Feasibility of using a fully immersive virtual reality system for kinematic data collection

Commercially-available Virtual Reality (VR) systems have the potential to be effective tools for simultaneous visual manipulation and kinematic data collection. Previously, these systems have been integrated with research-grade motion capture systems to provide both functionalities; however, they are yet to be used as stand-alone systems for kinematic data collection. The present study aimed to validate the HTC VIVE VR system for kinematic data collection by evaluating the accuracy of its position and orientation signals. The VIVE controller and tracker were each compared to a Polhemus Liberty magnetic tracking system sensor for angular and translational measurement error and signal drift. A sensor from each system was mounted to opposite ends of a rigid segment which was driven through fifty rotations and fifty translations. Mean angular errors for both the VIVE tracker and controller were below 0.4°. Mean translational error for both sensors was below 3 mm. Drift in the Liberty signal components was consistently lower than drift in VIVE components. However, all mean rotational drift measures were below 0.1° and all mean translational measures were below 0.35 mm. These data indicate that the HTC VIVE system has the potential to be a valid and reliable means of kinematic data collection. However, further investigation is necessary to determine the VIVE’s suitability for capturing extremely minute or high-volume movements.     

Validation data for periprosthetic bone remodelling theories

Periprosthetic adaptive bone remodelling after total hip arthroplasty (THA) has been frequently simulated in computer models, combining bone remodelling theory with finite element analysis. Unfortunately, there still subsist a lack of clinical data, which are necessary for validation of these simulation results. Therefore, the objective of the current project is to collect prospective volumetric bone density data with a clinical computerized tomography study in seven patients after THA. A retrospective study 12 years after implantation in 11 patients was added. A data set of about 100 000 bone voxels for each femur was collected. In all prospective cases, the predominant change is seen during the first year. The average density reduction in the horizontal slices was between 50 and 150 Hounsfield units (HU) (approx. 10%; p<0.001) after 2 years. Loss of density is particularly strong distal of the minor trochanter and decreases from proximal to distal.

For the 12 years retrospective study, the contralateral femur provided the control. Similar trends comparable to the prospective 2-year follow-up CT density values were seen in most cases with density reductions of up to 400 HU (30%). However, in one of these cases there was no difference between the operated and the control density.

As far as we are aware, this is the first collection of fully prospective 3D validation data in vivo for periprosthetic adaptive bone remodelling theories. The data are also unique as they are suitable for direct patient-specific 3D finite element meshing and individual weight-related loading.     

Validation of surrogate markers in multiple randomized clinical trials with repeated measurements: canonical correlation approach

Part of the recent literature on the evaluation of biomarkers as surrogate endpoints starts from a multitrial context, which leads to a definition of validity in terms of the quality of both trial-level and individual-level association between the surrogate and true endpoints (Buyse et al., 2000, Biostatistics1, 49-67). These authors concentrated on cross-sectional continuous responses. However, in many randomized clinical studies, repeated measurements are encountered on either or both endpoints. A challenge in this setting is the formulation of a simple and meaningful concept of "surrogacy."Alonso et al. (2003, Biometrical Journal45, 931-945) proposed the variance reduction factor (VRF) to evaluate surrogacy at the individual level. They also showed how and when this concept should be extended to study surrogacy at the trial level. Here, we approach the problem from the natural canonical correlation perspective. We define a class of canonical correlation functions that can be used to study surrogacy at the trial and individual level. We show that the VRF and the R2 measure defined by Buyse et al. (2000) follow as special cases. Simulations are conducted to evaluate the performance of different members of this family. The methodology is illustrated on data from a meta-analysis of five clinical trials comparing antipsychotic agents for the treatment of chronic schizophrenia.     

Partial hepatectomy hemodynamics changes: Experimental data explained by closed-loop lumped modeling

The liver function may be degraded after partial liver ablation surgery. Adverse liver hemodynamics have been shown to be associated to liver failure. The link between these hemodynamics changes and ablation size is however poorly understood. This article proposes to explain with a closed-loop lumped model the hemodynamics changes observed during twelve surgeries in pigs. The portal venous tree is modeled with a pressure-dependent variable resistor. The variables measured, before liver ablation, are used to tune the model parameters. Then, the liver partial ablation is simulated with the model and the simulated pressures and flows are compared with post-operative measurements. Fluid infusion and blood losses occur during the surgery. The closed-loop model presented accounts for these blood volume changes. Moreover, the impact of blood volume changes and the liver lobe mass estimations on the simulated variables is studied. The typical increase of portal pressure, increase of liver pressure loss, slight decrease of portal flow and major decrease in arterial flow are quantitatively captured by the model for a 75% hepatectomy. It appears that the 75% decrease in hepatic arterial flow can be explained by the resistance increase induced by the surgery, and that no hepatic arterial buffer response (HABR) mechanism is needed to account for this change. The different post-operative states, observed in experiments, are reproduced with the proposed model. Thus, an explanation for inter-subjects post-operative variability is proposed. The presented framework can easily be adapted to other species circulations and to different pathologies for clinical hepatic applications.     

Determination of disodium clodronate in human plasma and urine using gas-chromatography-nitrogen-phosphorous detections: validation and application in pharmacokinetic study

We present a specific method for the determination of disodium clodronate in human plasma and urine using a gas-chromatographic system with nitrogen phosphorus detector (NPD). The compound was extracted from plasma and urine samples by an anion-exchange resin and derivatizated with bistrimethylsilyltrifluoroacetamide (BSTFA). Sodium bromobisphosphonate was used as internal standard. The calibration curves were linear in both plasma and urine, with a regression coefficient r > 0.9975 in plasma and r > 0.9977 in urine.The limit of quantitation was 0.3 microg/ml in plasma and 0.5 microg/ml in urine. The method was validated by intra-day assays at three concentration levels. During the study we carried out inter-day assays to confirm the feasibility of the method. The precision in plasma at 0.5, 15, and 45 microg/ml was 12.4, 0.2, and 6.5% (n = 40), respectively; in urine at 0.8, 8, and 40 microg/ml it was 8.6, 6.4, and 9.3% (n = 40), respectively.The method was accurate and reproducible, and was successfully applied to determine the pharmacokinetic parameters of clodronate in healthy volunteers after intravenous infusion and intramuscular injection of 200 mg of the compound. The Cmax after intravenous infusion and intramuscular injection was 16.1 and 12.8 microg/ml, respectively. AUC(0-48 h) after infusion administration and intramuscular injection was 44.2 +/- 18.0 and 47.5 +/- 12.4 h microg/ml, respectively. The elimination half-life in both administrations was 6.31 +/- 2.7 h.     

Radiostereometric analysis using clinical radiographic views: Development of a universal calibration object

Radiostereometric analysis (RSA) is a highly accurate technique used to provide three-dimensional (3D) measurements of orthopaedic implant migration for clinical research applications, yet its implementation in routine clinical examinations has been limited. Previous studies have introduced a modified RSA procedure that separates the calibration examinations from the patient examinations, allowing routine clinical radiographs to be analyzed using RSA. However, in order to calibrate the wide range of clinical views, a new calibration object is required. In this study, a universal, isotropic calibration object was designed to calibrate any pair of radiographic views used in the clinic for RSA. A numerical simulation technique was used to design the calibration object, followed by a phantom validation test of a prototype to verify the performance of the novel object, and to compare the measurement reliability to the conventional calibration cage. The 3D bias for the modified calibration method using the new calibration object was 0.032 ± 0.006 mm, the 3D repeatability standard deviation was 0.015 mm, and the 3D repeatability limit was 0.042 mm. Although statistical differences were present between the universal calibration object and the conventional cage, the differences were considered to be not clinically meaningful. The 3D bias and repeatability values obtained using the universal calibration object were well under the threshold acceptable for RSA, therefore it was successfully validated. The universal calibration object will help further the adoption of RSA into a more routine practice, providing the opportunity to generate quantitative databases on joint replacement performance.     

The validation of surrogate endpoints in meta-analyses of randomized experiments

The validation of surrogate endpoints has been studied by Prentice (1989). He presented a definition as well as a set of criteria, which are equivalent only if the surrogate and true endpoints are binary. Freedman et al. (1992) supplemented these criteria with the so-called 'proportion explained'. Buyse and Molenberghs (1998) proposed replacing the proportion explained by two quantities: (1) the relative effect linking the effect of treatment on both endpoints and (2) an individual-level measure of agreement between both endpoints. The latter quantity carries over when data are available on several randomized trials, while the former can be extended to be a trial-level measure of agreement between the effects of treatment of both endpoints. This approach suggests a new method for the validation of surrogate endpoints, and naturally leads to the prediction of the effect of treatment upon the true endpoint, given its observed effect upon the surrogate endpoint. These ideas are illustrated using data from two sets of multicenter trials: one comparing chemotherapy regimens for patients with advanced ovarian cancer, the other comparing interferon-alpha with placebo for patients with age-related macular degeneration.     

Antibody performance in western blot applications is context‐dependent

An important concern for the use of antibodies in various applications, such as western blot (WB) or immunohistochemistry (IHC), is specificity. This calls for systematic validations using well‐designed conditions. Here, we have analyzed 13 000 antibodies using western blot with lysates from human cell lines, tissues, and plasma. Standardized stratification showed that 45% of the antibodies yielded supportive staining, and the rest either no staining (12%) or protein bands of wrong size (43%). A comparative study of WB and IHC showed that the performance of antibodies is application‐specific, although a correlation between no WB staining and weak IHC staining could be seen. To investigate the influence of protein abundance on the apparent specificity of the antibody, new WB analyses were performed for 1369 genes that gave unsupportive WBs in the initial screening using cell lysates with overexpressed full‐length proteins. Then, more than 82% of the antibodies yielded a specific band corresponding to the full‐length protein. Hence, the vast majority of the antibodies (90%) used in this study specifically recognize the target protein when present at sufficiently high levels. This demonstrates the context‐ and application‐dependence of antibody validation and emphasizes that caution is needed when annotating binding reagents as specific or cross‐reactive. WB is one of the most commonly used methods for validation of antibodies. Our data implicate that solely using one platform for antibody validation might give misleading information and therefore at least one additional method should be used to verify the achieved data.     

A semiparametric empirical likelihood method for data from an outcome-dependent sampling scheme with a continuous outcome

Outcome-dependent sampling (ODS) schemes can be a cost effective way to enhance study efficiency. The case-control design has been widely used in epidemiologic studies. However, when the outcome is measured on a continuous scale, dichotomizing the outcome could lead to a loss of efficiency. Recent epidemiologic studies have used ODS sampling schemes where, in addition to an overall random sample, there are also a number of supplemental samples that are collected based on a continuous outcome variable. We consider a semiparametric empirical likelihood inference procedure in which the underlying distribution of covariates is treated as a nuisance parameter and is left unspecified. The proposed estimator has asymptotic normality properties. The likelihood ratio statistic using the semiparametric empirical likelihood function has Wilks-type properties in that, under the null, it follows a chi-square distribution asymptotically and is independent of the nuisance parameters. Our simulation results indicate that, for data obtained using an ODS design, the semiparametric empirical likelihood estimator is more efficient than conditional likelihood and probability weighted pseudolikelihood estimators and that ODS designs (along with the proposed estimator) can produce more efficient estimates than simple random sample designs of the same size. We apply the proposed method to analyze a data set from the Collaborative Perinatal Project (CPP), an ongoing environmental epidemiologic study, to assess the relationship between maternal polychlorinated biphenyl (PCB) level and children's IQ test performance.