Barry T. Peterson

Validity of activity monitors in health and chronic disease: a systematic review

The assessment of physical activity in healthy populations and in those with chronic diseases is challenging. The aim of this systematic review was to identify whether available activity monitors (AM) have been appropriately validated for use in assessing physical activity in these groups. Following a systematic literature search we found 134 papers meeting the inclusion criteria; 40 conducted in a field setting (validation against doubly labelled water), 86 in a laboratory setting (validation against a metabolic cart, metabolic chamber) and 8 in a field and laboratory setting. Correlation coefficients between AM outcomes and energy expenditure (EE) by the criterion method (doubly labelled water and metabolic cart/chamber) and percentage mean differences between EE estimation from the monitor and EE measurement by the criterion method were extracted. Random-effects meta-analyses were performed to pool the results across studies where possible. Types of devices were compared using meta-regression analyses. Most validation studies had been performed in healthy adults (n = 118), with few carried out in patients with chronic diseases (n = 16). For total EE, correlation coefficients were statistically significantly lower in uniaxial compared to multisensor devices. For active EE, correlations were slightly but not significantly lower in uniaxial compared to triaxial and multisensor devices. Uniaxial devices tended to underestimate TEE (−12.07 (95%CI; -18.28 to −5.85) %) compared to triaxial (−6.85 (95%CI; -18.20 to 4.49) %, p = 0.37) and were statistically significantly less accurate than multisensor devices (−3.64 (95%CI; -8.97 to 1.70) %, p<0.001). TEE was underestimated during slow walking speeds in 69% of the lab validation studies compared to 37%, 30% and 37% of the studies during intermediate, fast walking speed and running, respectively. The high level of heterogeneity in the validation studies is only partly explained by the type of activity monitor and the activity monitor outcome. Triaxial and multisensor devices tend to be more valid monitors. Since activity monitors are less accurate at slow walking speeds and information about validated activity monitors in chronic disease populations is lacking, proper validation studies in these populations are needed prior to their inclusion in clinical trials.

A randomized, double-blind, 6-week, dose-ranging study of pregabalin in patients with restless legs syndrome

OBJECTIVE This study evaluated the dose-related efficacy and safety of pregabalin in patients with idiopathic restless legs syndrome (RLS). METHODS This six-arm, double-blind, placebo-controlled, dose-response study randomized patients (N=137) with moderate-to-severe idiopathic RLS in an equal ratio to placebo or pregabalin 50, 100, 150, 300, or 450 mg/day. The dose-response was characterized using an exponential decay model, which estimates the maximal effect (E(max)) for the primary endpoint, the change in the International Restless Legs Study Group Rating Scale (IRLS) total score from baseline to week 6 of treatment. Secondary outcomes included Clinical Global Impressions-Improvement Scale (CGI-I) responders, sleep assessments, and safety. RESULTS The separation of treatment effect between placebo and pregabalin began to emerge starting at week 1 which continued and increased through week 6 for all dose groups. The IRLS total score for pregabalin was dose dependent and well characterized for change from baseline at week 6. The model estimated 50% (ED(50)) and 90% (ED(90)) of the maximal effect in reducing RLS symptoms that occurred at pregabalin doses of 37.3 and 123.9 mg/day, respectively. A higher proportion of CGI-I responders was observed at the two highest doses of pregabalin (300 and 450 mg/day) versus placebo. Dizziness and somnolence were the most common adverse events and appeared to be dose-related. CONCLUSIONS In this 6-week phase 2b study, pregabalin reduced RLS symptoms in patients with moderate-to-severe idiopathic RLS. The symptom reduction at week 6 was dose-dependent with 123.9 mg/day providing 90% efficacy. Pregabalin was safe and well tolerated across the entire dosing range.

Hyperpolarized (3)He apparent diffusion coefficient MRI of the lung: Reproducibility and volume dependency in healthy volunteers and patients with emphysema.

To measure the apparent diffusion coefficient (ADC) of hyperpolarized (HP) 3He gas using diffusion weighted MRI in healthy volunteers and patients with emphysema and examine the reproducibility and volume dependency.

Validity of apparent diffusion coefficient hyperpolarized 3He-MRI using MSCT and pulmonary function tests as references.

PURPOSE To compare apparent diffusion coefficient (ADC) measurements from hyperpolarized (HP) helium ((3)He)-magnetic resonance imaging (MRI) with quantitative data from multislice Computed Tomography (CT) (MSCT) of the whole lungs and pulmonary function tests (PFT). MATERIALS AND METHODS Twenty-seven subjects, 22 with established emphysema and 5 with preclinical emphysema defined by PFT criteria, were examined with HP (3)He-MRI and MSCT. Mean age was 55 (+/-12) years, 18 female and 9 male. Mean ADC from (3)He-MRI was compared with emphysema index (EI), 15th percentile and mean lung density (MLD) values from MSCT. Both mean ADC and MSCT data were compared to PFT, especially percent of predicted diffusing capacity of carbon monoxide (%predicted DLCO), using Pearsons correlation test. RESULTS Mean ADC and standard deviation values were 0.392+/-0.119 cm(2)/s for the established emphysema group and 0.216+/-0.046 for the pre-clinical emphysema group. MSCT values for the established emphysema group and pre-clinical emphysema group were: EI (%) 11+/-12 and 0.4+/-0.6, respectively; 15th percentile (Hounsfield Units (HU)), -956+/-25 and -933+/-13, respectively and MLD (HU) -877+/-20 and -863+/-15, respectively. Correlations between mean ADC and EI and 15th percentile were both r=0.90 and for MLD r=0.59. There was higher correlation between mean ADC and %predicted DLCO (r=0.90) than between EI and %predicted DLCO (r=0.76). CONCLUSION HP (3)He-MRI correlates well with density measurements from MSCT and agrees better than MSCT with %predicted DLCO which is the PFT most related to emphysema.

Comparison of actigraphy and polysomnography to assess effects of zolpidem in a clinical research unit.

OBJECTIVE This study sought to compare devices that use actigraphy for measuring sleep endpoints in the clinical research unit (CRU) and home environment. The abilities of polysomnography (PSG) and actigraphy monitors to detect drug effects in a CRU were also investigated. METHODS Eleven healthy subjects were recruited and monitored with PSG for four consecutive nights in a CRU after receiving no treatment (night 1, N1), and then placebo or 5 mg day(-1) or 10 mg day(-1) zolpidem in a randomised, cross-over design. Subjects wore two devices that use actigraphy (a Respironics® Actiwatch® on the wrist and a BodyMedia® Sensewear® Armband on the upper-arm) on the non-dominant arm for five nights at home and four nights in the CRU during PSG. RESULTS Wake after sleep onset (WASO) and total sleep time (TST) measured by PSG and estimates of WASO by the Actiwatch decreased significantly with 5mg but not 10mg of zolpidem versus placebo. Direct activity (counts/min) with the Actiwatch decreased in response to zolpidem (both 5 and 10 mg day(-1)) versus placebo. Armband recordings of direct activity were similar to the Actiwatch but not significantly different versus placebo. Both actigraphy device estimates of TST were approximately 1h longer in CRU versus home. Agreement between actigraphy estimates of TST and WASO and PSG values of TST and WASO were closer during nights with zolpidem treatment. CONCLUSIONS PSG can detect the effects of zolpidem on sleep in a CRU setting. Actigraphy can provide useful assessment of sleep, but direct activity endpoints may be more effective than estimates of TST and WASO.

Serial MR imaging with MS-325 for evaluating female sexual arousal response: Determination of intrasubject reproducibility

To determine if a similar sexual arousal response in normal, healthy women could be obtained and monitored by serial magnetic resonance (MR) imaging at two separate sessions.

Progression of Emphysema in a 12-month Hyperpolarized 3 He-MRI Study: Lacunarity Analysis Provided a More Sensitive Measure than Standard ADC Analysis 1

RATIONALE AND OBJECTIVES Inhaled hyperpolarized (3)He magnetic resonance (MR) imaging has been used to measure alveolar size in patients with emphysema. The aim of this study was to test the hypothesis that (3)He MR images could be used to develop a biomarker of emphysema progression. MATERIALS AND METHODS Twelve healthy controls and 18 patients with emphysema (eight current smokers, 10 ex-smokers) were imaged at baseline and 6 and 12 months. An additional nine subjects with alpha-1 antitrypsin deficiency (four with emphysema, six without symptoms) were also imaged at baseline and at 6 months. Each subject was imaged at two lung volumes: functional residual capacity (FRC) and FRC plus 15% of total lung capacity. Means and standard deviations of apparent diffusion coefficients (ADCs) were calculated from coronal images of the entire lung and correlated with pulmonary function test results. The lacunarity hypothesis was tested and calculated from the data using a range of 2 x 2 x 2 to 6 x 6 x 6 voxels, and the average was calculated. RESULTS There was no change in the mean ADC at either lung volume in any subject over the 6- or 12-month period. FRC and residual volume increased over the 12 months, suggesting air trapping. The lacunarity of images collected at FRC increased at 6 and 12 months in smokers only (P = .063 and P = .023, respectively). CONCLUSIONS The mean ADC calculated from MR images of the lungs with helium was not sufficiently sensitive to detect changes over a 12-month period. However, lacunarity captured more of the spatial information in the images and detected emphysema progress in the smokers.

Influence of PDE5 inhibitor on MRI measurement of clitoral volume response in women with FSAD: a feasibility study of a potential technique for evaluating drug response

The purpose of this study was to determine if magnetic resonance imaging (MRI) could quantify a difference in clitoral response following administration of a vasoactive medication, in 12 women with female sexual arousal disorder (FSAD). Subjects were entered into a double-blind, randomized two-way crossover study of sildenafil 50 mg vs placebo administered 1 h prior to genital MRI. Each subject underwent two MR studies, performed while subjects viewed alternating segments of nonerotic and erotic video. MR images were analyzed for change in clitoral volume during each session. The mean change in clitoral volume for the entire group was higher in the sildenafil MRI session (1282 mm3) compared with placebo (849 mm3) but did not reach statistical significance (P=0.064). Comparison using analysis of variance between the two sessions for each individual subject revealed a significant increase in clitoral volume following sildenafil compared with placebo in 6 of 12 subjects, no significant change in either imaging session in three subjects and in three subjects, there was a robust clitoral response in both MR sessions. In conclusion, MR measurements of clitoral volume can provide an objective measure of engorgement change following a vasoactive medication in women with FSAD.

Implementation of a Biomarker into Drug Development: Example of Identifying the Right Imaging “Tool” for an Oncology Study

The development and validation of biomarkers can often follow well-established principles of scientific investigation, but implementation of biomarkers into drug development requires careful consideration of many other practical issues. During the study planning process, careful consideration must be given to the suitability of the biomarker for the specific needs and objectives of the drug development team, performance of the biomarker at the specific sites, standardization and data transmittal, potential use of the biomarker at other stages in the life cycle of the compound, and a clear understanding of how the results will be used to make decisions about the compound. A close collaboration between the biomarker expert and the drug development team is needed maximize the likelihood that the full value of the biomarker will be realized.