Louise Marston

Rethinking Clinical Trials of Transcranial Direct Current Stimulation: Participant and Assessor Blinding Is Inadequate at Intensities of 2mA

Background Many double-blind clinical trials of transcranial direct current stimulation (tDCS) use stimulus intensities of 2 mA despite the fact that blinding has not been formally validated under these conditions. The aim of this study was to test the assumption that sham 2 mA tDCS achieves effective blinding. Methods A randomised double blind crossover trial. 100 tDCS-naïve healthy volunteers were incorrectly advised that they there were taking part in a trial of tDCS on word memory. Participants attended for two separate sessions. In each session, they completed a word memory task, then received active or sham tDCS (order randomised) at 2 mA stimulation intensity for 20 minutes and then repeated the word memory task. They then judged whether they believed they had received active stimulation and rated their confidence in that judgement. The blinded assessor noted when red marks were observed at the electrode sites post-stimulation. Results tDCS at 2 mA was not effectively blinded. That is, participants correctly judged the stimulation condition greater than would be expected to by chance at both the first session (kappa level of agreement (κ) 0.28, 95% confidence interval (CI) 0.09 to 0.47 p = 0.005) and the second session (κ = 0.77, 95%CI 0.64 to 0.90), p = <0.001) indicating inadequate participant blinding. Redness at the reference electrode site was noticeable following active stimulation more than sham stimulation (session one, κ = 0.512, 95%CI 0.363 to 0.66, p<0.001; session two, κ = 0.677, 95%CI 0.534 to 0.82) indicating inadequate assessor blinding. Conclusions Our results suggest that blinding in studies using tDCS at intensities of 2 mA is inadequate. Positive results from such studies should be interpreted with caution.

Outdoor air pollution and respiratory health in patients with COPD

Objectives Time series studies have shown adverse effects of outdoor air pollution on mortality and hospital admissions in patients with chronic obstructive pulmonary disease (COPD) but panel studies have been inconsistent. This study investigates short-term effects of outdoor nitrogen dioxide, ozone, sulfur dioxide, particulate matter (PM10) and black smoke on exacerbations, respiratory symptoms and lung function in 94 patients with COPD in east London. Methods Patients were recruited from an outpatient clinic and were asked to complete daily diary cards (median follow-up 518 days) recording exacerbations, symptoms and lung function, and the amount of time spent outdoors. Outdoor air pollution exposure (lag 1 day) was obtained from local background monitoring stations. Results Symptoms but not lung function showed associations with raised pollution levels. Dyspnoea was significantly associated with PM10 (increase in odds for an IQR change in pollutant: 13% (95% CI 4% to 23%)) and this association remained after adjustment for other the pollutants measured. An IQR increase in nitrogen dioxide was associated with a 6% (0–13%) increase in the odds of a symptomatic fall in peak flow rate. The corresponding effect sizes for PM10 and black smoke were 12% (2–25%) and 7% (1–13%), respectively. Conclusion It is concluded that outdoor air pollution is associated with important adverse effects on symptoms in patients with COPD living in London.

Particulate air pollution and hospital admissions for cardiorespiratory diseases: are the elderly at greater risk?

A systematic literature review suggests that particulate air pollution is associated with daily admissions for both respiratory and cardiac diseases in people aged >65 yrs. A model of acute effects is proposed which shows how admissions can be brought forward by a relatively short period of time as well as events being added that would not have happened at all except for air pollution. A model of the effects of air pollution on chronic disease is proposed that provides the background of long-term vulnerability upon which the increased short-term vulnerability is superimposed. A study of daily hospital admissions in London shows that for respiratory disease the relative risks of admission associated with particles reduce with increasing age, while for cardiac disease, there is no trend. When the attributable risk is estimated using baseline admission rates for respiratory disease, it is children who have the highest attributable risk, followed by the elderly. For cardiac disease there is a steep increase in attributable risk with age, reflecting the dominant influence of baseline risks. The attributable risk for cardiovascular disease in the elderly is considerably greater than for respiratory disease, due to higher baseline admission rates.

Making inferences on treatment effects from real world data: propensity scores, confounding by indication, and other perils for the unwary in observational research

Propensity score based methods are used increasingly to evaluate the effectiveness of treatments when evidence from randomised trials is not available. However, users need to be aware of their strengths and limitations

Religion, spirituality and mental health: results from a national study of English households

BACKGROUND Religious participation or belief may predict better mental health but most research is American and measures of spirituality are often conflated with well-being. AIMS To examine associations between a spiritual or religious understanding of life and psychiatric symptoms and diagnoses. METHOD We analysed data collected from interviews with 7403 people who participated in the third National Psychiatric Morbidity Study in England. RESULTS Of the participants 35% had a religious understanding of life, 19% were spiritual but not religious and 46% were neither religious nor spiritual. Religious people were similar to those who were neither religious nor spiritual with regard to the prevalence of mental disorders, except that the former were less likely to have ever used drugs (odds ratio (OR) = 0.73, 95% CI 0.60-0.88) or be a hazardous drinker (OR = 0.81, 95% CI 0.69-0.96). Spiritual people were more likely than those who were neither religious nor spiritual to have ever used (OR = 1.24, 95% CI 1.02-1.49) or be dependent on drugs (OR = 1.77, 95% CI 1.20-2.61), and to have abnormal eating attitudes (OR = 1.46, 95% CI 1.10-1.94), generalised anxiety disorder (OR = 1.50, 95% CI 1.09-2.06), any phobia (OR = 1.72, 95% CI 1.07-2.77) or any neurotic disorder (OR = 1.37, 95% CI 1.12-1.68). They were also more likely to be taking psychotropic medication (OR = 1.40, 95% CI 1.05-1.86). CONCLUSIONS People who have a spiritual understanding of life in the absence of a religious framework are vulnerable to mental disorder.

Prescribing of antipsychotics in UK primary care: a cohort study

Objective To examine the recorded indication for antipsychotic prescriptions in UK primary care. Design Cohort study. Setting Primary care. Participants Individuals prescribed antipsychotics between 2007 and 2011. Measures The proportion of individuals prescribed antipsychotics with a diagnosis of (1) psychosis and bipolar disorder, (2) other diagnoses including depression, anxiety and dementia and (3) none of these diagnoses. Results We identified 47 724 individuals prescribed antipsychotic agents. 13 941 received first-generation agents and 27 966 received second-generation agents. The rates of prescribing were higher in females (incidence rate ratio (IRR) 1.092 (95% CI 1.088 to 1.095), older people (80+ vs 40–49; IRR 2.234 (2.222 to 2.246)) and in those from the most deprived areas (most deprived vs least deprived IRR 3.487 (3.567 to 3.606). Of those receiving first-generation antipsychotics, less than 50% had a diagnosis of psychosis/bipolar disorder. For the second-generation agents, the numbers ranged from 4824 (36%) for quetiapine to 7094 (62%) for olanzapine. In patients without psychosis/bipolar disorder, common diagnoses included anxiety, depression, dementia, sleep and personality disorders. For example, in risperidone users, 14% had an anxiety code, 22% depression, 12% dementia, 11% sleep disorder and 4% personality disorder. The median daily doses and duration of treatment were greater in those with schizophrenia (eg, risperidone median daily dose 4 mg; IQR 2–6: median duration 1.2 years) than in those with non-psychotic/bipolar disorders such as depression or anxiety (eg, risperidone 1 mg; IQR 1–2: 0.6 years). A relatively large proportion (between 6% and 17%) of people receiving individual antipsychotics had none of the diagnoses stated above. Conclusions In UK primary care, a large proportion of people prescribed antipsychotics have no record of psychotic or bipolar disorder. They are often older people with conditions including dementia, non-psychotic depression, anxiety and sleep disorders.

Issues in multiple imputation of missing data for large general practice clinical databases

Missing data are a substantial problem in clinical databases. This paper aims to examine patterns of missing data in a primary care database, compare this to nationally representative datasets and explore the use of multiple imputation (MI) for these data.

Cardiovascular risk prediction models for people with severe mental illness: results from the prediction and management of cardiovascular risk in people with severe mental illnesses (PRIMROSE) research program

IMPORTANCE People with severe mental illness (SMI), including schizophrenia and bipolar disorder, have excess rates of cardiovascular disease (CVD). Risk prediction models validated for the general population may not accurately estimate cardiovascular risk in this group. OBJECTIVE To develop and validate a risk model exclusive to predicting CVD events in people with SMI incorporating established cardiovascular risk factors and additional variables. DESIGN, SETTING, AND PARTICIPANTS We used anonymous/deidentified data collected between January 1, 1995, and December 31, 2010, from the Health Improvement Network (THIN) to conduct a primary care, prospective cohort and risk score development study in the United Kingdom. Participants included 38,824 people with a diagnosis of SMI (schizophrenia, bipolar disorder, or other nonorganic psychosis) aged 30 to 90 years. During a median follow-up of 5.6 years, 2324 CVD events (6.0%) occurred. MAIN OUTCOMES AND MEASURES Ten-year risk of the first cardiovascular event (myocardial infarction, angina pectoris, cerebrovascular accidents, or major coronary surgery). Predictors included age, sex, height, weight, systolic blood pressure, diabetes mellitus, smoking, body mass index (BMI), lipid profile, social deprivation, SMI diagnosis, prescriptions for antidepressants and antipsychotics, and reports of heavy alcohol use. RESULTS We developed 2 CVD risk prediction models for people with SMI: the PRIMROSE BMI model and the PRIMROSE lipid model. These models mutually excluded lipids and BMI. In terms of discrimination, from cross-validations for men, the PRIMROSE lipid model D statistic was 1.92 (95% CI, 1.80-2.03) and C statistic was 0.80 (95% CI, 0.76-0.83) compared with 1.74 (95% CI, 1.63-1.86) and 0.78 (95% CI, 0.75-0.82) for published Cox Framingham risk scores. The corresponding results in women were 1.87 (95% CI, 1.76-1.98) and 0.79 (95% CI, 0.76-0.82) for the PRIMROSE lipid model and 1.58 (95% CI, 1.48-1.68) and 0.77 (95% CI, 0.73-0.81) for the Cox Framingham model. Discrimination statistics for the PRIMROSE BMI model were comparable to those for the PRIMROSE lipid model. Calibration plots suggested that both PRIMROSE models were superior to the Cox Framingham models. CONCLUSIONS AND RELEVANCE The PRIMROSE BMI and lipid CVD risk prediction models performed better in SMI compared with models that include only established CVD risk factors. Further work on the clinical effectiveness and cost-effectiveness of the PRIMROSE models is needed to ascertain the best thresholds for offering CVD interventions.

Randomised trial of high frequency oscillatory ventilation or conventional ventilation in babies of gestational age 28 weeks or less: respiratory and neurological outcomes at 2 years

Background: The long term outcome of children entered into neonatal trials of high frequency oscillatory ventilation (HFOV) or conventional ventilation (CV) has been rarely studied. Objective: To evaluate respiratory and neurodevelopmental outcomes for children entered into the United Kingdom Oscillation Study, which was designed to evaluate these outcomes. Methods: Surviving infants were followed until 2 years of age corrected for prematurity. Study forms were completed by local paediatricians at routine assessments, and parents were asked to complete a validated neurodevelopmental questionnaire. Results: Paediatricians’ forms were returned for 73% of the 585 surviving infants. Respiratory symptoms were common in all infants, and 41% had received inhaled medication. Mode of ventilation had no effect on frequency of any symptoms. At 24 months of age, severe neurodevelopmental disability was present in 9% and other disabilities in 38% of children, but the prevalence of disability was similar in children who received HFOV or CV (relative risk 0.93; 95% confidence interval 0.74 to 1.16). The prevalence of disability did not vary by gestational age, but boys were more likely to have overall disability. Developmental scores were unaffected by mode of ventilation (relative risk 1.13; 95% confidence interval 0.78 to 1.63) and were lower in infants born before 26 weeks gestation compared with babies born at 26–28 weeks. Conclusions: Initial mode of ventilation in very preterm infants has no impact on respiratory or neurodevelopmental morbidity at 2 years. HFOV and CV appear equally effective for the early treatment of respiratory distress syndrome.

Transcranial direct current stimulation of the motor cortex in the treatment of chronic nonspecific low back pain: a randomized, double-blind exploratory study.

Objectives:To test the proof of principle that active anodal transcranial direct current stimulation (tDCS) applied to the motor cortex reduces pain significantly more than sham stimulation in a group of participants with chronic nonspecific low back pain. Methods:The study utilized a within-participants sham-controlled, interrupted time series design. A sample of 8 participants was recruited. After 3 days of baseline measures, patients entered a 15-day experimental period (Mondays to Fridays) for 3 consecutive weeks. During this period each patient received sham stimulation daily until a randomly allocated day when active stimulation was commenced. Active stimulation was then given daily for the remaining days of the experimental period. Both the participants and the assessors were blinded. The primary outcomes were average pain intensity and unpleasantness in the last 24 hours measured using a visual analogue scale. Secondary outcomes included self-reported disability, depression and anxiety, a battery of cognitive tests to monitor for unwanted effects of stimulation, and patients’ perceptions of whether they had received active or sham stimulation. Data were analyzed using generalized estimating equations. Results:No significant effect was seen in the primary outcomes between active and sham stimulation (average pain intensity P=0.821, unpleasantness P=0.937) or across any other clinical variables. There was evidence that patients may have been able to distinguish between the active and sham conditions (P=0.035). Discussion:These results do not provide evidence that tDCS is effective in the treatment of chronic back pain. The use of a small convenience sample limits the generalizability of these findings and precludes definitive conclusions on the efficacy of tDCS in chronic nonspecific low back pain.