 The strong relationship between bone mineral density and fracture risk has lead to the standard use of dual x-ray absorptiometry (DXA) and quantitative computed tomography (QCT) in clinical trials. DXA scanners are widely available and offer an inexpensive and precise method to assess bone mineral density at many skeletal sites including the lumbar spine, proximal femur, forearm and total body. However the quality of DXA measurements is dependent on the level of training and experience of the personnel operating the equipment. The quality will vary widely from clinic to clinic and among geographical regions. In addition, the performance of the scanner itself will impact the quality of the measurement. Aging scanners with drifting calibration, software and hardware upgrades, scanner relocation, even inattentive service engineers can all disturb scanner performance, decrease the reproducibility of the BMD measurements and add bias that affects the measurement of longitudinal change.
Synarc's founders were among the first to bring scientific rigor to the use of DXA in multicenter clinical trials. Synarc has successfully employed these comprehensive programs of quality control in numerous global clinical trials and epidemiological studies, improving the quality of DXA measurements and adding confidence to the conclusions drawn from these data.
In addition, Synarc has developed DXAsure™, a propriety data tracking system which limits the risk of lost data to an extreme minimum. Scans are logged upon receipt and tracked through each step of the DXAsure system, providing a complete audit trail from scan receipt to the densitometry results.
There are three primary goals for quality assurance of DXA measurements
in clinical trials:
- Improving the quality of individual subject scans.
- Ensuring the stable longitudinal performance of the DXA scanners.
- Evaluating the differences in DXA scanner calibration between study sites.
Synarc is able to achieve all of these goals using a program of services guided by scientific expertise and grounded in unparalleled experience in the osteoporosis clinical trail arena. By creating a customized program Synarc offers services tailored to a particular trial’s needs.
1. Improving the Quality of Individual
Subject Scans
Synarc improves the quality of subjects’ scans by standardizing the measurement through written procedure manuals, training and real-time review of study scans with feedback to the DXA technologist. Synarc’s written procedure manuals and training programs have been developed over many years with real world testing in dozens of clinical trials. DXA technologists who have completed this training are tracked in our technologist registry.
In addition to the benefits of Synarc training, further improvements can be achieved by reviewing the actual DXA scans. The highest quality DXA data is achieved by central analysis of DXA scans at Synarc. DXA scans collected at each investigator site are sent to Synarc where they are analyzed in a careful and controlled fashion by our trained and experienced research associates. This ensures the most consistent analysis over time. Moreover the central review of all scans identifies acquisition problems, which allow the scan to be rejected and a repeat scan performed. This approach can be recommended for any type of study and has the greatest benefit when working with less experienced sites or in long duration studies where technologist turnover can be a problem. The central scan analysis approach offers the additional benefit of blinding the clinical trial investigators to the bone density results and preventing possible un-blinding of the subjects’ treatment assignment. The primary goal of central reading of DXA scans is to improve the precision of the DXA measurements of bone mineral density. These improvements can reduce the sample size, shorten the trial or improve the statistical power of a study. Gluer et al (Osteoporosis Int 1994) investigated the effect of improving measurement precision on sample size. He found that reductions of 10-20% were possible even with the most conservative assumptions.
2. Ensuring Longitudinal Stability of DXA
Scans
Evaluating change in bone mineral density in subjects on an investigational therapy will be compromised by unstable scanner calibration. DXA scanners may experience component aging or component failure that can change the scanner calibration, mimicking a change in the subjects’ bone mineral density. Other events such as scanner relocation or hardware and software upgrades can have a similar effect. It is important to identify these potential error sources and ensure that measured changes in bone mineral density represent true changes in the subject. At Synarc we have developed a program for Instrument Quality Control (IQC) that defines the process of monitoring the longitudinal performance of the DXA scanner to ensure stable performance during the course of the study.
The Synarc IQC program begins with an initial evaluation of the scanner performance history and establishing a baseline calibration. We also implement a program for reporting events that can impact on scanner performance. This includes a process for prospective review and approval of certain interventions with the scanner. The hallmark of the Synarc IQC program is a controlled process for measuring and analyzing the scanner calibration history and identifying the time and magnitude of calibration drifts or shifts. These steps provide a mechanism to identify calibration changes, prevent these changes from affecting the bone mineral density measurement in study subjects and if necessary, for quantifying the changes and adjusting the subject results to remove the effect of scanner failure.
By using a standardized bone mineral density test object or “phantom” the calibration of each densitometer in a clinical trial can be measured on a daily basis. By comparing these daily measurements against control limits the DXA technologist can identify scanner problems and request service from the DXA manufacturer. By collecting, reviewing and analyzing these data, Synarc can further evaluate scanner calibration history over the course of a clinical trial.
Longitudinal quality control data are analyzed using various control chart methods, including Shewhart charts, cumulative sum charts and moving average charts. These different approaches were first compared by Lu et al who found that cumulative sum charts performed best in DXA. This approach has been implemented at Synarc and is used to analyze quality control data from DXA scanners. |
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It is important to recognize the strengths and weaknesses of phantom-based measurements of DXA scanner calibration when interpreting longitudinal data. Through the experience gained from analyzing the data of hundreds of DXA scanners over many years, Synarc has a broad understanding of scanner behavior providing a unique perspective for this task.
3. Evaluating the differences in DXA scanner calibration.
The calibration of DXA scanners varies from instrument to instrument. Known differences exist between the calibration of scanners from the three primary manufacturers – Lunar, Hologic and Norland [Genant et al J Bone Miner Res 1994]. In addition to these systematic differences among manufacturers, scanners from a single manufacturer show random variation around the nominal calibration of that scanner type. Calibration differences among scanners participating in a clinical trial can be measured and if desired adjustments made to reduce this variation. This allows pooling of data from different scanners to determine baseline characteristics of the entire study population.
 Scanner calibration is measured by scanning a bone mineral density phantom on each scanner. There are a variety of choices available. Some common choices are the Hologic Spine Phantom in combination with the Hologic Linearity Phantom (also called the Block Phantom) or the European Spine Phantom. In practice a single phantom is circulated to each study site and scanned on the DXA equipment used there. In general, Synarc has found that variation in scanner calibration is small. Roughly 50% of scanners have a calibration within +/- 0.5% of the nominal calibration and 70-75% of scanners within +/- 1%.
There are limitations to using phantoms for cross-calibration. In particular, because of limitations in the design, it is not possible to exactly quantify the differences between scanners from different manufacturers using phantoms alone. When adjusting for differences in calibration between manufacturers, better results may be achieved by using standardization equations developed from scans of human beings. The DXA manufacturers have adopted formal, generalized standardization equations developed through the activities of the International Committee for Standards in Bone Measurement. Synarc founders are active members of this committee and helped to collect and analyze the data on which the equations are based.
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