screening for prostate and breast cancer based on age and polygenic risk-profile compared to the standard approach based on age alone.
We compared the number of cases potentially detectable by screening in a population undergoing personalised screening with a population undergoing screening based on age alone. Polygenic disease risk was assumed to have a log-normal relative risk distribution predicted for the currently known prostate or breast cancer susceptibility variants (N=31 & N=18 respectively).
Compared to screening men based on age alone (aged 55-79: 10-year absolute risk ≥2%), personalised screening of men age 45-79 at the same risk threshold would result in 16% fewer men being eligible for screening at a cost of 3% fewer screen detectable cases, but with added benefit of detecting additional cases in younger men at high risk. Similarly, compared to screening women based on age alone (aged 47-79: 10-year absolute risk ≥2.5%), personalised screening of women age 35-79 at the same risk threshold would result in 24% fewer women being eligible for screening at a cost of 14% fewer screen detectable cases.
Personalised screening approach could improve the efficiency of screening programmes. This has potential implications on informing public health policy on cancer screening.
PMCID: PMC3093360  PMID: 21468051
Polygenic risk; personalised screening; breast cancer; prostate cancer
21.  Validation of a modelling approach to estimating the likely effectiveness of cancer screening using cancer data on prevalence screening and incidence Modelling effectiveness of cancer screening 
Cancer epidemiology  2010;35(2):139-144.
This study aims to validate a biostatistical approach to predict the likely effectiveness of screening in reducing advanced disease in the absence of data on incident screen and interval cancers.
We derived the predicted relative reduction in advanced stage disease following screening from the expected proportion of advanced disease following screening and the observed proportion of advanced disease detected clinically among the controls. We compared the predicted estimates to those observed in a randomised trial.
Using our method, the predicted estimates of relative reduction in node positive breast cancer following screening were comparable to the observed estimates for the age groups 50-59 and 60-69 in the screening study (predicted 32% vs. observed 40% (p=0.274) and predicted 34% vs. observed 45% (p=0.068), respectively). However, for the age groups 40-49 and 70-74 the predicted values were overestimates of the likely effectiveness of screening compared to the observed values (predicted 38% vs. observed 16% (p=0.014) and predicted 34% vs. observed 0% (p=0.001), respectively).
When the number of cancer cases is more than hundred, the method of prediction using only prevalence screen data may be accurate. Where cancers are less common, for example in small populations or young age groups, further data from interval cancers or incidence screens may be necessary.
PMCID: PMC3110612  PMID: 20719587
Screening; prevalence screen; incident cancer; relative reduction; advanced cancer; overdiagnosis; prediction
22.  Absolute numbers of lives saved and overdiagnosis in breast cancer screening, from a randomized trial and from the Breast Screening Programme in England 
Journal of Medical Screening  2010;17(1):25-30.
To estimate the absolute numbers of breast cancer deaths prevented and the absolute numbers of tumours overdiagnosed in mammographic screening for breast cancer at ages 50–69 years.
The Swedish Two-County randomized trial of mammographic screening for breast cancer, and the UK Breast Screening Programme in England, ages 50–69 years.
We estimated the absolute numbers of deaths avoided and additional cases diagnosed in the study group (active study population) of the Swedish Two-County Trial, by comparison with the control group (passive study population). We estimated the same quantities for the mortality and incidence rates in England (1974–2004 and 1974–2003, respectively). We used Poisson regression for statistical inference.
A substantial and significant reduction in breast cancer mortality was associated with screening in both the Two-County Trial (P < 0.001) and the screening programme in England (P < 0.001). The absolute benefits were estimated as 8.8 and 5.7 breast cancer deaths prevented per 1000 women screened for 20 years starting at age 50 from the Two-County Trial and screening programme in England, respectively. The corresponding estimated numbers of cases overdiagnosed per 1000 women screened for 20 years were, respectively, 4.3 and 2.3 per 1000.
The benefit of mammographic screening in terms of lives saved is greater in absolute terms than the harm in terms of overdiagnosis. Between 2 and 2.5 lives are saved for every overdiagnosed case.
PMCID: PMC3104821  PMID: 20356942
23.  Using mammographic density to predict breast cancer risk: dense area or percentage dense area 
Mammographic density (MD) is one of the strongest risk factors for breast cancer. It is not clear whether this association is best expressed in terms of absolute dense area or percentage dense area (PDA).
We measured MD, including nondense area (here a surrogate for weight), in the mediolateral oblique (MLO) mammogram using a computer-assisted thresholding technique for 634 cases and 1,880 age-matched controls from the Cambridge and Norwich Breast Screening programs. Conditional logistic regression was used to estimate the risk of breast cancer, and fits of the models were compared using likelihood ratio tests and the Bayesian information criteria (BIC). All P values were two-sided.
Square-root dense area was the best single predictor (for example, χ12 = 53.2 versus 44.4 for PDA). Addition of PDA and/or square-root nondense area did not improve the fit (both P > 0.3). Addition of nondense area improved the fit of the model with PDA (χ12 = 11.6; P < 0.001). According to the BIC, the PDA and nondense area model did not provide a better fit than the dense area alone model. The fitted values of the two models were highly correlated (r = 0.97). When a measure of body size is included with PDA, the predicted risk is almost identical to that from fitting dense area alone.
As a single parameter, dense area provides more information than PDA on breast cancer risk.
PMCID: PMC3046440  PMID: 21087468
24.  Avoiding bias from aggregate measures of exposure 
Sometimes in descriptive epidemiology or in the evaluation of a health intervention policy change, proportions exposed to a risk factor or to an intervention are used as explanatory variables in log‐linear regressions for disease incidence or mortality.
To demonstrate how estimates from such models can be substantially inaccurate as estimates of the effect of the risk factor or intervention at individual level. To show how the individual level effect can be correctly estimated by excess relative risk models.
The problem and solution are demonstrated using data on prostate‐specific antigen testing and prostate cancer incidence.
PMCID: PMC2465682  PMID: 17435216
25.  Mean sojourn time, overdiagnosis and reduction in advanced stage prostate cancer due to screening with PSA 
British journal of cancer  2009;100(7):1198-1204.
This study aimed to assess the mean sojourn time (MST) of prostate cancer, to estimate the probability of overdiagnosis and to predict the potential reduction in advanced stage disease due to screening with PSA. The MST of prostate cancer was derived from detection rates at PSA prevalence testing in 43,842 men 50-69 years as part of the ProtecT study, from the incidence of non-screen detected cases obtained from the English population-based cancer registry database, and from PSA sensitivity obtained from the medical literature. The relative reduction in advanced stage disease was derived from the expected and observed incidence of advanced stage prostate cancer.
The age-specific MST for men aged 50-59 and 60-69 were11.3 and 12.6 years respectively. Overdiagnosis estimates increased with age; 10% to 31% of the PSA-detected cases were estimated to be overdiagnosed. An inter-screening interval of 2 years was predicted to result in 37% and 63% reduction in advanced stage disease in men 65-69 and 50-54 years respectively. If the overdiagnosed cases were excluded, the estimated reductions were 9% and 54% respectively.
Thus, the benefit of screening in reducing advanced stage disease is limited by overdiagnosis, which is greater in older men.
PMCID: PMC2670005  PMID: 19293796
Prostate cancer; screening; mean sojourn time; overdiagnosis; advanced stage

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