Effect of the HPV vaccination programme on incidence of cervical cancer and grade 3 cervical intraepithelial neoplasia by socioeconomic deprivation in England: population based observational study.

OBJECTIVES: To replicate previous analyses on the effectiveness of the English human papillomavirus (HPV) vaccination programme on incidence of cervical cancer and grade 3 cervical intraepithelial neoplasia (CIN3) using 12 additional months of follow-up, and to investigate effectiveness across levels of socioeconomic deprivation. DESIGN: Observational study. SETTING: England, UK. PARTICIPANTS: Women aged 20-64 years resident in England between January 2006 and June 2020 including 29 968 with a diagnosis of cervical cancer and 335 228 with a diagnosis of CIN3. In England, HPV vaccination was introduced nationally in 2008 and was offered routinely to girls aged 12-13 years, with catch-up campaigns during 2008-10 targeting older teenagers aged <19 years. MAIN OUTCOME MEASURES: Incidence of invasive cervical cancer and CIN3. RESULTS: In England, 29 968 women aged 20-64 years received a diagnosis of cervical cancer and 335 228 a diagnosis of CIN3 between 1 January 2006 and 30 June 2020. In the birth cohort of women offered vaccination routinely at age 12-13 years, adjusted age standardised incidence rates of cervical cancer and CIN3 in the additional 12 months of follow-up (1 July 2019 to 30 June 2020) were, respectively, 83.9% (95% confidence interval (CI) 63.8% to 92.8%) and 94.3% (92.6% to 95.7%) lower than in the reference cohort of women who were never offered HPV vaccination. By mid-2020, HPV vaccination had prevented an estimated 687 (95% CI 556 to 819) cervical cancers and 23 192 (22 163 to 24 220) CIN3s. The highest rates remained among women living in the most deprived areas, but the HPV vaccination programme had a large effect in all five levels of deprivation. In women offered catch-up vaccination, CIN3 rates decreased more in those from the least deprived areas than from the most deprived areas (reductions of 40.6% v 29.6% and 72.8% v 67.7% for women offered vaccination at age 16-18 and 14-16, respectively). The strong downward gradient in cervical cancer incidence from high to low deprivation in the reference unvaccinated group was no longer present among those offered the vaccine. CONCLUSIONS: The high effectiveness of the national HPV vaccination programme previously seen in England continued during the additional 12 months of follow-up. HPV vaccination was associated with a substantially reduced incidence of cervical cancer and CIN3 across all five deprivation groups, especially in women offered routine vaccination.

audit_cc: A Stata command for the analysis of matched case-control audits of cervical cancer screening.

Background and objectives: Cervical screening programmes are crucial for the early diagnosis and prevention of cancer of the cervix. Regular auditing is vital for ensuring that these programmes achieve their full potential and meet their objectives in practice. Unfortunately, the time and skills required for the statistical analysis of the data collected are often important limiting factors. Comparisons across countries and over time have also been particularly difficult due to a lack of standardized definitions and methodology. We aimed to overcome these problems. Methods: Using the statistical software Stata, we developed a new command called audit_cc for the analysis of matched case-control audits of cervical cancer screening. Analyses are reported for two measures of screening history: time since last test and time since last negative test. Results: The command carries out the data manipulation which is required for the analysis and allows to save the resulting data set in an external file for further investigations. It promotes consistent evaluations of screening programmes over time and across studies and facilitates the creation of automatic publication-quality reports, which are especially useful in the context of routine audits. Conclusions: audit_cc is a valid tool that not only simplifies the analysis and reporting of cervical screening audits but also allows meaningful international comparisons. Although it is specific for cervical cancer, it can be seen as an example of how the standardisation of exposure definitions and key methodological issues can enable consistent and comparable evaluations of screening programmes across different countries and settings.

Time trends in access to smoking cessation support for people with depression or severe mental illness: a cohort study in English primary care.

OBJECTIVES: To investigate delivery of smoking cessation interventions, recorded quit attempts and successful quitting rates within primary care in smokers with depression or severe mental illness (SMI) compared with those without. DESIGN: Longitudinal cohort study using primary healthcare records. SETTING: English primary care. PARTICIPANTS: 882 849 patients registered with participating practices recorded as current smokers during 2007-2014, including three groups: (1) 13 078 with SMI, (2) 55 630 with no SMI but recent depression and (3) 814 141 with no SMI nor recent depression. OUTCOMES: Recorded advice to quit smoking, referrals to smoking cessation services, prescriptions for smoking cessation medication, recorded quit attempts and changes of smoking status. RESULTS: The majority (>70%) of smokers had recorded smoking cessation advice. This was consistently higher in those with SMI than the other cohorts of patients, although the gap greatly reduced in more recent years. Increases in smoking cessation advice over time were not accompanied by increases in recorded attempts to quit or changes of smoking status. Overall nicotine replacement therapy prescribing by general practitioners (GPs) was higher in those with SMI (10.1%) and depression (8.7%) than those without (5.9%), but a downward time trend was observed in all groups. Bupropion and varenicline prescribing was very low and lower for those with SMI. Few smokers (<5%) had referrals to stop smoking services, though this increased over time, but no significant differences were observed between those with and without mental health problems. CONCLUSIONS: There was no evidence of consistent inequalities in access to GP-delivered smoking cessation interventions for people with mental health conditions. Smoking cessation advice was widely reported as taking place in all groups. In order to address the widening gap in smoking prevalence in those with poor mental health compared with those without, the emphasis should be on addressing the quality of advice and support given.

The effects of the national HPV vaccination programme in England, UK, on cervical cancer and grade 3 cervical intraepithelial neoplasia incidence: a register-based observational study.

BACKGROUND: Human papillomavirus (HPV) immunisation with a bivalent vaccine (Cervarix) was introduced in England, UK, in Sept 1, 2008: routine vaccination was offered to girls aged 12-13 years with a catch-up programme for females aged 14-18 years in 2008-10. We quantified the early effect of this immunisation programme on cervical cancer and cervical carcinoma in situ, namely grade 3 cervical intraepithelial neoplasia (CIN3), registrations. METHODS: In this observational study, we used an extension of the age-period-cohort Poisson model to estimate the relative risk of cervical cancer in three vaccinated cohorts compared with earlier cohorts that were not eligible for HPV vaccination. Data from a population-based cancer registry were extracted on Jan 26, 2021, and were assessed for diagnoses of cervical cancer and CIN3 from Jan 1, 2006 to June 30, 2019 in women aged 20-64 years and who were a resident in England. We used three vaccinated cohorts to account for differences in the school year in which the vaccine was offered and its national coverage. Adjustment for confounding was made using information on changes in cervical screening policy and historical events that affected cervical cancer incidence. Results were compared across models with different adjustments for confounders. FINDINGS: We used data from a total of 13·7 million-years of follow-up of women aged 20 years to younger than 30 years. The estimated relative reduction in cervical cancer rates by age at vaccine offer were 34% (95% CI 25-41) for age 16-18 years (school year 12-13), 62% (52-71) for age 14-16 years (school year 10-11), and 87% (72-94) for age 12-13 years (school year 8), compared with the reference unvaccinated cohort. The corresponding risk reductions for CIN3 were 39% (95% CI 36-41) for those offered at age 16-18 years, 75% (72-77) for age 14-16 years, and 97% (96-98) for age 12-13 years. These results remained similar across models. We estimated that by June 30, 2019 there had been 448 (339-556) fewer than expected cervical cancers and 17 235 (15 919-18 552) fewer than expected cases of CIN3 in vaccinated cohorts in England. INTERPRETATION: We observed a substantial reduction in cervical cancer and incidence of CIN3 in young women after the introduction of the HPV immunisation programme in England, especially in individuals who were offered the vaccine at age 12-13 years. The HPV immunisation programme has successfully almost eliminated cervical cancer in women born since Sept 1, 1995. FUNDING: Cancer Research UK.

Factors associated with discontinuation of antidepressant treatment after a single prescription among patients aged 55 or over: evidence from English primary care.

PURPOSE: Antidepressants are frequently prescribed to older people with depression but little is known on predictors of discontinuation in this population. We, therefore, investigated factors associated with early discontinuation of antidepressants in older adults with new diagnoses or symptoms of depression in English primary care. METHODS: Data from a nationally representative cohort of patients aged 55 and over were used to evaluate the association between discontinuation of antidepressant medication after a single prescription and potential explanatory variables, including socio-demographic factors, polypharmacy and age-related problems such as dementia. RESULTS: Overall, during the study period we observed 34,715 new courses of antidepressant treatment initiated after recorded symptoms or diagnoses of depression. Antidepressant discontinuation after a single prescription was more common in people with depressive symptoms (32%) than in those with diagnosed depression (21.6%). In those diagnosed with depression and in women with depressive symptoms we found that, after adjusting for confounders, the odds of early discontinuation significantly increased after age 65 with a peak at around age 80 and then either levelled or reduced thereafter. Early discontinuation was also significantly less common in people with dementia and in those with diagnosed depression living in more rural areas. CONCLUSIONS: Early discontinuation of antidepressants increases in the post-retirement years and is higher in those with no formal diagnosis of depression, those without dementia and those with diagnosed depression living in urban areas. Alternative treatment strategies, such as non-drug therapies, or more active patient follow-up should be further considered in these circumstances.

Prevalence of frailty in rural community-dwelling older adults in Kegalle district of Sri Lanka: a population-based cross-sectional study.

OBJECTIVE: Our main objective was to describe the prevalence and associated sociodemographic factors of frailty and pre-frailty in rural community-dwelling older adults in Kegalle district of Sri Lanka. DESIGN: Community-based cross-sectional study. SETTING: The study was conducted in rural areas of Kegalle district in Sri Lanka. PARTICIPANTS: A total of 746 community-dwelling older adults aged ≥60 years were included in the study. RESULTS: The prevalence of frailty and pre-frailty in rural Kegalle district was 15.2% (95% CI 12.3% to 18.6%) and 48.5% (95% CI 43.8% to 53.2%), respectively. We found a strong association between age and both frailty and pre-frailty. There were strong associations between longest-held occupation and frailty and education level and pre-frailty. CONCLUSIONS: The prevalence of frailty in this rural Sri Lankan older population was high compared with high-income and upper middle-income countries. The profile of health and social care services in Sri Lanka needs to address frailty and its consequences.

Alcohol Consumption and Risk of Incident Frailty: The English Longitudinal Study of Aging.

BACKGROUND: Alcohol consumption is a common modifiable lifestyle factor. Alcohol may be a risk factor for frailty, however, there is limited evidence in the literature. OBJECTIVE: The objectives of this study were to examine the association of alcohol consumption with the risk of incident frailty. METHODS: This is a prospective panel study of 2544 community-dwelling people aged 60 years and older in England. Frailty status defined by frailty phenotype criteria was measured at baseline and 4 years later. Participants free of frailty at baseline were divided into 5 groups based on quantity of self-reported alcohol consumption per week with cut-points at 0, 7, 14, and 21 UK units per week. Adjusted odds ratios (OR) were calculated for incident frailty according to the alcohol consumption using logistic regression models. RESULTS: Compared with the low consumption group (>0 and ≤7 units per week), incident frailty risk over 4 years was significantly higher among nondrinkers [OR 1.71, 95% confidence interval (CI) 1.12‒2.60, P value = .01], after controlling for sociodemographic confounders. In a supplementary analysis this became nonsignificant after further adjustment for baseline health status. Heavy drinkers (>21 units per week) had a significantly lower incident frailty risk (unadjusted OR 0.45, 95% CI 0.27‒0.75, P < .01), which became nonsignificant on adjustment for sociodemographic factors (OR 0.64, 95% CI 0.37‒1.13, P = .12). CONCLUSIONS/IMPLICATIONS: We found that nondrinkers were more likely than those with low alcohol consumption to develop frailty, but this appeared to be explained by poorer baseline health status. No evidence was found for an association between high levels of alcohol consumption and becoming frail. Future studies with information on life-course history of alcohol use, especially for those classified as nondrinkers in old age, are warranted.

Correcting bias due to missing stage data in the non-parametric estimation of stage-specific net survival for colorectal cancer using multiple imputation.

BACKGROUND: Population-based net survival by tumour stage at diagnosis is a key measure in cancer surveillance. Unfortunately, data on tumour stage are often missing for a non-negligible proportion of patients and the mechanism giving rise to the missingness is usually anything but completely at random. In this setting, restricting analysis to the subset of complete records gives typically biased results. Multiple imputation is a promising practical approach to the issues raised by the missing data, but its use in conjunction with the Pohar-Perme method for estimating net survival has not been formally evaluated. METHODS: We performed a resampling study using colorectal cancer population-based registry data to evaluate the ability of multiple imputation, used along with the Pohar-Perme method, to deliver unbiased estimates of stage-specific net survival and recover missing stage information. We created 1000 independent data sets, each containing 5000 patients. Stage data were then made missing at random under two scenarios (30% and 50% missingness). RESULTS: Complete records analysis showed substantial bias and poor confidence interval coverage. Across both scenarios our multiple imputation strategy virtually eliminated the bias and greatly improved confidence interval coverage. CONCLUSIONS: In the presence of missing stage data complete records analysis often gives severely biased results. We showed that combining multiple imputation with the Pohar-Perme estimator provides a valid practical approach for the estimation of stage-specific colorectal cancer net survival. As usual, when the percentage of missing data is high the results should be interpreted cautiously and sensitivity analyses are recommended.

BMI upon discharge from hospital and its relationship with survival: an observational study utilising linked patient records.

OBJECTIVE: Current advice for patients being discharged from hospital suggests a body mass index of 18.5 to 24 kgm-2, although this aspirational target may often not be achieved. We examined the relationship between body mass index on discharge from hospital and subsequent mortality over a maximum follow-up of 3.8 years. DESIGN: We conducted a survival analysis using linked hospital records data with national hospital episode statistics and national death certification data. PARTICIPANTS & SETTING: The analysis included adult patients who were admitted to University Hospitals Birmingham NHS Foundation Trust for a period of over 24 h during 2011, excluding day cases and regular day case attenders. MAIN OUTCOME MEASURES: The relationship between body mass index and mortality at medium term was estimated separately in both men and women, after accounting for case-mix. RESULTS: For both males and females, the relationship between body mass index at discharge and the loge hazard of death was strongly non-linear (p = 0.0002 for females and p < 0.0001 for males) and predictive (both p < 0.0001). In all models, the optimal body mass index range associated with best survival was 25 to 35 kgm-2, with a sharp increase in risk for lower body mass index. CONCLUSIONS: There was little evidence to support current aspirational body mass index targets in the discharge population. Hospitals should ensure adequate nutrition especially among those with a reduced body mass index.

Estimating excess hazard ratios and net survival when covariate data are missing: strategies for multiple imputation.

BACKGROUND: Net survival is the survival probability we would observe if the disease under study were the only cause of death. When estimated from routinely collected population-based cancer registry data, this indicator is a key metric for cancer control. Unfortunately, such data typically contain a non-negligible proportion of missing values on important prognostic factors (eg, tumor stage). METHODS: We carried out an empirical study to compare the performance of complete records analysis and several multiple imputation strategies when net survival is estimated via a flexible parametric proportional hazards model that includes stage, a partially observed categorical covariate. Starting from fully observed cancer registry data, we induced missingness on stage under three scenarios. For each of these scenarios, we simulated 100 incomplete datasets and evaluated the performance of the different strategies. RESULTS: Ordinal logistic models are not suitable for the imputation of tumor stage. Complete records analysis may lead to grossly misleading estimates of net survival, even when the missing data mechanism is conditionally independent of survival time given the covariates and the bias on the excess hazard ratios estimates is negligible. CONCLUSIONS: As key covariates are unlikely missing completely at random, studies estimating net survival should not use complete records. When the missingness can be inferred from available data, appropriate multiple imputation should be performed. In the context of flexible parametric proportional hazards models with a partially observed stage covariate, a multinomial logistic imputation model for stage should be used and should include the Nelson-Aalen cumulative hazard estimate and the event indicator.

A multimodal approach to emotion recognition ability in autism spectrum disorders.

BACKGROUND: Autism spectrum disorders (ASD) are characterised by social and communication difficulties in day-to-day life, including problems in recognising emotions. However, experimental investigations of emotion recognition ability in ASD have been equivocal, hampered by small sample sizes, narrow IQ range and over-focus on the visual modality. METHODS: We tested 99 adolescents (mean age 15;6 years, mean IQ 85) with an ASD and 57 adolescents without an ASD (mean age 15;6 years, mean IQ 88) on a facial emotion recognition task and two vocal emotion recognition tasks (one verbal; one non-verbal). Recognition of happiness, sadness, fear, anger, surprise and disgust were tested. Using structural equation modelling, we conceptualised emotion recognition ability as a multimodal construct, measured by the three tasks. We examined how the mean levels of recognition of the six emotions differed by group (ASD vs. non-ASD) and IQ (≥ 80 vs. < 80). RESULTS: We found no evidence of a fundamental emotion recognition deficit in the ASD group and analysis of error patterns suggested that the ASD group were vulnerable to the same pattern of confusions between emotions as the non-ASD group. However, recognition ability was significantly impaired in the ASD group for surprise. IQ had a strong and significant effect on performance for the recognition of all six emotions, with higher IQ adolescents outperforming lower IQ adolescents. CONCLUSIONS: The findings do not suggest a fundamental difficulty with the recognition of basic emotions in adolescents with ASD.

Loss of language in early development of autism and specific language impairment.

BACKGROUND: Several authors have highlighted areas of overlap in symptoms and impairment among children with autism spectrum disorder (ASD) and children with specific language impairment (SLI). By contrast, loss of language and broadly defined regression have been reported as relatively specific to autism. We compare the incidence of language loss and language progression of children with autism and SLI. METHODS: We used two complementary studies: the Special Needs and Autism Project (SNAP) and the Manchester Language Study (MLS) involving children with SLI. This yielded a combined sample of 368 children (305 males and 63 females) assessed in late childhood for autism, history of language loss, epilepsy, language abilities and nonverbal IQ. RESULTS: language loss occurred in just 1% of children with SLI but in 15% of children classified as having autism or autism spectrum disorder. Loss was more common among children with autism rather than milder ASD and is much less frequently reported when language development is delayed. For children who lost language skills before their first phrases, the phrased speech milestone was postponed but long-term language skills were not significantly lower than children with autism but without loss. For the few who experienced language loss after acquiring phrased speech, subsequent cognitive performance is more uncertain. CONCLUSIONS: Language loss is highly specific to ASD. The underlying developmental abnormality may be more prevalent than raw data might suggest, its possible presence being hidden for children whose language development is delayed.

Estimating intervention effects in a complex multi-level smoking prevention study.

This paper illustrates how to estimate cumulative and non-cumulative treatment effects in a complex school-based smoking intervention study. The Instrumental Variable method is used to tackle non-compliance and measurement error for a range of treatment exposure measures (binary, ordinal and continuous) in the presence of clustering and dropout. The results are compared to more routine analyses. The empirical findings from this study provide little encouragement for believing that poorly resourced school-based interventions can bring about substantial long-lasting reductions in smoking behaviour but that novel components such as a computer game might have some short-term effect.

A flexible model for multivariate interval-censored survival times with complex correlation structure.

We focus on the analysis of multivariate survival times with highly structured interdependency and subject to interval censoring. Such data are common in developmental genetics and genetic epidemiology. We propose a flexible mixed probit model that deals naturally with complex but uninformative censoring. The recorded ages of onset are treated as possibly censored ordinal outcomes with the interval censoring mechanism seen as arising from a coarsened measurement of a continuous variable observed as falling between subject-specific thresholds. This bypasses the requirement for the failure times to be observed as falling into non-overlapping intervals. The assumption of a normal age-of-onset distribution of the standard probit model is relaxed by embedding within it a multivariate Box-Cox transformation whose parameters are jointly estimated with the other parameters of the model. Complex decompositions of the underlying multivariate normal covariance matrix of the transformed ages of onset become possible. The new methodology is here applied to a multivariate study of the ages of first use of tobacco and first consumption of alcohol without parental permission in twins. The proposed model allows estimation of the genetic and environmental effects that are shared by both of these risk behaviours as well as those that are specific.

Linkage analysis of cross-sectional and longitudinally derived phenotypic measures to identify loci influencing blood pressure.

BACKGROUND: The design of appropriate strategies to analyze and interpret linkage results for complex human diseases constitutes a challenge. Parameters such as power, definition of phenotype, and replicability have to be taken into account in order to reach meaningful conclusions. Incorporating data on repeated phenotypic measures may increase the power to detect linkage but requires sophisticated analysis methods. Using the simulated Genetic Analysis Workshop 13 data set, we have estimated a variety of systolic blood pressure (SBP) phenotypic measures and examined their performance with respect to consistency among replicates and to true and false positive linkage signals. RESULTS: The whole-genome scan conducted on a dichotomous hypertension phenotype indicated the involvement of few true loci with nominal significance and gave rise to a high rate of false positives. Analysis of a cross-sectional quantitative SBP measure performed better, although genome-wide significance was again not reached. Additional phenotypic measures were derived from the longitudinal data using random effects modelling for censored data with varying levels of covariate adjustment. These models provided evidence for significant linkage to most genes influencing SBP and produced few false positive results. Overall, replicability of results was poor for loci, representing weak effects. CONCLUSION: Longitudinally derived phenotypes performed better than cross-sectional measures in linkage analyses. Bearing in mind the sample design and size of these data, linkage results that fail to replicate should not be dismissed; instead, different lines of evidence derived from complementary analysis methods should be combined to prioritize follow up.