Meta-analysis for individual participant data with a continuous exposure: A case study

OBJECTIVE: Methods for meta-analysis of studies with individual participant data and continuous exposure variables are well described in the statistical literature but are not widely used in clinical and epidemiological research. The purpose of this case study is to make the methods more accessible. STUDY DESIGN AND SETTING: A two-stage process is demonstrated. Response curves are estimated separately for each study using fractional polynomials. The study-specific curves are then averaged pointwise over all studies at each value of the exposure. The averaging can be implemented using fixed effects or random effects methods. RESULTS: The methodology is illustrated using samples of real data with continuous outcome and exposure data and several covariates. The sample data set, segments of Stata and R code, and outputs are provided to enable replication of the results. CONCLUSION: These methods and tools can be adapted to other situations, including for time-to-event or categorical outcomes, different ways of modelling exposure-outcome curves, and different strategies for covariate adjustment

Towards Quantum Repeaters with Solid-State Qubits: Spin-Photon Entanglement Generation using Self-Assembled Quantum Dots

In this chapter we review the use of spins in optically-active InAs quantum dots as the key physical building block for constructing a quantum repeater, with a particular focus on recent results demonstrating entanglement between a quantum memory (electron spin qubit) and a flying qubit (polarization- or frequency-encoded photonic qubit). This is a first step towards demonstrating entanglement between distant quantum memories (realized with quantum dots), which in turn is a milestone in the roadmap for building a functional quantum repeater. We also place this experimental work in context by providing an overview of quantum repeaters, their potential uses, and the challenges in implementing them.Comment: 51 pages. Expanded version of a chapter to appear in "Engineering the Atom-Photon Interaction" (Springer-Verlag, 2015; eds. A. Predojevic and M. W. Mitchell

Relationships between intensity, duration, cumulative dose, and timing of smoking with age at menopause: A pooled analysis of individual data from 17 observational studies.

BackgroundCigarette smoking is associated with earlier menopause, but the impact of being a former smoker and any dose-response relationships on the degree of smoking and age at menopause have been less clear. If the toxic impact of cigarette smoking on ovarian function is irreversible, we hypothesized that even former smokers might experience earlier menopause, and variations in intensity, duration, cumulative dose, and age at start/quit of smoking might have varying impacts on the risk of experiencing earlier menopause.Methods and findingsA total of 207,231 and 27,580 postmenopausal women were included in the cross-sectional and prospective analyses, respectively. They were from 17 studies in 7 countries (Australia, Denmark, France, Japan, Sweden, United Kingdom, United States) that contributed data to the International collaboration for a Life course Approach to reproductive health and Chronic disease Events (InterLACE). Information on smoking status, cigarettes smoked per day (intensity), smoking duration, pack-years (cumulative dose), age started, and years since quitting smoking was collected at baseline. We used multinomial logistic regression models to estimate multivariable relative risk ratios (RRRs) and 95% confidence intervals (CIs) for the associations between each smoking measure and categorised age at menopause (ConclusionsThe probability of earlier menopause is positively associated with intensity, duration, cumulative dose, and earlier initiation of smoking. Smoking duration is a much stronger predictor of premature and early menopause than others. Our findings highlight the clear benefits for women of early smoking cessation to lower their excess risk of earlier menopause

The InterLACE study: Design, Data Harmonization and Characteristics Across 20 Studies on Women’s Health

Objectives: The International Collaboration for a Life Course Approach to Reproductive Health and Chronic Disease Events (InterLACE) project is a global research collaboration that aims to advance understanding of women’s reproductive health in relation to chronic disease risk by pooling individual participant data from several cohort and cross-sectional studies. The aim of this paper is to describe the characteristics of contributing studies and to present the distribution of demographic and reproductive factors and chronic disease outcomes in InterLACE. Study design: InterLACE is an individual-level pooled study of 20 observational studies (12 of which are longitudinal) from ten countries. Variables were harmonized across studies to create a new and systematic synthesis of life-course data. Main outcome measures: Harmonized data were derived in three domains: 1) socio-demographic and lifestyle factors, 2) female reproductive characteristics, and 3) chronic disease outcomes (cardiovascular disease (CVD) and diabetes). Results: InterLACE pooled data from 229,054 mid-aged women. Overall, 76% of the women were Caucasian and 22% Japanese; other ethnicities (of 300 or more participants) included Hispanic/Latin American (0.2%), Chinese (0.2%), Middle Eastern (0.3%), African/black (0.5%), and Other (1.0%). The median age at baseline was 47 years (Inter-quartile range (IQR): 41–53), and that at the last follow-up was 56 years (IQR: 48–64). Regarding reproductive characteristics, half of the women (49.8%) had their first menstruation (menarche) at 12–13 years of age. The distribution of menopausal status and the prevalence of chronic disease varied considerably among studies. At baseline, most women (57%) were pre- or peri-menopausal, 20% reported a natural menopause (range 0.8–55.6%) and the remainder had surgery or were taking hormones. By the end of follow-up, the prevalence rates of CVD and diabetes were 7.2% (range 0.9–24.6%) and 5.1% (range 1.3–13.2%), respectively. Conclusions: The scale and heterogeneity of InterLACE data provide an opportunity to strengthen evidence concerning the relationships between reproductive health through life and subsequent risks of chronic disease, including cross-cultural comparisons

Activation-Induced Apoptosis of Autoreactive and Alloreactive T Lymphocytes in the Target Organ as a Major Mechanism of Tolerance

Normal individuals have mature T lymphocytes that are capable of reacting to self-antigens and can be activated by cross-reacting environmental antigens. The mechanism that maintains immune tolerance and prevents these activated autoreactive T cells from causing autoimmune disease is unclear. We have previously hypothesized that activation-induced apoptosis of previously activated autoreactive T cells in the target organ is a major mechanism for maintaining tolerance. Here I review the current evidence to support this hypothesis. It is proposed that when activated autoreactive T cells enter the target organ, they are reactivated mainly by non-professional antigen-presenting cells (APC) and deleted by activation-induced apoptosis through the Fas (CD95) pathway before producing significant target organ damage. This apoptosis occurs because the reactivated T cells do not receive sufficient costimulation from the non-professional APC to up-regulate their expression of Bcl-2-related anti-apoptotic proteins, which inhibit the CD95 pro-apoptotic pathway. This is in contrast to the situation in peripheral lymphoid organs, where reactivation of T cells by professional APC results in sufficient costimulation-induced up-regulation of Bcl-2-related proteins to inhibit the CD95 pathway and allow T cell proliferation and survival as memory T cells. Activation-induced apoptosis of alloreactive T cells in allografts can similarly account for spontaneous allograft acceptance, as occurs after MHC-mismatched liver transplantation

Apoptosis of Inflammatory Cells in Immune Control of the Nervous System: Role of Glia

Normal individuals have T lymphocytes capable of reacting to central nervous system (CNS) antigens such as myelin basic protein (MBP) (Martin et al., [1990]). In view of recent evidence indicating that T cells are much more cross-reactive than previously thought (Mason, [1998]), it is likely that these autoreactive T cells are often primed by exposure to cross-reacting environmental antigens. Indeed it has been shown that viral and bacterial peptides can activate myelin-reactive human T cells (Wucherpfennig and Strominger, [1995]; Hemmer et al., [1997]). Furthermore, normal healthy subjects experience surges of increased frequencies of circulating myelin-reactive T cells that might be driven by cross-reactive environmental antigens (Pender et al., [2000]). Such activated myelin-reactive T cells would be expected to enter the CNS in healthy individuals, because activated T cells of any specificity, including autoreactive T cells, enter the normal CNS parenchyma (Wekerle et al., [1986]; Hickey et al., [1991]). If CNS-reactive T cells survive in the CNS, they have the potential to attack the CNS, either directly or through the recruitment of other inflammatory cells, and thus lead to CNS damage such as demyelination. Therefore, the physiological control of autoreactive T cells in the CNS is likely to have an important role in preventing the development of autoimmune CNS disorders such as multiple sclerosis (MS) (Pender, [1998]). T-cell apoptosis in the CNS has been proposed to be an important mechanism for controlling autoimmune attacks on the CNS (Pender et al., [1992]; Schmied et al., [1993]). Although other mechanisms, such as immune deviation (Wenkel et al., [2000]), may possibly also contribute to the control of the immune response in the CNS, this review will focus on T-cell apoptosis in the CNS and the role of glia in this process

Central nervous system rather than immune cell-derived BDNF mediates axonal protective effects early in autoimmune demyelination

Brain-derived neurotrophic factor (BDNF) is involved in neuronal and glial development and survival. While neurons and astrocytes are its main cellular source in the central nervous system (CNS), bioactive BDNF is also expressed in immune cells and in lesions of multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE). Previous data revealed that BDNF exerts neuroprotective effects in myelin oligodendrocyte glycoprotein-induced EAE. Using a conditional knock-out model with inducible deletion of BDNF, we here show that clinical symptoms and structural damage are increased when BDNF is absent during the initiation phase of clinical EAE. In contrast, deletion of BDNF later in the disease course of EAE did not result in significant changes, either in the disease course or in axonal integrity. Bone marrow chimeras revealed that the deletion of BDNF in the CNS alone, with no deletion of BDNF in the infiltrating immune cells, was sufficient for the observed effects. Finally, the therapeutic effect of glatiramer acetate, a well-characterized disease-modifying drug with the potential to modulate BDNF expression, was partially reversed in mice in which BDNF was deleted shortly before the onset of disease. In summary, our data argue for an early window of therapeutic opportunity where modulation of BDNF may exert neuroprotective effects in experimental autoimmune demyelination

Which interventions offer best value for money in primary prevention of cardiovascular disease?

BackgroundDespite many decades of declining mortality rates in the Western world, cardiovascular disease remains the leading cause of death worldwide. In this research we evaluate the optimal mix of lifestyle, pharmaceutical and population-wide interventions for primary prevention of cardiovascular disease.Methods and FindingsIn a discrete time Markov model we simulate the ischaemic heart disease and stroke outcomes and cost impacts of intervention over the lifetime of all Australian men and women, aged 35 to 84 years, who have never experienced a heart disease or stroke event. Best value for money is achieved by mandating moderate limits on salt in the manufacture of bread, margarine and cereal. A combination of diuretic, calcium channel blocker, ACE inhibitor and low-cost statin, for everyone with at least 5% five-year risk of cardiovascular disease, is also cost-effective, but lifestyle interventions aiming to change risky dietary and exercise behaviours are extremely poor value for money and have little population health benefit.ConclusionsThere is huge potential for improving efficiency in cardiovascular disease prevention in Australia. A tougher approach from Government to mandating limits on salt in processed foods and reducing excessive statin prices, and a shift away from lifestyle counselling to more efficient absolute risk-based prescription of preventive drugs, could cut health care costs while improving population health.<br /

The InterLACE study: design, data harmonization and characteristics across 20 studies on women's health

The International Collaboration for a Life Course Approach to Reproductive Health and Chronic Disease Events (InterLACE) project is a global research collaboration that aims to advance understanding of women's reproductive health in relation to chronic disease risk by pooling individual participant data from several cohort and cross-sectional studies. The aim of this paper is to describe the characteristics of contributing studies and to present the distribution of demographic and reproductive factors and chronic disease outcomes in InterLACE

Age at natural menopause and risk of incident cardiovascular disease: A pooled analysis of individual patient data

Background: Early menopause is linked to an increased risk of cardiovascular disease mortality; however, the association between early menopause and incidence and timing of cardiovascular disease is unclear. We aimed to assess the associations between age at natural menopause and incidence and timing of cardiovascular disease. Methods: We harmonised and pooled individual-level data from 15 observational studies done across five countries and regions (Australia, Scandinavia, the USA, Japan, and the UK) between 1946 and 2013. Women who had reported their menopause status, age at natural menopause (if postmenopausal), and cardiovascular disease status (including coronary heart disease and stroke) were included. We excluded women who had hysterectomy or oophorectomy and women who did not report their age at menopause. The primary endpoint of this study was the occurrence of first non-fatal cardiovascular disease, defined as a composite outcome of incident coronary heart disease (including heart attack and angina) or stroke (including ischaemic stroke or haemorrhagic stroke). We used Cox proportional hazards models to estimate multivariate hazard ratios (HRs) and 95% CIs for the associations between age at menopause and incident cardiovascular disease event. We also adjusted the model to account for smoking status, menopausal hormone therapy status, body-mass index, and education levels. Age at natural menopause was categorised as premenopausal or perimenopausal, younger than 40 years (premature menopause), 40–44 years (early menopause), 45–49 years (relatively early), 50–51 years (reference category), 52–54 years (relatively late), and 55 years or older (late menopause). Findings: Overall, 301 438 women were included in our analysis. Of these 301 438 women, 12 962 (4·3%) had a first non-fatal cardiovascular disease event after menopause, of whom 9369 (3·1%) had coronary heart disease and 4338 (1·4%) had strokes. Compared with women who had menopause at age 50–51 years, the risk of cardiovascular disease was higher in women who had premature menopause (age <40 years; HR 1·55, 95% CI 1·38–1·73; p<0·0001), early menopause (age 40–44 years; 1·30, 1·22–1·39; p<0·0001), and relatively early menopause (age 45–49 years; 1·12, 1·07–1·18; p<0·0001), with a significantly reduced risk of cardiovascular disease following menopause after age 51 years (p<0·0001 for trend). The associations persisted in never smokers, and were strongest before age 60 years for women with premature menopause (HR 1·88, 1·62–2·20; p<0·0001) and early menopause (1·40, 1·27–1·54; p<0·0001), but were attenuated at age 60–69 years, with no significant association observed at age 70 years and older. Interpretation: Compared with women who had menopause at age 50–51 years, women with premature and early menopause had a substantially increased risk of a non-fatal cardiovascular disease event before the age of 60 years, but not after age 70 years. Women with earlier menopause need close monitoring in clinical practice, and age at menopause might also be considered as an important factor in risk stratification of cardiovascular disease for women