Assessing the validity of a Parkinson's care evaluation: the PRIME-NL study.

INTRODUCTION: The PRIME-NL study prospectively evaluates a new integrated and personalized care model for people with parkinsonism, including Parkinson's disease, in a selected region (PRIME) in the Netherlands. We address the generalizability and sources of selection and confounding bias of the PRIME-NL study by examining baseline and 1-year compliance data. METHODS: First, we assessed regional baseline differences between the PRIME and the usual care (UC) region using healthcare claims data of almost all people with Parkinson's disease in the Netherlands (the source population). Second, we compared our questionnaire sample to the source population to determine generalizability. Third, we investigated sources of bias by comparing the PRIME and UC questionnaire sample on baseline characteristics and 1-year compliance. RESULTS: Baseline characteristics were similar in the PRIME (n = 1430) and UC (n = 26,250) source populations. The combined questionnaire sample (n = 920) was somewhat younger and had a slightly longer disease duration than the combined source population. Compared to the questionnaire sample in the PRIME region, the UC questionnaire sample was slightly younger, had better cognition, had a longer disease duration, had a higher educational attainment and consumed more alcohol. 1-year compliance of the questionnaire sample was higher in the UC region (96%) than in the PRIME region (92%). CONCLUSION: The generalizability of the PRIME-NL study seems to be good, yet we found evidence of some selection bias. This selection bias necessitates the use of advanced statistical methods for the final evaluation of PRIME-NL, such as inverse probability weighting or propensity score matching. The PRIME-NL study provides a unique window into the validity of a large-scale care evaluation for people with a chronic disease, in this case parkinsonism.

Enhancing recruitment of individuals living with frailty, multimorbidity and cognitive impairment to Parkinson's research: experiences from the PRIME-UK cross-sectional study.

BACKGROUND AND OBJECTIVES: People with parkinsonism who are older, living in a care home, with frailty, multimorbidity or impaired capacity to consent are under-represented in research, limiting its generalisability. We aimed to evaluate more inclusive recruitment strategies. METHODS: From one UK centre, we invited people with parkinsonism to participate in a cross-sectional study. Postal invitations were followed by telephone reminders and additional support to facilitate participation. Personal consultees provided information on the views regarding research participation of adults with impaired capacity. These approaches were evaluated: (i) using external data from the Parkinson's Real World Impact assesSMent (PRISM) study and Clinical Practice Research Datalink (CPRD), a sample of all cases in UK primary care, and (ii) comparing those recruited with or without intensive engagement. RESULTS: We approached 1,032 eligible patients, of whom 542 (53%) consented and 477 (46%) returned questionnaires. The gender ratio in PRIME-UK (65% male) closely matched CPRD (61% male), unlike in the PRISM sample (46%). Mean age of PRIME participants was 75.9 (SD 8.5) years, compared to 75.3 (9.5) and 65.4 (8.9) years for CPRD and PRISM, respectively. More intensive engagement enhanced recruitment of women (13.3%; 95% CI 3.8, 22.9%; P = 0.005), care home residents (6.2%; 1.1, 11.2%; P = 0.004), patients diagnosed with atypical parkinsonism (13.7%; 5.4, 19.9%; P < 0.001), and those with a higher frailty score (mean score 0.2, 0.1, 0.2; P < 0.001). CONCLUSIONS: These recruitment strategies resulted in a less biased and more representative sample, with greater inclusion of older people with more complex parkinsonism.

NMR metabolomic modeling of age and lifespan: A multicohort analysis.

Metabolomic age models have been proposed for the study of biological aging, however, they have not been widely validated. We aimed to assess the performance of newly developed and existing nuclear magnetic resonance spectroscopy (NMR) metabolomic age models for prediction of chronological age (CA), mortality, and age-related disease. Ninety-eight metabolic variables were measured in blood from nine UK and Finnish cohort studies (N ≈31,000 individuals, age range 24-86 years). We used nonlinear and penalized regression to model CA and time to all-cause mortality. We examined associations of four new and two previously published metabolomic age models, with aging risk factors and phenotypes. Within the UK Biobank (N ≈102,000), we tested prediction of CA, incident disease (cardiovascular disease (CVD), type-2 diabetes mellitus, cancer, dementia, and chronic obstructive pulmonary disease), and all-cause mortality. Seven-fold cross-validated Pearson's r between metabolomic age models and CA ranged between 0.47 and 0.65 in the training cohort set (mean absolute error: 8-9 years). Metabolomic age models, adjusted for CA, were associated with C-reactive protein, and inversely associated with glomerular filtration rate. Positively associated risk factors included obesity, diabetes, smoking, and physical inactivity. In UK Biobank, correlations of metabolomic age with CA were modest (r = 0.29-0.33), yet all metabolomic model scores predicted mortality (hazard ratios of 1.01 to 1.06/metabolomic age year) and CVD, after adjustment for CA. While metabolomic age models were only moderately associated with CA in an independent population, they provided additional prediction of morbidity and mortality over CA itself, suggesting their wider applicability.

Motor Complications in Parkinson's Disease: Results from 3343 Patients Followed for up to 12 Years.

BACKGROUND: Motor complications are well recognized in Parkinson's disease (PD), but their reported prevalence varies and functional impact has not been well studied. OBJECTIVES: To quantify the presence, severity, impact and associated factors for motor complications in PD. METHODS: Analysis of three large prospective cohort studies of recent-onset PD patients followed for up to 12 years. The MDS-UPDRS part 4 assessed motor complications and multivariable logistic regression tested for associations. Genetic risk score (GRS) for Parkinson's was calculated from 79 single nucleotide polymorphisms. RESULTS: 3343 cases were included (64.7% male). Off periods affected 35.0% (95% CI 33.0, 37.0) at 4-6 years and 59.0% (55.6, 62.3) at 8-10 years. Dyskinesia affected 18.5% (95% CI 16.9, 20.2) at 4-6 years and 42.1% (38.7, 45.5) at 8-10 years. Dystonia affected 13.4% (12.1, 14.9) at 4-6 years and 22.8% (20.1, 25.9) at 8-10 years. Off periods consistently caused greater functional impact than dyskinesia. Motor complications were more common among those with higher drug doses, younger age at diagnosis, female gender, and greater dopaminergic responsiveness (in challenge tests), with associations emerging 2-4 years post-diagnosis. Higher Parkinson's GRS was associated with early dyskinesia (0.026 ≤ P ≤ 0.050 from 2 to 6 years). CONCLUSIONS: Off periods are more common and cause greater functional impairment than dyskinesia. We confirm previously reported associations between motor complications with several demographic and medication factors. Greater dopaminergic responsiveness and a higher genetic risk score are two novel and significant independent risk factors for the development of motor complications.

Genetics impact risk of Alzheimer's disease through mechanisms modulating structural brain morphology in late life.

BACKGROUND: Alzheimer's disease (AD)-related neuropathological changes can occur decades before clinical symptoms. We aimed to investigate whether neurodevelopment and/or neurodegeneration affects the risk of AD, through reducing structural brain reserve and/or increasing brain atrophy, respectively. METHODS: We used bidirectional two-sample Mendelian randomisation to estimate the effects between genetic liability to AD and global and regional cortical thickness, estimated total intracranial volume, volume of subcortical structures and total white matter in 37 680 participants aged 8-81 years across 5 independent cohorts (Adolescent Brain Cognitive Development, Generation R, IMAGEN, Avon Longitudinal Study of Parents and Children and UK Biobank). We also examined the effects of global and regional cortical thickness and subcortical volumes from the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium on AD risk in up to 37 741 participants. RESULTS: Our findings show that AD risk alleles have an age-dependent effect on a range of cortical and subcortical brain measures that starts in mid-life, in non-clinical populations. Evidence for such effects across childhood and young adulthood is weak. Some of the identified structures are not typically implicated in AD, such as those in the striatum (eg, thalamus), with consistent effects from childhood to late adulthood. There was little evidence to suggest brain morphology alters AD risk. CONCLUSIONS: Genetic liability to AD is likely to affect risk of AD primarily through mechanisms affecting indicators of brain morphology in later life, rather than structural brain reserve. Future studies with repeated measures are required for a better understanding and certainty of the mechanisms at play.

Prostate-Specific Antigen Screening and 15-Year Prostate Cancer Mortality: A Secondary Analysis of the CAP Randomized Clinical Trial.

Importance: The Cluster Randomized Trial of PSA Testing for Prostate Cancer (CAP) reported no effect of prostate-specific antigen (PSA) screening on prostate cancer mortality at a median 10-year follow-up (primary outcome), but the long-term effects of PSA screening on prostate cancer mortality remain unclear. Objective: To evaluate the effect of a single invitation for PSA screening on prostate cancer-specific mortality at a median 15-year follow-up compared with no invitation for screening. Design, Setting, and Participants: This secondary analysis of the CAP randomized clinical trial included men aged 50 to 69 years identified at 573 primary care practices in England and Wales. Primary care practices were randomized between September 25, 2001, and August 24, 2007, and men were enrolled between January 8, 2002, and January 20, 2009. Follow-up was completed on March 31, 2021. Intervention: Men received a single invitation for a PSA screening test with subsequent diagnostic tests if the PSA level was 3.0 ng/mL or higher. The control group received standard practice (no invitation). Main Outcomes and Measures: The primary outcome was reported previously. Of 8 prespecified secondary outcomes, results of 4 were reported previously. The 4 remaining prespecified secondary outcomes at 15-year follow-up were prostate cancer-specific mortality, all-cause mortality, and prostate cancer stage and Gleason grade at diagnosis. Results: Of 415 357 eligible men (mean [SD] age, 59.0 [5.6] years), 98% were included in these analyses. Overall, 12 013 and 12 958 men with a prostate cancer diagnosis were in the intervention and control groups, respectively (15-year cumulative risk, 7.08% [95% CI, 6.95%-7.21%] and 6.94% [95% CI, 6.82%-7.06%], respectively). At a median 15-year follow-up, 1199 men in the intervention group (0.69% [95% CI, 0.65%-0.73%]) and 1451 men in the control group (0.78% [95% CI, 0.73%-0.82%]) died of prostate cancer (rate ratio [RR], 0.92 [95% CI, 0.85-0.99]; P = .03). Compared with the control, the PSA screening intervention increased detection of low-grade (Gleason score [GS] ≤6: 2.2% vs 1.6%; P < .001) and localized (T1/T2: 3.6% vs 3.1%; P < .001) disease but not intermediate (GS of 7), high-grade (GS ≥8), locally advanced (T3), or distally advanced (T4/N1/M1) tumors. There were 45 084 all-cause deaths in the intervention group (23.2% [95% CI, 23.0%-23.4%]) and 50 336 deaths in the control group (23.3% [95% CI, 23.1%-23.5%]) (RR, 0.97 [95% CI, 0.94-1.01]; P = .11). Eight of the prostate cancer deaths in the intervention group (0.7%) and 7 deaths in the control group (0.5%) were related to a diagnostic biopsy or prostate cancer treatment. Conclusions and Relevance: In this secondary analysis of a randomized clinical trial, a single invitation for PSA screening compared with standard practice without routine screening reduced prostate cancer deaths at a median follow-up of 15 years. However, the absolute reduction in deaths was small. Trial Registration: isrctn.org Identifier: ISRCTN92187251.

Use of drugs for hyperlipidaemia and diabetes and risk of primary and secondary brain tumours: nested case-control studies using the UK Clinical Practice Research Datalink (CPRD).

OBJECTIVES: Previous studies have suggested that fibrates and glitazones may have a role in brain tumour prevention. We examined if there is support for these observations using primary care records from the UK Clinical Practice Research Datalink (CPRD). DESIGN: We conducted two nested case-control studies using primary and secondary brain tumours identified within CPRD between 2000 and 2016. We selected cases and controls among the population of individuals who had been treated with any anti-diabetic or anti-hyperlipidaemic medication to reduce confounding by indication. SETTING: Adults older than 18 years registered with a general practitioner in the UK contributing data to CPRD. RESULTS: We identified 7496 individuals with any brain tumour (4471 primary; 3025 secondary) in total. After restricting cases and controls to those prescribed any anti-diabetic or anti-hyperlipidaemic medication, there were 1950 cases and 7791 controls in the fibrate and 480 cases with 1920 controls in the glitazone analyses. Longer use of glitazones compared with all other anti-diabetic medications was associated with a reduced risk of primary (adjusted OR (aOR) 0.89 per year, 95% CI 0.80 to 0.98), secondary (aOR 0.87 per year, 95% CI 0.77 to 0.99) or combined brain tumours (aOR 0.88 per year, 95% CI 0.81 to 0.95). There was little evidence that fibrate exposure was associated with risk of either primary or secondary brain tumours. CONCLUSIONS: Longer exposure to glitazones was associated with reduced primary and secondary brain tumour risk. Further basic science and population-based research should explore this finding in greater detail, in terms of replication and mechanistic studies.

Prodromal multiple sclerosis: considerations and future utility.

A multiple sclerosis (MS) prodrome has recently been described and is characterised by increased rates of healthcare utilisation and an excess frequency of fatigue, bladder problems, sensory symptoms and pain, in the years leading up to clinical onset of disease. This important observation may have several potential applications including in the identification of risk factors for disease, the potential to delay or prevent disease onset and early opportunities to alter disease course. It may also offer possibilities for the use of risk stratification algorithms and effective population screening. If standardised, clearly defined and disease specific, an MS prodrome is also likely to have a profound influence on research and clinical trials directed at the earliest stages of disease. In order to achieve these goals, it is essential to consider experience already gleaned from other disorders. More specifically, in some chronic neurological disorders the understanding of disease pro-drome is now well advanced and has been successfully applied. However, understanding of the MS prodrome remains at an early stage with key questions including the length of the prodrome, symptom specificity and potential benefits of early intervention as yet unanswered. In this review we will explore the evidence available to date and suggest future research strategies to address unanswered questions. In addition, whilst current understanding of the MS prodrome is not yet sufficient to justify changes in public health policy or MS management, we will consider the practical utility and future application of the MS prodrome in a wider health care setting.

Psychosocial Health Among Young Adults With Kidney Failure: A Longitudinal Follow-up of the SPEAK (Surveying Patients Experiencing Young Adult Kidney Failure) Study.

Rationale & Objective: There have been no longitudinal studies examining the evolution of psychosocial health of young adults with kidney failure as they age. We aimed to address this in the Surveying Patients Experiencing Young Adult Kidney Failure-2 (SPEAK-2) study. Study Design: 5-year follow-up longitudinal survey of the original SPEAK cohort. Setting & Participants: 16- to 30-year-olds in the UK receiving kidney replacement therapy (KRT) between 2015 and 2017 who participated in the SPEAK study. Exposure: Kidney failure and KRT modality. Outcomes: Psychosocial health and lifestyle behaviors. Analytical Approach: Within-cohort changes in psychosocial health were analyzed using the paired t test, Wilcoxon signed-rank test and McNemar's test. We compared responses to the age-matched population and examined the impact of changes in KRT modality on psychological health using linear regression for continuous outcome variables as well as logistic, ordered logistic and multinomial logistic regression for binary, ordered categorical and unordered categorical variables, respectively. Results: We obtained 158 survey responses; 129 had previously responded to SPEAK. Of these, 90% had a kidney transplant. Compared to the general population, respondents were less likely to be married or have children and were more likely to be living with their parents. Respondents had nearly 15 times greater odds of being unable to work due to health (odds ratio [OR] = 14.41; 95% confidence interval [CI], 8.0-26.01; P < 0.001). Respondents had poorer quality of life and mental wellbeing and were more likely to report psychological problems (OR = 5.37; 95% CI, 3.45-8.35; P < 0.001). A negative association between remaining on or moving to dialysis and psychosocial health was observed, although this was attenuated when controlling for the psychosocial state in SPEAK. Limitations: Low response rate resulting in imprecise and potentially biased estimates and impact of COVID-19 pandemic while survey was active on psychosocial health. Conclusions: Young adults with kidney failure have persistent poorer psychosocial health compared to their healthy peers as they age. Our findings also suggest a potential causal relationship between KRT modality and psychosocial health.

The psychosocial impact of kidney failure in young adults is implicated in the observed higher risk of transplant loss and death. The Surveying Patients Experiencing Young Adult Kidney Failure (SPEAK) study investigated the psychosocial health of young adults (16-30 years) in the UK receiving kidney replacement therapy and found they had poorer outcomes than the age-matched general population. In this 5-year follow-up study, we observed that as this group matured, they lagged behind their peers in terms of both lifecourse and psychological outcomes. Dialysis recipients had poorer psychosocial health compared to transplant recipients. This emphasizes the lasting impact of kidney failure on young adults' psychosocial health, particularly for those receiving dialysis, highlighting the need for better mental health support and treatment.

Life course plasma metabolomic signatures of genetic liability to Alzheimer's disease.

Mechanisms through which most known Alzheimer's disease (AD) loci operate to increase AD risk remain unclear. Although Apolipoprotein E (APOE) is known to regulate lipid homeostasis, the effects of broader AD genetic liability on non-lipid metabolites remain unknown, and the earliest ages at which metabolic perturbations occur and how these change over time are yet to be elucidated. We examined the effects of AD genetic liability on the plasma metabolome across the life course. Using a reverse Mendelian randomization framework in two population-based cohorts [Avon Longitudinal Study of Parents and Children (ALSPAC, n = 5648) and UK Biobank (n ≤ 118,466)], we estimated the effects of genetic liability to AD on 229 plasma metabolites, at seven different life stages, spanning 8 to 73 years. We also compared the specific effects of APOE ε4 and APOE ε2 carriage on metabolites. In ALSPAC, AD genetic liability demonstrated the strongest positive associations with cholesterol-related traits, with similar magnitudes of association observed across all age groups including in childhood. In UK Biobank, the effect of AD liability on several lipid traits decreased with age. Fatty acid metabolites demonstrated positive associations with AD liability in both cohorts, though with smaller magnitudes than lipid traits. Sensitivity analyses indicated that observed effects are largely driven by the strongest AD instrument, APOE, with many contrasting effects observed on lipids and fatty acids for both ε4 and ε2 carriage. Our findings indicate pronounced effects of the ε4 and ε2 genetic variants on both pro- and anti-atherogenic lipid traits and sphingomyelins, which begin in childhood and either persist into later life or appear to change dynamically.

The epidemiology of Parkinson's disease.

The epidemiology of Parkinson's disease shows marked variations in time, geography, ethnicity, age, and sex. Internationally, prevalence has increased over and above demographic changes. There are several potential reasons for this increase, including the decline in other competing causes of death. Whether incidence is increasing, especially in women or in many low-income and middle-income countries where there is a shortage of high-quality data, is less certain. Parkinson's disease is more common in older people and men, and a variety of environmental factors have been suggested to explain why, including exposure to neurotoxic agents. Within countries, there appear to be ethnic differences in disease risk, although these differences might reflect differential access to health care. The cause of Parkinson's disease is multifactorial, and involves genetic and environmental factors. Both risk factors (eg, pesticides) and protective factors (eg, physical activity and tendency to smoke) have been postulated to have a role in Parkinson's disease, although elucidating causality is complicated by the long prodromal period. Following the establishment of public health strategies to prevent cardiovascular diseases and some cancers, chronic neurodegenerative diseases such as Parkinson's disease and dementia are gaining a deserved higher priority. Multipronged prevention strategies are required that tackle population-based primary prevention, high-risk targeted secondary prevention, and Parkinson's disease-modifying therapies for tertiary prevention. Future international collaborations will be required to triangulate evidence from basic, applied, and epidemiological research, thereby enhancing the understanding and prevention of Parkinson's disease at a global level.

Two sample Mendelian Randomisation using an outcome from a multilevel model of disease progression.

Identifying factors that are causes of disease progression, especially in neurodegenerative diseases, is of considerable interest. Disease progression can be described as a trajectory of outcome over time-for example, a linear trajectory having both an intercept (severity at time zero) and a slope (rate of change). A technique for identifying causal relationships between one exposure and one outcome in observational data whilst avoiding bias due to confounding is two sample Mendelian Randomisation (2SMR). We consider a multivariate approach to 2SMR using a multilevel model for disease progression to estimate the causal effect an exposure has on the intercept and slope. We carry out a simulation study comparing a naïve univariate 2SMR approach to a multivariate 2SMR approach with one exposure that effects both the intercept and slope of an outcome that changes linearly with time since diagnosis. The simulation study results, across six different scenarios, for both approaches were similar with no evidence against a non-zero bias and appropriate coverage of the 95% confidence intervals (for intercept 93.4-96.2% and the slope 94.5-96.0%). The multivariate approach gives a better joint coverage of both the intercept and slope effects. We also apply our method to two Parkinson's cohorts to examine the effect body mass index has on disease progression. There was no strong evidence that BMI affects disease progression, however the confidence intervals for both intercept and slope were wide.

The bidirectional effects between cognitive ability and brain morphology: A life course Mendelian randomization analysis.

Introduction: Little is understood about the dynamic interplay between brain morphology and cognitive ability across the life course. Additionally, most existing research has focused on global morphology measures such as estimated total intracranial volume, mean thickness, and total surface area. Methods: Mendelian randomization was used to estimate the bidirectional effects between cognitive ability, global and regional measures of cortical thickness and surface area, estimated total intracranial volume, total white matter, and the volume of subcortical structures (N=37,864). Analyses were stratified for developmental periods (childhood, early adulthood, mid-to-late adulthood; age range: 8-81 years). Results: The earliest effects were observed in childhood and early adulthood in the frontoparietal lobes. A bidirectional relationship was identified between higher cognitive ability, larger estimated total intracranial volume (childhood, mid-to-late adulthood) and total surface area (all life stages). A thicker posterior cingulate cortex and a larger surface area in the caudal middle frontal cortex and temporal pole were associated with greater cognitive ability. Contrary, a thicker temporal pole was associated with lower cognitive ability. Discussion: Stable effects of cognitive ability on brain morphology across the life course suggests that childhood is potentially an important window for intervention.

NMR metabolomic modelling of age and lifespan: a multi-cohort analysis.

Metabolomic age models have been proposed for the study of biological aging, however they have not been widely validated. We aimed to assess the performance of newly developed and existing nuclear magnetic resonance spectroscopy (NMR) metabolomic age models for prediction of chronological age (CA), mortality, and age-related disease. 98 metabolic variables were measured in blood from nine UK and Finnish cohort studies (N ≈ 31,000 individuals, age range 24-86 years). We used non-linear and penalised regression to model CA and time to all-cause mortality. We examined associations of four new and two previously published metabolomic age models, with ageing risk factors and phenotypes. Within the UK Biobank (N≈ 102,000), we tested prediction of CA, incident disease (cardiovascular disease (CVD), type-2 diabetes mellitus, cancer, dementia, chronic obstructive pulmonary disease) and all-cause mortality. Cross-validated Pearson's r between metabolomic age models and CA ranged between 0.47-0.65 in the training set (mean absolute error: 8-9 years). Metabolomic age models, adjusted for CA, were associated with C-reactive protein, and inversely associated with glomerular filtration rate. Positively associated risk factors included obesity, diabetes, smoking, and physical inactivity. In UK Biobank, correlations of metabolomic age with chronological age were modest (r = 0.29-0.33), yet all metabolomic model scores predicted mortality (hazard ratios of 1.01 to 1.06 / metabolomic age year) and CVD, after adjustment for CA. While metabolomic age models were only moderately associated with CA in an independent population, they provided additional prediction of morbidity and mortality over CA itself, suggesting their wider applicability.

Investigation of the genetic aetiology of Lewy body diseases with and without dementia.

Up to 80% of Parkinson's disease patients develop dementia, but time to dementia varies widely from motor symptom onset. Dementia with Lewy bodies presents with clinical features similar to Parkinson's disease dementia, but cognitive impairment precedes or coincides with motor onset. It remains controversial whether dementia with Lewy bodies and Parkinson's disease dementia are distinct conditions or represent part of a disease spectrum. The biological mechanisms underlying disease heterogeneity, in particular the development of dementia, remain poorly understood, but will likely be key to understanding disease pathways and ultimately therapy development. Previous genome-wide association studies in Parkinson's disease and dementia with Lewy bodies/Parkinson's disease dementia have identified risk loci differentiating patients from controls. We collated data for 7,804 patients of European ancestry from Tracking Parkinson's (PRoBaND), The Oxford Discovery Cohort, and AMP-PD. We conducted a discrete phenotype genome-wide association studies comparing Lewy body diseases with and without dementia to decode disease heterogeneity by investigating the genetic drivers of dementia in Lewy body diseases. We found that risk alleles rs429358 tagging APOEe4 and rs7668531 near the MMRN1 and SNCA-AS1 genes, increase the odds of developing dementia and that an intronic variant rs17442721 tagging LRRK2 G2019S, on chromosome 12 is protective against dementia. These results should be validated in autopsy confirmed cases in future studies.

Predictors and prognosis of population-based subjective cognitive decline: longitudinal evidence from the Caerphilly Prospective Study (CaPS).

OBJECTIVES: To understand associations between the subjective experience of cognitive decline and objective cognition. This subjective experience is often conceptualised as an early step towards neurodegeneration, but this has not been scrutinised at the population level. An alternative explanation is poor meta-cognition, the extreme of which is seen in functional cognitive disorder (FCD). DESIGN: Prospective cohort (Caerphilly Prospective Study). SETTING: Population-based, South Wales, UK. PARTICIPANTS: This men-only study began in 1979; 1225 men participated at an average age of 73 in 2002-2004, including assessments of simple subjective cognitive decline (sSCD, defined as a subjective report of worsening memory or concentration). Dementia outcomes were followed up to 2012-2014. Data on non-completers was additionally obtained from death certificates and local health records. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome measure was incident dementia over 10 years. Secondary outcome measures included prospective change in objective cognition and cross-sectional cognitive internal inconsistency (the existence of a cognitive ability at some times, and its absence at other times, with no intervening explanatory factors except for focus of attention). RESULTS: sSCD was common (30%) and only weakly associated with prior objective cognitive decline (sensitivity 36% (95% CI 30 to 42) and specificity 72% (95% CI 68 to 75)). Independent predictors of sSCD were older age, poor sleep quality and higher trait anxiety. Those with sSCD did not have excess cognitive internal inconsistency, but results suggested a mild attentional deficit. sSCD did not predict objective cognitive change (linear regression coefficient -0.01 (95% CI -0.13 to 0.15)) nor dementia (odds ratio 1.35 (0.61 to 2.99)) 10 years later. CONCLUSIONS: sSCD is weakly associated with prior objective cognitive decline and does not predict future cognition. Prior sleep difficulties and anxiety were the most robust predictors of sSCD. sSCD in the absence of objective decline appears to be a highly prevalent example of poor meta-cognition (ie, poor self-awareness of cognitive performance), which could be a driver for later FCD.

Antidepressants in pregnancy: applying causal epidemiological methods to understand service-use outcomes in women and long-term neurodevelopmental outcomes in exposed children.

Background: Antidepressants are commonly prescribed during pregnancy, despite a lack of evidence from randomised trials on the benefits or risks. Some studies have reported associations of antidepressants during pregnancy with adverse offspring neurodevelopment, but whether or not such associations are causal is unclear. Objectives: To study the associations of antidepressants for depression in pregnancy with outcomes using multiple methods to strengthen causal inference. Design: This was an observational cohort design using multiple methods to strengthen causal inference, including multivariable regression, propensity score matching, instrumental variable analysis, negative control exposures, comparison across indications and exposure discordant pregnancies analysis. Setting: This took place in UK general practice. Participants: Participants were pregnant women with depression. Interventions: The interventions were initiation of antidepressants in pregnancy compared with no initiation, and continuation of antidepressants in pregnancy compared with discontinuation. Main outcome measures: The maternal outcome measures were the use of primary care and secondary mental health services during pregnancy, and during four 6-month follow-up periods up to 24 months after pregnancy, and antidepressant prescription status 24 months following pregnancy. The child outcome measures were diagnosis of autism, diagnosis of attention deficit hyperactivity disorder and intellectual disability. Data sources: UK Clinical Practice Research Datalink. Results: Data on 80,103 pregnancies were used to study maternal primary care outcomes and were linked to 34,274 children with at least 4-year follow-up for neurodevelopmental outcomes. Women who initiated or continued antidepressants during pregnancy were more likely to have contact with primary and secondary health-care services during and after pregnancy and more likely to be prescribed an antidepressant 2 years following the end of pregnancy than women who did not initiate or continue antidepressants during pregnancy (odds ratioinitiation 2.16, 95% confidence interval 1.95 to 2.39; odds ratiocontinuation 2.40, 95% confidence interval 2.27 to 2.53). There was little evidence for any substantial association with autism (odds ratiomultivariableregression 1.10, 95% confidence interval 0.90 to 1.35; odds ratiopropensityscore 1.06, 95% confidence interval 0.84 to 1.32), attention deficit hyperactivity disorder (odds ratiomultivariableregression 1.02, 95% confidence interval 0.80 to 1.29; odds ratiopropensityscore 0.97, 95% confidence interval 0.75 to 1.25) or intellectual disability (odds ratiomultivariableregression 0.81, 95% confidence interval 0.55 to 1.19; odds ratiopropensityscore 0.89, 95% confidence interval 0.61 to 1.31) in children of women who continued antidepressants compared with those who discontinued antidepressants. There was inconsistent evidence of an association between initiation of antidepressants in pregnancy and diagnosis of autism in offspring (odds ratiomultivariableregression 1.23, 95% confidence interval 0.85 to 1.78; odds ratiopropensityscore 1.64, 95% confidence interval 1.01 to 2.66) but not attention deficit hyperactivity disorder or intellectual disability; however, but results were imprecise owing to smaller numbers. Limitations: Several causal-inference analyses lacked precision owing to limited numbers. In addition, adherence to the prescribed treatment was not measured. Conclusions: Women prescribed antidepressants during pregnancy had greater service use during and after pregnancy than those not prescribed antidepressants. The evidence against any substantial association with autism, attention deficit hyperactivity disorder or intellectual disability in the children of women who continued compared with those who discontinued antidepressants in pregnancy is reassuring. Potential association of initiation of antidepressants during pregnancy with offspring autism needs further investigation. Future work: Further research on larger samples could increase the robustness and precision of these findings. These methods applied could be a template for future pharmaco-epidemiological investigation of other pregnancy-related prescribing safety concerns. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (15/80/19) and will be published in full in Health Technology Assessment; Vol. 27, No. 15. See the NIHR Journals Library website for further project information.

About one in seven women experience depression during pregnancy. Left untreated, this may harm them and their unborn babies. However, the decision to take antidepressants during pregnancy is difficult because women often worry about the risks to their unborn baby. Research findings have been inconsistent, so women often do not have clear information to enable them to make informed decisions. We studied women's and children's outcomes after starting (compared with not starting) or continuing (compared with stopping) antidepressants in pregnancy. We used a large UK primary care database and several novel methods of analysis. We tracked 80,103 pregnancies of women with depression for up to 2 years after pregnancy. We also tracked 34,274 children from these pregnancies for at least 4 years to check for developmental outcomes. Women prescribed antidepressants were more likely than women not prescribed antidepressants to use general practice and mental health services during and after pregnancy, and to be prescribed antidepressants 2 years after pregnancy. This suggests that antidepressants were being prescribed to women with greater clinical need. Women who continued antidepressants in pregnancy had no higher likelihood than those who discontinued antidepressants of autism, attention deficit hyperactivity disorder or intellectual disability in their children. This should reassure women making the decision to continue taking their medications in pregnancy. Women who started antidepressants in pregnancy may possibly have had a slightly higher likelihood of autism in their children than those who did not start them. These findings were not seen in all analyses and were based on smaller numbers; therefore, they should be viewed with caution. Importantly, over 98 in every 100 children of women who initiated or continued antidepressants in pregnancy did not receive an autism diagnosis. The findings may help women and clinicians make informed decisions on treatment with antidepressants in pregnancy.

Quality of relationships in mothers and their partners in the Avon Longitudinal Study of Parents and Children.

Quality of relationship between partners is associated with a wide range of physical and psychological outcomes like anxiety and depression. There are relatively few longitudinal studies with detailed and repeated measures for quality of relationship, particularly in both partners. The Avon Longitudinal Study of Parents and Children (ALSPAC) is a large birth cohort study in the UK with five post-partum repeated measures of quality of relationship between mothers and their partners assessed using the Intimate Bond Measure (IBM). The Measure includes two subscales named "Care" and "Control". These were measured at 2.75, 6, 9, 12, and 18 years post-partum (baseline N for mothers: 8675; baseline N for partners: 5499). The aims of this data note are to provide a comprehensive overview on the existing IBM data in ALSPAC and to describe both its strengths and limitations for future users. The internal consistency of the subscales were high (Cronbach's alpha 0.95 and 0.88 for the Care and Control subscales) in both mothers and their partners at the baseline. In the Care subscale, all 12 items were highly correlated with the overall score (r>0.62) at the baseline, but in the Control subscale there were three items that had relatively low correlations with the total subscale (r<0.46). This should be taken into account in future research. The longitudinal nature of this data on both mothers and partners will enable detailed explorations of the causes and consequences of differences in quality of relationship.

Comparative Effectiveness of Dynamic Treatment Strategies for Medication Use and Dosage: Emulating a Target Trial Using Observational Data.

BACKGROUND: Availability of detailed data from electronic health records (EHRs) has increased the potential to examine the comparative effectiveness of dynamic treatment strategies using observational data. Inverse probability (IP) weighting of dynamic marginal structural models can control for time-varying confounders. However, IP weights for continuous treatments may be sensitive to model choice. METHODS: We describe a target trial comparing strategies for treating anemia with darbepoetin in hemodialysis patients using EHR data from the UK Renal Registry 2004 to 2016. Patients received a specified dose (microgram/week) or did not receive darbepoetin. We compared 4 methods for modeling time-varying treatment: (A) logistic regression for zero dose, standard linear regression for log dose; (B) logistic regression for zero dose, heteroscedastic linear regression for log dose; (C) logistic regression for zero dose, heteroscedastic linear regression for log dose, multinomial regression for patients who recently received very low or high doses; and (D) ordinal logistic regression. RESULTS: For this dataset, method (C) was the only approach that provided a robust estimate of the mortality hazard ratio (HR), with less-extreme weights in a fully weighted analysis and no substantial change of the HR point estimate after weight truncation. After truncating IP weights at the 95th percentile, estimates were similar across the methods. CONCLUSIONS: EHR data can be used to emulate target trials estimating the comparative effectiveness of dynamic strategies adjusting treatment to evolving patient characteristics. However, model checking, monitoring of large weights, and adaptation of model strategies to account for these is essential if an aspect of treatment is continuous.