Shona Fielding

Primary and repeat surgical treatment for female pelvic organ prolapse and incontinence in parous women in the UK: a register linkage study

Objectives To determine the lifetime risk of undergoing pelvic floor surgery in a cohort of UK parous women and the re-operation rates for pelvic floor surgery, time intervals for repeat surgery and independent risk factors for undergoing primary and repeat pelvic floor surgery. Study design A register linkage study. Main outcome measures The primary outcome was lifetime risk of parous women in the UK undergoing pelvic floor surgery for pelvic organ prolapse (POP), urinary incontinence (UI), and rectal prolapse or faecal incontinence (RP-FI). Secondary outcomes were re-operation rates and time interval of repeat surgery for POP/UI, and independent risk factors for undergoing primary and repeat pelvic floor surgery. Results 34 631 women identified from the Aberdeen Maternity and Neonatal Database were linked with the Scottish Morbidity Records databases of NHS Scotland to assess relevant outcomes. The lifetime risk for women by age 80 years of undergoing any form of pelvic floor surgery was 12.2%. 2130 (6.2%) women had at least one pelvic floor surgery, of whom 407 (19%) had repeat operations. The median time intervals (IQR) between index and repeat UI and POP surgery were 2.80 (0.94–8.07) years and 3 (1.00–8.25) years, respectively. There is a reduced lifetime risk of pelvic floor surgery in women who had all deliveries by caesarean section (p<0.001) and those aged <20 years at first delivery (p=0.021). Women who sustained at least one perineal laceration (in the absence of a classified perineal tear) during delivery or who had at least one instrumental delivery with forceps use were at increased risk (p<0.001 and p=0.015, respectively). Conclusions Our study shows that in the UK more than one in 10 parous women will require at least one surgical procedure for pelvic floor disorders over their lifetime. The study also identifies independent risk and protective factors for pelvic floor surgery in parous women.

A review of RCTs in four medical journals to assess the use of imputation to overcome missing data in quality of life outcomes

BackgroundRandomised controlled trials (RCTs) are perceived as the gold-standard method for evaluating healthcare interventions, and increasingly include quality of life (QoL) measures. The observed results are susceptible to bias if a substantial proportion of outcome data are missing. The review aimed to determine whether imputation was used to deal with missing QoL outcomes.MethodsA random selection of 285 RCTs published during 2005/6 in the British Medical Journal, Lancet, New England Journal of Medicine and Journal of American Medical Association were identified.ResultsQoL outcomes were reported in 61 (21%) trials. Six (10%) reported having no missing data, 20 (33%) reported ≤ 10% missing, eleven (18%) 11%–20% missing, and eleven (18%) reported >20% missing. Missingness was unclear in 13 (21%). Missing data were imputed in 19 (31%) of the 61 trials. Imputation was part of the primary analysis in 13 trials, but a sensitivity analysis in six. Last value carried forward was used in 12 trials and multiple imputation in two. Following imputation, the most common analysis method was analysis of covariance (10 trials).ConclusionThe majority of studies did not impute missing data and carried out a complete-case analysis. For those studies that did impute missing data, researchers tended to prefer simpler methods of imputation, despite more sophisticated methods being available.

Outcomes of Childhood Asthma and Wheezy Bronchitis. A 50-Year Cohort Study

RATIONALE Cohort studies suggest that airflow obstruction is established early in life, manifests as childhood asthma and wheezy bronchitis, and continues into early adulthood. Although an association between childhood asthma and chronic obstructive pulmonary disease (COPD) in later life has been demonstrated, it is unclear if childhood wheezy bronchitis is associated with COPD. OBJECTIVES To investigate whether childhood wheezy bronchitis increases the risk of COPD in the seventh decade. METHODS A cohort of children recruited in 1964 at age 10 to 15 years, which was followed up in 1989, 1995, and 2001, was followed up again in 2014 when at age 60 to 65 years. Discrete time-to-event and linear mixed effects models were used. MEASUREMENTS AND MAIN RESULTS FEV1 and FVC were measured. COPD was defined as post-bronchodilator FEV1/FVC <0.7. Childhood wheezing phenotype was related to 1989, 1995, 2001, and 2014 spirometry data. Three hundred thirty subjects, mean age 61 years, were followed up: 38 with childhood asthma; 53 with childhood wheezy bronchitis; and 239 control subjects (of whom 57 developed adulthood-onset wheeze between ages 16 and 46 yr). In adjusted multivariate analyses, childhood asthma was associated with an increased risk of COPD (odds ratio, 6.37; 95% confidence interval, 3.73-10.94), as was childhood wheezy bronchitis (odd ratio 1.81; 95% confidence interval, 1.12-2.91). The COPD risk increased with childhood asthma, and wheezy bronchitis was associated with reduced FEV1 that was evident by the fifth decade and not an accelerated rate of FEV1 decline. In contrast, adulthood-onset wheeze was associated with accelerated FEV1 decline. CONCLUSIONS Childhood wheezy bronchitis and asthma are associated with an increased risk of COPD and reduced ventilatory function.

Contemporary Hormonal Contraception and the Risk of Breast Cancer

Background Little is known about whether contemporary hormonal contraception is associated with an increased risk of breast cancer. Methods We assessed associations between the use of hormonal contraception and the risk of invasive breast cancer in a nationwide prospective cohort study involving all women in Denmark between 15 and 49 years of age who had not had cancer or venous thromboembolism and who had not received treatment for infertility. Nationwide registries provided individually updated information about the use of hormonal contraception, breast‐cancer diagnoses, and potential confounders. Results Among 1.8 million women who were followed on average for 10.9 years (a total of 19.6 million person‐years), 11,517 cases of breast cancer occurred. As compared with women who had never used hormonal contraception, the relative risk of breast cancer among all current and recent users of hormonal contraception was 1.20 (95% confidence interval [CI], 1.14 to 1.26). This risk increased from 1.09 (95% CI, 0.96 to 1.23) with less than 1 year of use to 1.38 (95% CI, 1.26 to 1.51) with more than 10 years of use (P=0.002). After discontinuation of hormonal contraception, the risk of breast cancer was still higher among the women who had used hormonal contraceptives for 5 years or more than among women who had not used hormonal contraceptives. Risk estimates associated with current or recent use of various oral combination (estrogen–progestin) contraceptives varied between 1.0 and 1.6. Women who currently or recently used the progestin‐only intrauterine system also had a higher risk of breast cancer than women who had never used hormonal contraceptives (relative risk, 1.21; 95% CI, 1.11 to 1.33). The overall absolute increase in breast cancers diagnosed among current and recent users of any hormonal contraceptive was 13 (95% CI, 10 to 16) per 100,000 person‐years, or approximately 1 extra breast cancer for every 7690 women using hormonal contraception for 1 year. Conclusions The risk of breast cancer was higher among women who currently or recently used contemporary hormonal contraceptives than among women who had never used hormonal contraceptives, and this risk increased with longer durations of use; however, absolute increases in risk were small. (Funded by the Novo Nordisk Foundation.)

Investigating the missing data mechanism in quality of life outcomes: a comparison of approaches

BackgroundMissing data is classified as missing completely at random (MCAR), missing at random (MAR) or missing not at random (MNAR). Knowing the mechanism is useful in identifying the most appropriate analysis. The first aim was to compare different methods for identifying this missing data mechanism to determine if they gave consistent conclusions. Secondly, to investigate whether the reminder-response data can be utilised to help identify the missing data mechanism.MethodsFive clinical trial datasets that employed a reminder system at follow-up were used. Some quality of life questionnaires were initially missing, but later recovered through reminders. Four methods of determining the missing data mechanism were applied. Two response data scenarios were considered. Firstly, immediate data only; secondly, all observed responses (including reminder-response).ResultsIn three of five trials the hypothesis tests found evidence against the MCAR assumption. Logistic regression suggested MAR, but was able to use the reminder-collected data to highlight potential MNAR data in two trials.ConclusionThe four methods were consistent in determining the missingness mechanism. One hypothesis test was preferred as it is applicable with intermittent missingness. Some inconsistencies between the two data scenarios were found. Ignoring the reminder data could potentially give a distorted view of the missingness mechanism. Utilising reminder data allowed the possibility of MNAR to be considered.

Simple imputation methods were inadequate for missing not at random (MNAR) quality of life data

ObjectiveQoL data were routinely collected in a randomised controlled trial (RCT), which employed a reminder system, retrieving about 50% of data originally missing. The objective was to use this unique feature to evaluate possible missingness mechanisms and to assess the accuracy of simple imputation methods.MethodsThose patients responding after reminder were regarded as providing missing responses. A hypothesis test and a logistic regression approach were used to evaluate the missingness mechanism. Simple imputation procedures were carried out on these missing scores and the results compared to the actual observed scores.ResultsThe hypothesis test and logistic regression approaches suggested the reminder data were missing not at random (MNAR). Reminder-response data showed that simple imputation procedures utilising information collected close to the point of imputation (last value carried forward, next value carried backward and last-and-next), were the best methods in this setting. However, although these methods were the best of the simple imputation procedures considered, they were not sufficiently accurate to be confident of obtaining unbiased results under imputation.ConclusionThe use of the reminder data enabled the conclusion of possible MNAR data. Evaluating this mechanism was important in determining if imputation was useful. Simple imputation was shown to be inadequate if MNAR are likely and alternative strategies should be considered.

Effect of Omega-3 fatty acid supplementation on markers of platelet and endothelial function in patients with peripheral arterial disease

OBJECTIVE Omega-3 fatty acids have been shown to reduce platelet and endothelial activation in patients with or at risk of cardiac disease. We aimed to determine if Omega-3 fatty acid supplementation in addition to best medical therapy can reduce the increased platelet and endothelial activity that is present in patients with intermittent claudication. METHODS One hundred and fifty patients who were receiving aspirin and statin therapy were recruited into a randomised cross-over double blind study involving 6 week supplementation with OMACOR fish oil (850-882 mg eicosapentaenoic and docosahexaenoic acid) versus placebo. A 12 week washout period occurred between treatments. Patients with diabetes were excluded. For each outcome a random effects model was fitted in which treatment and period were fixed effects and patients were random effects. RESULTS Omega-3 supplementation had no effect on the primary outcome measure von Willebrand factor. Similarly Omega-3 supplementation resulted in no change in unstimulated or stimulated P-selectin expression and fibrinogen binding, or platelet aggregation (Ultegra point of care). Pulse wave velocity was also unchanged. High-sensitivity C-reactive protein, s-ICAM and IL-6 were also unchanged. CONCLUSION Supplementation with Omega-3 fatty acids had no affect on platelet and endothelial activation or markers of inflammation in patients with peripheral arterial disease.

A cohort study of influences, health outcomes and costs of patients’ health-seeking behaviour for minor ailments from primary and emergency care settings

Objectives To compare health-related and cost-related outcomes of consultations for symptoms suggestive of minor ailments in emergency departments (EDs), general practices and community pharmacies. Design Observational study; prospective cohort design. Setting EDs (n=2), general practices (n=6) and community pharmacies (n=10) in a mix of rural/urban and deprived/affluent areas across North East Scotland and East Anglia. Participants Adults (≥18 years) presenting between 09:00 and 18:00 (Monday–Friday) in general practices and 09:00–18:00 (Monday–Saturday) in pharmacies and EDs with ≥1 of the following: musculoskeletal pain; eye discomfort; gastrointestinal disturbance; or upper respiratory tract-related symptoms. Interventions Participants completed three questionnaires: baseline (prior to index consultation); satisfaction with index consultation and follow-up (2 weeks after index consultation). Main outcome measures Symptom resolution, quality of life, costs, satisfaction and influences on care-seeking behaviour. Results 377 patients participated, recruited from EDs (81), general practices (162) and community pharmacies (134). The 2-week response rate was 70% (264/377). Symptom resolution was similar across all three settings: ED (37.3%), general practice (35.7%) and pharmacy (44.3%). Mean overall costs per consultation were significantly lower for pharmacy (£29.30 (95% CI £21.60 to £37.00)) compared with general practice (£82.34 (95% CI £63.10 to £101.58)) and ED (£147.09 (95% CI £125.32 to £168.85)). Satisfaction varied across settings and by measure used. Compared with pharmacy and general practice use, ED use was significantly (p<0.001) associated with first episode and short duration of symptom(s), as well as higher levels of perceived seriousness and urgency for seeking care. Convenience of location was the most common reason for choice of consultation setting. Conclusions These results suggest similar health-related outcomes and substantially lower costs with pharmacy consultations for minor ailments. Effective strategies are now needed to shift demand for minor ailment management away from EDs and general practices to the community pharmacy setting.

Analysing randomised controlled trials with missing data: Choice of approach affects conclusions

BACKGROUND The publication of a wrong conclusion from a randomised trial could have disastrous consequences. Missing data are unavoidable in most studies, but ignoring the problem may introduce bias to the results. Finding an appropriate way to deal with missing data is of paramount importance. We show how the choice of analysis method can impact on the conclusion of the trial with regard to the quality of life outcomes. METHODS Various analysis strategies (analysis of covariance, linear mixed effects model) with and without imputation were carried out to assess treatment difference in four quality of life outcomes in an example clinical trial. RESULTS Across all four quality of life outcomes, the various analysis approaches provided different estimates of treatment difference, with varying precision, using different numbers of patients. In some cases the decision about statistical significance differed. The results suggested that where possible extra effort should be made to retrieve missing responses. In the presence of data missing at random, simple imputation was inappropriate with multiple imputation or a linear mixed effects model more useful. CONCLUSION Different trial conclusions were obtained for a variety of analysis approaches for the same outcome. Collecting as much data as possible is of paramount importance. Careful consideration should be taken when deciding on the most appropriate strategy for analysis when missing data are involved and this strategy should be pre-specified in the trial protocol. Making inappropriate decisions could result in inappropriate conclusions potentially leading to the adoption of a clinical intervention in error.

Methods for handling missing data in palliative care research.

Missing data is a common problem in palliative care research due to the special characteristics (deteriorating condition, fatigue and cachexia) of the population. Using data from a palliative study, we illustrate the problems that missing data can cause and show some approaches for dealing with it. Reasons for missing data and ways to deal with missing data (including complete case analysis, imputation and modelling procedures) are explored. Possible mechanisms behind the missing data are: missing completely at random, missing at random or missing not at random. In the example study, data are shown to be missing at random. Imputation of missing data is commonly used (including last value carried forward, regression procedures and simple mean). Imputation affects subsequent summary statistics and analyses, and can have a substantial impact on estimated group means and standard deviations. The choice of imputation method should be carried out with caution and the effects reported.