Spline-based self-controlled case series method

The self-controlled case series (SCCS) method is an alternative to study designs such as cohort and case control methods and is used to investigate potential associations between the timing of vaccine or other drug exposures and adverse events. It requires information only on cases, individuals who have experienced the adverse event at least once, and automatically controls all fixed confounding variables that could modify the true association between exposure and adverse event. Time-varying confounders such as age, on the other hand, are not automatically controlled and must be allowed for explicitly. The original SCCS method used step functions to represent risk periods (windows of exposed time) and age effects. Hence, exposure risk periods and/or age groups have to be prespecified a priori, but a poor choice of group boundaries may lead to biased estimates. In this paper, we propose a nonparametric SCCS method in which both age and exposure effects are represented by spline functions at the same time. To avoid a numerical integration of the product of these two spline functions in the likelihood function of the SCCS method, we defined the first, second, and third integrals of I-splines based on the definition of integrals of M-splines. Simulation studies showed that the new method performs well. This new method is applied to data on pediatric vaccines

Investigating the assumptions of the self-controlled case series method.

We describe some simple techniques for investigating two key assumptions of the self-controlled case series (SCCS) method, namely that events do not influence subsequent exposures, and that events do not influence the length of observation periods. For each assumption we propose some simple tests based on the standard SCCS model, along with associated graphical displays. The methods also enable the user to investigate the robustness of the results obtained using the standard SCCS model to failure of assumptions. The proposed methods are investigated by simulations, and applied to data on measles, mumps and rubella vaccine, and antipsychotics

Smooth Risk Functions for Self-Controlled Case Series Models

The self-controlled case series (SCCS) method is commonly used to investigate associations between vaccine exposures and adverse events (side effects). It is an alternative to cohort and case control study designs. It requires information only on cases, individuals who have experienced the adverse event at least once, and automatically controls all fixed confounders that could modify the true association between exposure and adverse event. However, time-varying confounders (age, season) are not automatically controlled. The SCCS method has parametric and semi-parametric versions in terms of controlling the age effect. The parametric method uses piecewise constant functions with a priori chosen age groups and the semi-parametric method leaves the age effect unspecified. Mis-specification of age groups in the parametric version may lead to biased estimates of the exposure effect, and the semi-parametric approach runs into computational problems when the sample size is moderately large. Moreover, both versions of SCCS represent the time-varying exposures using step functions with pre-determined cut-points. A less prescriptive approach may be beneficial when the shape of the relative risk function associated with exposure is not known a priori, especially when exposure effects can be long-lasting. This thesis focuses on extending the SCCS method to avoid the aforementioned limitations by modelling the age and exposure effects using flexible smooth functions. Specifically, we used penalised regression splines based on cubic M-splines, which are piecewise polynomials of degree 3. We developed three new extensions: a method that represents only the age effect with splines, a method that uses splines to model only the exposure effect and a non-parametric SCCS method that represents both effects by splines. Simulation studies showed that these new methods outperformed the parametric and semi-parametric methods. The new methods are illustrated using large data sets. Review of SCCS vaccine studies and directions on how to use the method are also given

Self-controlled case series with multiple event types

Self-controlled case series methods for events that may be classified as one of several types are described. When the event is non-recurrent, the different types correspond to competing risks. It is shown that, under circumstances that are likely to arise in practical applications, the SCCS multi-type likelihood reduces to the product of the type-specific likelihoods. For recurrent events, this applies whether or not the marginal type-specific counts are dependent. As for the standard SCCS method, a rare disease assumption is required for non-recurrent events. Several forms of this assumption are investigated by simulation. The methods are applied to data on MMR vaccine and convulsions (febrile and non-febrile), and to data on thiazolidinediones and fractures (at different sites)

Experimental Study on Mechanical Behaviour of Glass Fiber Reinforced Polymer Bars under Compression

The requirements for using GFRP bars are growing as several researchers have shown the functionality of bars in concrete columns. The demand to characterize the mechanical properties of GFRP bars is therefore rising, although there is no standardized test method for evaluating the compressive behavior of these bars. This experimental study presents the determination of the mechanical properties of GFRP composite bars in compression, namely the stress-strain curves, compressive strength, ultimate crushing strain, and modulus of elasticity. The compressive properties of these bars were calculated following ASTM D695-10 (Compression Test) with some modifications. A total of 27 specimens were tested for the proposed test procedure. The diameter of the GFRP tendon used in the test was 10, 12, and 14 mm, and the length to bar diameter ratio Le/db (4, 8, and 16) was investigated for the compressive strength of the bars. These two parameters were used to establish the relationship between the length to diameter ratio and strength. Besides, two steel caps with a length of 50 mm each were installed to both ends of each specimen to avoid premature failure. It was observed that the test method enables to successfully evaluate the compressive characteristics of the GFRP bars. Experimental discussions were performed based on the test results from stress-strain curves, bar graphs, and scatter curves. The results indicate the increase in length to diameter ratio decrease the buckling stress and the compressive to tensile strength ratio for Le/db ratio of 16 specimens in buckling failure mode. The failure mode transformed from crushing to buckling and a combination of crushing and buckling between the two different failures modes with an improvement in the Le/db ratio. It shows that there was no yield section on the test specimens during the entire test loading process. The compressive GFRP bars present typical brittle failure. Keywords: Compressive Test, GFRP Bars, Diameter, Le/Db Ratio, Stress-Strain Curve, Buckling DOI: 10.7176/CER/13-5-04 Publication date:August 31st 202

Experimental Research on Material Behaviour of Glass Fiber Reinforced Polymer Bars in Tension

Glass Fiber Reinforced Polymer (GFRP) rebars have been widely used to solve the corrosion problem of steel bars in concrete structures. It has been produced as a lightweight and corrosion-resistant than steel reinforcement in many structural applications. They are regarded as a promising substitute for steel bars in concrete infrastructures. It is necessary to test GFRP bars to fully understand their material properties to ensure the safe and efficient use of the material. In this study, five specimens of each type of GFRP bars with a diameter of 6, 8, 10, 12, and 14 mm were tested under tension. Therefore, a total of 25 samples were examined from the same manufacturer. According to ASTM’s recommendations (D7205/D7205M-06) for tensile tests of GFRP bars, the diameter and thickness of the steel pipes for both ends were considered in the preparation of the test specimens to keep the GFRP bars consistent and aligned throughout the experiment. The experimental test results included the stress-strain curves, tensile strength, ultimate strain, and modulus of elasticity. The study showed an accurate result that indicated the tensile strength of the GFRP bars can be expressed by a linear distribution. For a bar diameter of 10mm, the length to diameter ratio Le/db=8 showed a maximum tensile to compressive strength ratio. In the failure results of the test, there were two-mode failures of GFRP bars: fracture failure and pull-out failure of GFRP bars. Most of the specimens had GFRP bar fracture failures, only two specimens (GBT1-10-2 and GBT1-10-3) were damaged due to the pull-off of the GFRP bars which was not a typical failure mode. Keywords: GFRP Bars, Tensile Test, Stress-Strain Curve, Fracture Failure DOI: 10.7176/CER/13-5-05 Publication date:August 31st 202

Self-controlled case series studies: just how rare does a rare non-recurrent outcome need to be?

The self-controlled case series method assumes that adverse outcomes arise according to a non-homogeneous Poisson process. This implies that it is applicable to independent recurrent outcomes. However, the self-controlled case series method may also be applied to unique, non-recurrent outcomes or first outcomes only, in the limit where these become rare. We investigate this rare outcome assumption when the self-controlled case series method is applied to non-recurrent outcomes. We study this requirement analytically and by simulation, and quantify what is meant by ‘rare’ in this context. In simulations we also apply the self-controlled risk interval design, a special case of the self-controlled case series design. To illustrate, we extract data on the incidence rate of some recurrent and non-recurrent outcomes within a defined study population to check whether outcomes are sufficiently rare for the rare outcome assumption to hold when applying the self-controlled case series method to first or unique outcomes. The main findings are that the relative bias should be no more than 5% when the cumulative incidence over total time observed is less than 0.1 per individual. Inclusion of age (or calendar time) effects will further reduce bias. Designs that begin observation with exposure maximise bias, whereas little or no bias will be apparent when there is no time trend in the distribution of exposures, or when exposure is central within time observed

Flexible modelling of vaccine effect in self-controlled case series models

The self-controlled case-series method (SCCS), commonly used to investigate the safety of vaccines, requires information on cases only and automatically controls all age-independent multiplicative confounders, while allowing for an age dependent baseline incidence. Currently the SCCS method represents the time-varying exposures using step functions with pre-determined cut-points. A less prescriptive approach may be beneficial when the shape of the relative risk function associated with exposure is not known a priori, especially when exposure effects can be long-lasting. We therefore propose to model exposure effects using flexible smooth functions. Specifically, we used a linear combination of cubic M-splines which, in addition to giving plausible shapes, avoids the integral in the log-likelihood function of the SCCS model. The methods, though developed specifically for vaccines, are applicable more widely. Simulations showed that the new approach generally performs better than the step function method. We applied the new method to two data sets, on febrile convulsion and exposure to MMR vaccine, and on fractures and thiazolidinedione use

Cord blood adipocytokines and body composition in early childhood : a systematic review and meta-analysis

Childhood obesity is a growing epidemic. Early identification of high-risk groups will allow for the development of prevention strategies. Cord blood adipocytokines have been previously examined as biomarkers predicting future obesity. We conducted a systematic review looking at the association between cord blood leptin and adiponectin with adiposity up to 5 years of age. A literature review was performed between January 1994 and August 2020 using two bibliographic databases (Medline/Pubmed and EMBASE) and was registered on PROSPERO (CRD42017069024). Studies using skinfold thickness and direct methods of assessing body composition in full term neonates were considered. Partial correlation and multiple regression models were used to present the results. Meta-analysis was performed, were possible, using a random effects model. Cochran’s Q test was used to assess heterogeneity and I2 statistics to calculate the percentage of variation across studies. The potential for publication bias was assessed using funnel plots. Data from 22 studies were retrieved and reviewed by two independent reviewers. Cord blood leptin was positively associated with adiposity at birth (r = 0.487; 95% CI: 0.444, 0.531) but was inversely related to adiposity up to 3 years of age. The association was not sustained at 5 years. There was a weak positive association between adiponectin in cord blood and adiposity at birth (r = 0.201; 95% CI: 0.125, 0.277). No correlation was found between cord blood adiponectin in young children, but data were limited. This review supports that cord blood leptin and adiponectin are associated with adiposity at birth. The results of this study provide insight into the role of adipocytokines at birth on future metabolic health and their potential use as risk stratification tools