COVID-19: using chest CT of major trauma patients to monitor and evaluate the second wave in London and the development of routine monitoring in practice.

AIM: To follow-up previous work evaluating incidental findings of COVID-19 signs on computed tomography (CT) images of major trauma patients to include the second wave prior to any major effects from vaccines. MATERIALS AND METHODS: The study population included all patients admitted following major trauma between 1 January 2020 and 28 February 2021 with CT including the lungs (n=1776). Major trauma patients admitted pre-COVID-19 from alternate months from January 2019 to November 2019 comprised a control group (n=837). The assessing radiologists were blinded to the time period and used double reading in consensus to determine if the patient had signs of COVID-19. Lung appearances were classified as no evidence of COVID-19, minor signs, or major signs. RESULTS: The method successfully tracked the second wave of the COVID-19 pandemic in London. The estimated population affected by the disease based on those with major signs was similar to estimates of the proportion of the population in London with antibodies (around 30% by end February 2021) and the total of major and minor signs produced a much higher figure of 68%, which may include all those with both antibody and just T-cell responses. CONCLUSIONS: Incidental findings on CT from major trauma patients may provide a novel and sensitive way of tracking the virus. It is recommended that all major trauma units include a simple question on signs of COVID-19 to provide an early warning system for further waves.

An analysis of screen-detected invasive cancers by grade in the English breast cancer screening programme: are we failing to detect sufficient small grade 3 cancers?

OBJECTIVE: Randomised controlled trials have shown a reduction in breast cancer mortality from mammography screening and it is the detection of high-grade invasive cancers that is responsible for much of this effect. We determined the detection rates of invasive cancers by grade, size and type of screen and estimated relative sensitivities with emphasis on grade 3 detection. METHODS: This observational study analysed data from over 11 million screening episodes (67,681 invasive cancers) from the English NHS breast screening programme over seven screening years 2009/2010 to 2015/2016 for women aged 45-70. RESULTS: At prevalent (first) screens (which are unaffected by screening interval), the detection rate of small (< 15 mm) invasive cancers was 0.95 per 1000 for grade 1, but for grade 3 only 0.30 per 1000. The ratio of small (< 15 mm) to large (≥ 15 mm) cancers was 1.8:1 for grade 1 but reversed to 0.5:1 for grade 3. We estimated that the relative sensitivity for grade 3 invasive cancers was 52% of that for grade 1 and the relative sensitivity for small (< 15 mm) grade 3 only 26% of that for small (< 15 mm) grade 1 invasive cancers. CONCLUSIONS: Sensitivity for small grade 3 invasive cancers is poor compared with that for grade 1 and 2 invasive cancers and larger grade 3 malignancies. This observation is likely a limitation of the current technology related to the absence of identifiable mammographic features for small high-grade cancers. Future work should focus on technologies and strategies to improve detection of these clinically most significant cancers. KEY POINTS: • The detection of small high-grade invasive cancers is vital to reduce breast cancer mortality. • We estimate the sensitivity for small grade 3 invasive cancers may be only 26% of that of small grade 1 invasive cancers. This is likely to be associated with the non-specific mammographic features for these cancers. • New technologies and appropriate strategies using current technology are required to maximise the detection of small grade 3 invasive cancers.

COVID-19: using chest CT of major trauma patients to monitor and evaluate the effect of lockdown and the importance of household size.

AIM: To use theory and practice to show how disease progression and regression can be described pre- and post-lockdown using an attack-sustain-decline-respite (ASDR) model and investigate how pre-lockdown disease prevalence and household size impacts on the effectiveness of lockdown. MATERIALS AND METHODS: Computed tomography (CT) scans from major trauma patients (considered as a random population sample) from the radiology department of St George's University Hospitals NHS Trust, London, have been used to explore COVID-19 disease at the population level. RESULTS: At lockdown on 23 March 2020 in the catchment area of St George's University Hospitals NHS Trust, an earlier paper showed that there was a high prevalence of disease of >20%. With further follow-up and at the end of lockdown, it have been now estimated that around 57% of the population had been affected, which was similar to that predicted from a simple model based on average household size and prevalence at lockdown. With an average household size of around three persons, there was a 2-week sustain period and a 5-week decline period before the prevalence of the disease returned to background levels. CONCLUSIONS: The present results suggest that the effect of lockdown is dependent on the disease prevalence at the start of lockdown and the average household size. It may therefore be important to lockdown early in an area with a high average household size. This paper is the second in a series of papers to show how radiology measurements of major trauma patients can be used to help monitor the spread of the COVID-19 pandemic.

COVID-19: could CT provide the best population level biomarker? Incidental COVID-19 in major trauma patients suggests higher than predicted rates of infection in London.

AIM: To evaluate incidental findings in major trauma patients, and to explore whether computed tomography (CT) could be used to assess prevalence and estimate disease spread in the general population. MATERIALS AND METHODS: The study population included all patients admitted following major trauma between 1 January 2020 and 30 April 2020 with CT including the lungs (n=523). Major trauma patients admitted pre-COVID-19 from 1-31 January and 1-31 March 2019 comprised a control group (n=252). The assessing radiologists, blinded to the time period, used double reading with consensus to determine if the patient had CT signs of COVID-19. Lung appearances were classified as no evidence of COVID-19; minor signs; or major signs. The proportion of patients with incidental COVID-19 changes was recorded over the study period, and the percentage of the population who had been affected by COVID-19 by the end of April 2020 estimated. RESULTS: CT appearances consistent with COVID-19 began to exceed a background pre-COVID rate in the second week of February and did not decline until 2 weeks after lockdown. By the end of April 2020, approximately 45% of the population had been infected. CONCLUSIONS: CT of major trauma patients can be used to monitor the spread of COVID-19. This novel technique could be used retrospectively or prospectively anywhere where trauma scans are available, to monitor the disease in the local population.

Correction to: An analysis of 11.3 million screening tests examining the association between recall and cancer detection rates in the English NHS breast cancer screening programme.

The original version of this article, published on 04 February 2019, unfortunately contained a mistake.

An analysis of 11.3 million screening tests examining the association between recall and cancer detection rates in the English NHS breast cancer screening programme.

OBJECTIVE: To develop methods to model the relationship between cancer detection and recall rates to inform professional standards. METHODS: Annual screening programme information for each of the 80 English NHSBSP units (totalling 11.3 million screening tests) for the seven screening years from 1 April 2009 to 31 March 2016 and some Dutch screening programme information were used to produce linear and non-linear models. The non-linear models estimated the modelled maximum values (MMV) for cancers detected at different grades and estimated how rapidly the MMV was reached (the modelled 'slope' (MS)). Main outcomes include the detection rate for combined invasive/micro-invasive and high-grade DCIS (IHG) detection rate and the low/intermediate grade DCIS (LIG) detection rate. RESULTS: At prevalent screens for IHG cancers, 99% of the MMV was reached at a recall rate of 7.0%. The LIG detection rate had no discernible plateau, increasing linearly at a rate of 0.12 per 1000 for every 1% increase in recall rate. At incident screens, 99% of the MMV for IHG cancer detection was 4.0%. LIG DCIS increased linearly at a rate of 0.18 per 1000 per 1% increase in recall rate. CONCLUSIONS: Our models demonstrate the diminishing returns associated with increasing recall rates. The screening programme in England could use the models to set recall rate ranges, and other countries could explore similar methodology. KEY POINTS: • Question: How can we determine optimum recall rates in breast cancer screening? • Findings: In this large observational study, we show that increases in recall rates above defined levels are almost exclusively associated with false positive recalls and a very small increase in low/intermediate grade DCIS. • Meaning: High recall rates are not associated with increases in detection of life-threatening cancers. The models developed in this paper can be used to help set recall rate ranges that maximise benefit and minimise harm.

An analysis of 11.3 million screening tests examining the association between needle biopsy rates and cancer detection rates in the English NHS Breast Cancer Screening Programme.

AIM: To examine the association between recall, needle biopsy, and cancer detection rates to inform the setting of target ranges to optimise the benefit to harm ratio of breast screening programmes. MATERIALS AND METHODS: Annual screening programme information from 2009/10 to 2015/16 for the 80 screening units of the English National Health Service Breast Screening Programme (totalling 11.3 million screening tests) was obtained from annual (KC62) returns. Linear regression models were used to examine the association between needle biopsy rates and recall rates and non-linear regression models to examine the association between cancer detection rates and needle biopsy rates. RESULTS: The models show and quantify the diminishing returns for prevalent screens with increasing biopsy rates. A biopsy rate increase from 10 to 20 per 1,000 increases the cancer detection rate by 2.13 per 1,000 with four extra biopsies per extra cancer detected. Increasing the biopsy rate from 40 to 50 per 1,000, increases the cancer detection rate by only 0.25 per 1,000, with 40 extra biopsies per extra cancer detected. Although diminishing returns are also seen at incident screens, screening is generally more efficient. CONCLUSIONS: Increasing needle biopsy rates leads to rapidly diminishing returns in cancer detection and a marked increase in non-malignant/benign needle biopsies. Much of the harms associated with screening in terms of false-positive recall rates and non-cancer biopsies occur at prevalent screens with much lower rates at incident screens. Needle biopsy rate targets should be considered together with recall rate targets to maximise benefit and minimise harm.

Role of performance metrics in breast screening imaging - where are we and where should we be?

The NHS Breast Screening Programme (NHSBSP) was started in 1988 and is a large, organised cancer screening programme. It is delivered by 80 services across England and screens over 2 million women each year. As a screening programme, it must balance the detection of cancers against possible harm to women who do not have cancer. The NHSBSP was therefore designed with detailed information gathering and performance metrics right from the start. In this review paper, we examine how performance metrics in screening mammography have improved the national screening programme and the further developments and challenges that are expected in the years to come.

Disability and participation in breast and bowel cancer screening in England: a large prospective study.

BACKGROUND: There is limited information about participation in organised population-wide screening programmes by people with disabilities. METHODS: Data from the National Health Service routine screening programmes in England were linked to information on disability reported by the Million Women Study cohort participants. RESULTS: Of the 473 185 women offered routine breast or bowel cancer screening, 23% reported some disability. Women with disabilities were less likely than other women to participate in breast cancer screening (RR=0.64, 95% CI: 0.62-0.65) and in bowel cancer screening (RR=0.75, 0.73-0.76). Difficulties with self-care or vision were associated with the greatest reduction in screening participation. CONCLUSION: Participation in routine cancer screening programmes in England is reduced in people with disabilities and participation varies by type of disability.

Nationwide bowel cancer screening programme in England: cohort study of lifestyle factors affecting participation and outcomes in women.

BACKGROUND: In 2006, the National Health Service Bowel Cancer Screening Programme in England (NHSBCSP) began offering routine population-based biennial faecal occult blood testing (FOBt) at ages 60-69. There is, however, limited information on how characteristics of individuals affect participation and outcomes of screening, and we studied this association by linking NHSBCSP data to a large prospective cohort of women. METHODS: Electronic linkage of the NHSBCSP and Million Women Study records identified 899 166 women in the study cohort with at least one invitation for screening. NHSBCSP provided information on screening acceptance, FOBt results, screen-detected colorectal cancer and other outcomes. The Million Women Study provided prospectively collected information on personal and lifestyle factors. Multiple regression was used to estimate relative risks (RRs) of factors associated with acceptance and outcomes of screening. RESULTS: Overall, 70% of women (628 976/899 166) accepted their first invitation for bowel cancer screening, of whom 9133 (1.5%) were FOBt-positive, 743 (0.1%) had screen-detected colorectal cancer and 3056 (0.5%) had screen-detected colorectal adenoma. Acceptance was lower in women from the most than the least deprived tertile, in South Asians and in Blacks than in Whites, in current than in never smokers and in obese than in normal weight women: adjusted RRs (95% confidence interval) for acceptance vs not, 0.90 (0.90-0.90); 0.77 (0.75-79); 0.94 (0.92-0.96); 0.78 (0.77-0.78); and 0.88 (0.88-0.89), respectively: P<0.001 for each. These factors were also associated with an increased risk of being FOBt-positive and of having screen-detected adenoma, but were not strongly associated with the risk of screen-detected colorectal cancer. Relative risks for screen-detected adenoma were 1.22 (1.12-1.34), 2.46 (1.75-3.45), 1.61 (1.05-2.48), 1.53 (1.38-1.68) and 1.77 (1.60-1.95), respectively (P<0.001 for all, except for Blacks vs Whites P=0.03). Use of hormone therapy for menopause was associated with reduced risk of screen-detected adenoma, RR ever vs never use, 0.87 (0.81-0.93), P<0.001 and colorectal cancer, 0.78 (0.68-0.91), P=0.001. INTERPRETATION: Among women in England, socioeconomic and lifestyle factors strongly affect participation in routine bowel cancer screening, risk of being FOBt-positive and risk of having screen-detected colorectal adenoma. However, screen-detected colorectal cancer risk is not strongly related to these factors.

Sustained efficacy of a single intra-articular dose of FX006 in a rat model of repeated localized knee arthritis.

OBJECTIVE: To evaluate the efficacy of a single intra-articular (IA) dose of FX006, an extended-release formulation of triamcinolone acetonide (TCA) in poly(lactic-co-glycolic acid) (PLGA) microspheres, on the sequelae of repeated episodes of synovitis. DESIGN: Three flares of localized synovitis in the right knee of rats were induced over 4 weeks following a single IA injection of various doses of FX006, Kenalog(®) (TCA immediate release or TCA IR), or vehicle. Gait scores were employed to assess analgesic effect, and the joints were evaluated by histology at the end of the study. TCA plasma concentrations and corticosterone levels were monitored through the study. RESULTS: A single IA dose of 0.28 mg FX006 significantly improved gait scores through all three reactivations. TCA IR at 0.06 mg (providing comparable plasma TCA exposure, 10-fold higher Cmax) demonstrated comparable benefit through the first reactivation only and reduced-to-no efficacy thereafter. Significantly improved histological joint scores were observed with effective doses of FX006 but not with TCA IR. Corticosterone levels were initially decreased following both TCA IR and FX006 treatment, but recovered by Day 14. CONCLUSIONS: In localized, repeated synovitis in rats, sustained release of TCA following a single IA injection of FX006 significantly prolonged analgesia relative to TCA IR and significantly improved histological scores with no adverse effect on the HPA axis. Since synovitis can contribute to the pathophysiology of multiple joint diseases such as osteoarthritis (OA), RA and gout, FX006 may be an important treatment option for these conditions.

Optimising faecal occult blood screening:retrospective analysis of NHS Bowel Cancer Screening data to improve the screening algorithm.

BACKGROUND: Colorectal neoplasia causes bleeding, enabling detection using Faecal Occult Blood tests (FOBt). The National Health Service (NHS) Bowel Cancer Screening Programme (BCSP) guaiac-based FOBt (gFOBt) kits contain six sample windows (or 'spots') and each kit returns either a positive, unclear or negative result. Test kits with five or six positive windows are termed 'abnormal' and the subject is referred for further investigation, usually colonoscopy. If 1-4 windows are positive, the result is initially 'unclear' and up to two further kits are submitted, further positivity leads to colonoscopy ('weak positive'). If no further blood is detected, the test is deemed 'normal' and subjects are tested again in 2 years' time. We studied the association between spot positivity % (SP%) and neoplasia. METHODS: Subjects in the Southern Hub completing the first of two consecutive episodes between April 2009 and March 2011 were studied. Each episode included up to three kits and a maximum of 18 windows (spots). For each positivity combination, the percentage of positive spots out of the total number of spots completed by an individual in a single-screening episode was derived and named 'SP%'. Fifty-five combinations of SP can occur if the position of positive/negative spots on the same test card is ignored.The proportion of individuals for whom neoplasia was identified in Episode 2 was derived for each of the 55 spot combinations. In addition, the Episode 1 spot pattern was analysed for subjects with cancer detected in Episode 2. RESULTS: During Episode 2, 284,261 subjects completed gFOBT screening and colonoscopies were performed on 3891 (1.4%) subjects. At colonoscopy, cancer was detected in 7.4% (n=286) and a further 39.8% (n=1550) had adenomas. Cancer was detected in 21.3% of subjects with an abnormal first kit (five or six positive spots) and in 5.9% of those with a weak positive test result.The proportion of cancers detected was positively correlated with SP%, with an R(2) correlation (linear) of 0.89. As the SP% increased from 11 to 100%, so the colorectal cancer (CRC) detection rate increased from 4 to 25%. At the lower SP%s, from 11to 25%, the CRC risk was relatively static at ~4%. Above an SP% of 25%, every 10-percentage points increase in the SP%, was associated with an increase in cancer detection of 2.5%. CONCLUSIONS: This study demonstrated a strong correlation between SP% and cancer detection within the NHS BCSP. At the population level, subjects' cancer risk ranged from 4 to 25% and correlated with the gFOBt spot pattern.Some subjects with an SP% of 11% proceed to colonoscopy, whereas others with an SP% of 22% do not. Colonoscopy on patients with four positive spots in kit 1 (SP% 22%) would, we estimate, detect cancer in ~4% of cases and increase overall colonoscopy volume by 6%. This study also demonstrated how screening programme data could be used to guide its ongoing implementation and inform other programmes.

Reduction in interval cancer rates following the introduction of two-view mammography in the UK breast screening programme.

BACKGROUND: The introduction of two-view mammography at incident (subsequent) screens in the National Health Service Breast Screening Programme (NHSBSP) has led to an increased number of cancers detected at screen. However, the effect of two-view mammography on interval cancer rates has yet to be assessed. METHODS: Routine screening and interval cancer data were collated from all screening programmes in the United Kingdom for women aged 50-64, screened between 1 April 2003 and 31 March 2005. Interval cancer rates were compared based on whether two-view mammography was in use at the last routine screen. RESULTS: The reduction in interval cancers following screening using two-view mammography compared with one view was 0.68 per 1,000 women screened. Overall, this suggests the introduction of two-view mammography at incident screen was accompanied by a 15-20% reduction in interval cancer rates in the NHSBSP. CONCLUSION: The introduction of two-view mammography at incident screens is associated with a reduction in incidence of interval cancers. This is consistent with previous publications on a contemporaneous increase in screen-detected cancers. The results provide further evidence of the benefit of the use of two-view mammography at incident screens.

Longer mean colonoscopy withdrawal time is associated with increased adenoma detection: evidence from the Bowel Cancer Screening Programme in England.

BACKGROUND AND STUDY AIMS: Increasing colonoscopy withdrawal time (CWT) is thought to be associated with increasing adenoma detection rate (ADR). Current English guidelines recommend a minimum CWT of 6 minutes. It is known that in the Bowel Cancer Screening Programme (BCSP) in England there is wide variation in CWT. The aim of this observational study was to examine the relationship between CWT and ADR. PATIENTS AND METHODS: The study examined data from 31 088 colonoscopies by 147 screening program colonoscopists. Colonoscopists were grouped in four levels of mean CWT ( < 7, 7 - 8.9, 9 - 10.9, and ≥ 11 minutes). Univariable and multivariable analysis (binary logistic and negative binomial regression) were used to explore the relationship between CWT, ADR, mean number of adenomas and number of right-sided and advanced adenomas. RESULTS: In colonoscopists with a mean CWT < 7 minutes, the mean ADR was 42.5 % compared with 47.1 % in the ≥ 11-minute group (P < 0.001). The mean number of adenomas detected per procedure increased from 0.77 to 0.94, respectively (P < 0.001). The increase in adenoma detection was mainly of subcentimeter or proximal adenomas; there was no increase in the detection of advanced adenomas. Regression models showed an increase in ADR from 43 % to 46.5 % for mean CWT times ranging from 6 to 10 minutes. CONCLUSIONS: This study demonstrates that longer mean withdrawal times are associated with increasing adenoma detection, mainly of small or right-sided adenomas. However, beyond 10 minutes the increase in ADR is minimal. Mean withdrawal times longer than 6 minutes are not associated with increased detection of advanced adenomas. Withdrawal time remains an important quality metric of colonoscopy.

An observational study to evaluate the performance of units using two radiographers to read screening mammograms.

AIM: To examine the performance of screening units in which a proportion of mammograms were double read using "non-discordant radiographer only (double) reading" (NDROR). MATERIALS AND METHODS: NDROR was used by seven pilot units between 2006 and 2009, and six further units in 2009 only. There were 51 comparison units. Screening performance outcome measures were calculated, and logistic regression was used to compare performance between the pilot and comparison units. RESULTS: Phase 1 pilot units read between on average 15 and 48% of mammograms per year using NDROR between 2006 and 2009 (median, 33%) and in 2009, phase 2 pilot units used NDROR to read between 4 and 77% of mammograms (median, 34%). The results showed an increase in recall rates in the phase 1 pilot units relative to the comparison units at both prevalent and incident screens (adjusted OR 1.09, 95% CI 1.05, 1.14; and adjusted OR 1.10, 95% CI 1.07, 1.14, respectively). There were also increases in the phase 2 pilot units relative to the comparison units; adjusted OR 1.08 (95% 1.00, 1.17) at prevalent screens, and adjusted OR 1.07 (95% CI 1.02, 1.14) at incident screens. There was no evidence to suggest a difference in cancer-detection rates between the pilot units and the comparison units. CONCLUSIONS: Evidence from the present study suggests that recall rates may increase as a result of units using radiographers to double read a proportion of their mammograms. However, there is little evidence to suggest that NDROR, as practiced by the pilot units in the present study, is likely to have major impacts on performance in the UK National Health Service Breast Screening Programme (NHSBSP), particularly if it is fully supported and closely monitored (particularly recall rates).

ABC3 Part II: a review of the new criteria for evaluating cervical cytology in England.

The new Achievable Standards, Benchmarks for Reporting, and Criteria for Evaluating Cervical Cytopathology, 3rd edn (ABC3) includes radical changes in the criteria for evaluating cervical cytology. First, they include a new mission statement 'the objective of cervical screening is to reduce cervical cancer incidence and mortality by screening with a high sensitivity for the detection of CIN2 or worse, whilst maintaining a high specificity'. Second, the original four performance measurement criteria where laboratories were examined further if they were below the 10th or above the 90th percentile has been changed to three and laboratories are only mandatorily examined if they fall below the 5th or above the 95th percentile. The old criteria related to the percentage of samples that were inadequate, the percentage of all adequate samples reported as moderate dyskaryosis or worse (equivalent to high-grade squamous intraepithelial lesion or cancer), the percentage of adequate samples reported as mild dyskaryosis or borderline (equivalent to low-grade squamous intraepithelial lesion or atypical squamous/glandular cells) and the positive predictive value. The new criteria are percentage of inadequate samples, positive predictive value and a new measure termed referral value. These changes mean that far fewer laboratories will require mandatory examination. Third, a raft of optional performance measures have been introduced to help laboratories examine their annual statistical return to the Department of Health in comparison with other laboratories. These measures have been designed to produce a more uniform national programme, and to help laboratories decide whether they are maximizing the benefit of screening while minimizing the harm, which is the goal of all screening programmes. This review examines in detail the new criteria and explains in more detail some of the thinking behind them.

Estimation of disease severity in the NHS cervical screening programme. Part I: artificial cut-off points and semi-quantitative solutions.

OBJECTIVE: Current cytology and histology classifications are based on ordered categories and have a strong emphasis on providing information that decides a woman's management rather than the best estimate of disease severity. This two-part paper explores the use of a quantitative approach to both cytology and histology disease severity measurements. METHODS: In Part I the problem of artificial cut-off points is discussed and a simple semi-quantitative solution to the problem is proposed. This closely relates to the revised British Society for Clinical Cytology (BSCC) terminology. The estimates of disease severity are designed as extensions of the existing methods, with an emphasis on probability rather than certainty, as a more natural way of approaching the problem. Borderline changes are treated as categorical variables, but koilocytosis, mild, moderate and severe dyskaryosis, and ?invasive as quasi-continuous and the disease severity estimated as a grade number (GN) with any value between 0-4 and the margin of error as a calculated grade range (CGR). RESULTS: As an example, if the reader is unsure between moderate dyskaryosis (HSIL favouring CIN2) and mild dyskaryosis (LSIL favouring CIN1) they can register this uncertainty as a probability, such as 60%/40% moderate/mild. With 2 and 1 as the mid-points of the grade numbers for moderate and mild dyskaryosis the GN value is ((60 × 2)+(40 × 1))/100 = 1.6. The CGR is 1.5 - 0.4 to 1.5 + 0.6 = 1.1 to 2.1. The GN (CGR) estimate of disease severity is therefore 1.6 (1.1-2.1). In a similar manner the disease severity from all slides showing koilocytosis or dyskaryosis can be estimated as a number between 0 and 4 with an associated error. Histology can be treated in a similar way. CONCLUSIONS: This semi-quantitative approach provides a framework more suitable for research and audit of disease severity estimates. It avoids the paradox inherent in the current systems using artificial cut-points to produce categories whereby increasing agreement can only be achieved by losing information.

Estimation of disease severity in the NHS cervical screening programme. Part II: quantitative methods of estimating disease severity and progression potential.

OBJECTIVE: This is the second of a two-part paper exploring the use of a more quantitative approach to both cytology and histology disease severity measurements. In Part I the problem of artificial cut-off points was discussed and a semi-quantitative solution to the problem proposed. In Part II quantitative methods are proposed that are used to predict the estimated progression probability (EPP) to invasive cancer. METHODS: Based on models derived from published data the grade number (GN) is related to the EPP to invasive cancer over the next 10 years for both cytology (CEPP) and histology (HEPP) using a look-up table. CEPP and HEPP are then adjusted by other factors such as age, persistence, HPV result, number of cells and lesion size to obtain the adjusted CEPP and HEPP (ACEPP and (AHEPP). The two factors can be combined to produce an adjusted weighted estimated progression potential using the formula AWEPP √((ACEPP + AHEPP)/2) × AHEPP) using a two to one bias in favour of the histology. RESULTS: As an example of the methodology consider a slide estimated as showing a 60% probability of moderate dyskaryosis (HSIL favouring CIN2) and 40% probability of mild dyskaryosis (LSIL favouring CIN1). The GN number would be 1.6 (as described in Part I) and the EPP over the next 10 years 0.78%. For a woman aged 52 years (correction factor ×2.0) with a second mildly dyskaryotic smear (correction factor ×1.25) and >50 dyskaryotic cells (correction factor 1.5) the ACEPP would be 0.78 × 2.00 × 1.25 × 1.5 = 2.9%. If the HEPP on histology was 50:50 between CIN1 and CIN2, the AHEPP can be calculated as 1.4%. The AWEPP would be √((2.9 + 1.4)/2 × 1.4) = 1.7%. The final estimate of disease progression potential based on both cytology and histology is 1.7% over 10 years. CONCLUSIONS: These quantitative approaches based on adjusted and weighted EPP provide a framework suitable for research, audit and comparison between screening centres, and for tailoring criteria for colposcopy referral and treatment. Further research is required to improve the estimates given in the paper.

Using a graph of the abnormal predictive value versus the positive predictive value for the determination of outlier laboratories in the National Health Service cervical screening programme.

OBJECTIVE: The positive predictive value (PPV) for the detection of cervical intraepithelial neoplasia (CIN) grade 2 or worse of referral to colposcopy from moderate dyskaryosis or worse (equivalent to high-grade squamous intraepithelial lesion or worse) is a standard performance measure in the National Health Service cervical screening programme. The current target is to examine 'outlier' laboratories with PPVs outside the 10th-90th percentile, which automatically identifies 20% of laboratories for further investigation. A more targeted method of identifying outliers may be more useful. METHODS: A similar measure to the PPV, the abnormal predictive value (APV), can be defined as the predictive value for CIN2 or worse for referrals from borderline (includes atypical squamous and glandular cells) and mild dyskaryosis (equivalent to low-grade squamous intraepithelial lesion) combined. A scatter plot of the APV versus the PPV can be produced (the APV-PPV diagram). Three kinds of 'outlier' can be defined on the diagram to help determine laboratories with unusual data. These are termed a true outlier value (TOV) or an extreme value (EV) for either PPV or APV, or a residual extreme value (REV) from the APV-PPV best line of fit. RESULTS: Using annual return information for 2007/8 from 124 laboratories, two were defined as having EVs for PPV (both had a relatively low PPV of 62%). For APV, four laboratories were considered to have EVs of 34%, 34%, 34% and 4% and one was considered to be a TO with an APV of 45%. Five were identified as REV laboratories, although three of these were also identified as having extreme or outlier values, leaving two that had not been identified by the other methods. A total of eight (6%) laboratories were therefore identified as meriting further investigation using this methodology. CONCLUSIONS: The method proposed could be a useful alternative to the current method of identifying outliers. Slide exchange studies between the identified laboratories, particularly those at opposing ends of the diagram, or other further investigations of such laboratories, may be instructive in understanding why such variation occurs, and could therefore potentially, lead to improvements in the national programme.