Christian Lederer

Disability as an outcome in MS clinical trials.

Background: Inferences about long-term effects of therapies in multiple sclerosis (MS) have been based on surrogate markers studied in short-term trials. Preventing progressive disability is the key therapeutic goal but there remains no validated definition for its measurement in a trial context. Meanwhile, MS trials continue to shorten and to depend on unvalidated surrogates. Since there have been no treatment claims for improving unremitting disability, worsening of disability in the placebo/control arm must occur for effectiveness on this outcome to be shown. Methods: We examined widely-used clinical surrogates of long-term disability progression in individual patients with MS within a unique database from the placebo arms of 31 randomized clinical trials. Results: Detection of treatment effects in secondary progressive MS trials is undermined by noise in disability measurement. Whereas existing measures can be partially validated in secondary progressive MS, this is not the case in relapsing-remitting MS. Here, examination of widely used definitions of treatment failure demonstrated that disability progression was no more likely than similarly defined improvement. Existing definitions of disease progression in short-term intervention trials in relapsing-remitting patients reflect random variation, measurement error, and remitting relapses. Conclusion: Clinical surrogates of unremitting disability used in trials of relapsing-remitting multiple sclerosis cannot be validated. Trials have been too short or degrees of disability change too small to measure the key outcomes. These analyses highlight the difficulty in determining effectiveness of therapy in chronic diseases.

Accuracy of the actibelt(®) accelerometer for measuring walking speed in a controlled environment among persons with multiple sclerosis.

BACKGROUND Advances in portable sensor technology have opened an era for objective, real-life monitoring of walking speed in persons with multiple sclerosis (MS). PURPOSE The present study examined the accuracy of the actibelt(®) accelerometer for measuring walking speed during a standard 6-min walk (6MW) and the possibility that disability status influenced the degree of accuracy among persons with MS. METHODS On a single testing session, 51 persons with MS and Expanded Disability Status Scale scores between 2.0 and 6.5 performed a 6MW while wearing an actibelt(®) in the bodys sagittal symmetry plane and close to the bodys centre of mass. RESULTS All 51 participants completed the 6MW without stopping, falling, or any adverse events, and the actibelt(®) provided walking speed data for each of the participants. The actibelt(®) significantly overestimated walking speed (actual minus actibelt(®)) by a mean±standard deviation of -0.12±0.17 m/s for the overall sample (p<0.0001). There was no significant overestimation in the sample with mild disability (-0.02±0.11 m/s), but there was in the samples with moderate (-0.10±0.16 m/s) and severe (-0.26±0.12 m/s) disability. CONCLUSION The actibelt(®) is ready for real-life monitoring of walking speed in persons with mild MS, but caution is necessary when interpreting the accuracy of the walking speed data for those with MS who have moderate and severe disability.

What is the "normal" fetal heart rate?

Aim. There is no consensus about the normal fetal heart rate. Current international guidelines recommend for the normal fetal heart rate (FHR) baseline different ranges of 110 to 150 beats per minute (bpm) or 110 to 160 bpm. We started with a precise definition of “normality” and performed a retrospective computerized analysis of electronically recorded FHR tracings. Methods. We analyzed all recorded cardiotocography tracings of singleton pregnancies in three German medical centers from 2000 to 2007 and identified 78,852 tracings of sufficient quality. For each tracing, the baseline FHR was extracted by eliminating accelerations/decelerations and averaging based on the “delayed moving windows” algorithm. After analyzing 40% of the dataset as “training set” from one hospital generating a hypothetical normal baseline range, evaluation of external validity on the other 60% of the data was performed using data from later years in the same hospital and externally using data from the two other hospitals. Results. Based on the training data set, the “best” FHR range was 115 or 120 to 160 bpm. Validation in all three data sets identified 120 to 160 bpm as the correct symmetric “normal range”. FHR decreases slightly during gestation. Conclusions. Normal ranges for FHR are 120 to 160 bpm. Many international guidelines define ranges of 110 to 160 bpm which seem to be safe in daily practice. However, further studies should confirm that such asymmetric alarm limits are safe, with a particular focus on the lower bound, and should give insights about how to show and further improve the usefulness of the widely used practice of CTG monitoring.

Development and Validation of a New Method to Measure Walking Speed in Free-Living Environments Using the Actibelt® Platform

Walking speed is a fundamental indicator for human well-being. In a clinical setting, walking speed is typically measured by means of walking tests using different protocols. However, walking speed obtained in this way is unlikely to be representative of the conditions in a free-living environment. Recently, mobile accelerometry has opened up the possibility to extract walking speed from long-time observations in free-living individuals, but the validity of these measurements needs to be determined. In this investigation, we have developed algorithms for walking speed prediction based on 3D accelerometry data (actibelt®) and created a framework using a standardized data set with gold standard annotations to facilitate the validation and comparison of these algorithms. For this purpose 17 healthy subjects operated a newly developed mobile gold standard while walking/running on an indoor track. Subsequently, the validity of 12 candidate algorithms for walking speed prediction ranging from well-known simple approaches like combining step length with frequency to more sophisticated algorithms such as linear and non-linear models was assessed using statistical measures. As a result, a novel algorithm employing support vector regression was found to perform best with a concordance correlation coefficient of 0.93 (95%CI 0.92–0.94) and a coverage probability CP1 of 0.46 (95%CI 0.12–0.70) for a deviation of 0.1 m/s (CP2 0.78, CP3 0.94) when compared to the mobile gold standard while walking indoors. A smaller outdoor experiment confirmed those results with even better coverage probability. We conclude that walking speed thus obtained has the potential to help establish walking speed in free-living environments as a patient-oriented outcome measure.

Validating Predictors of Disease Progression in a Large Cohort of Primary-Progressive Multiple Sclerosis Based on a Systematic Literature Review

Background New agents with neuroprotective or neuroregenerative potential might be explored in primary-progressive Multiple Sclerosis (PPMS) - the MS disease course with leading neurodegenerative pathology. Identification of patients with a high short-term risk for progression may minimize study duration and sample size. Cohort studies reported several variables as predictors of EDSS disability progression but findings were partially contradictory. Objective To analyse the impact of published predictors on EDSS disease progression in a large cohort of PPMS patients. Methods A systematic literature research was performed to identify predictors for disease progression in PPMS. Individual case data from the Sylvia Lawry Centre (SLC) and the Hamburg MS patient database (HAPIMS) was pooled for a retrospective validation of these predictors on the annualized EDSS change. Results The systematic literature analysis revealed heterogeneous data from 3 prospective and 5 retrospective natural history cohort studies. Age at onset, gender, type of first symptoms and early EDSS changes were available for validation. Our pooled cohort of 597 PPMS patients (54% female) had a mean follow-up of 4.4 years and mean change of EDSS of 0.35 per year based on 2503 EDSS assessments. There was no significant association between the investigated variables and the EDSS-change. Conclusion None of the analysed variables were predictive for the disease progression measured by the annualized EDSS change. Whether PPMS is still unpredictable or our results may be due to limitations of cohort assessments or selection of predictors cannot be answered. Large systematic prospective studies with new endpoints are needed.

A new method to estimate the real upper limit of the false alarm rate in a 3 accelerometry-based fall detector for the elderly

Falls are a major concern for the elderly and their ability to remain healthy. Fall detection systems may notify emergency responders when no one apart from the injured is present. However, their real-world application is limited by a number of factors such as high false positive rates, low-compliance, poor-usability and short battery lifetime. In order to improve these aspects we have developed a miniaturized 3D accelerometer integrated in a belt buckle, the actibelt®, and a fall detection algorithm. We have used a new evaluation method to assess the upper limit of the false alarm rate of our algorithm using a large set of long term standardized acceleration measurements recorded under real life conditions. Our algorithm has a false alarm rate of seventeen false alarms per month and has the potential to be reduced down to at most three false alarms per month when activities which require the sensor to be removed are eliminated. In laboratory settings, the algorithm has a sensitivity of 100%. The algorithm was sucessfully validated using data from a real-world fall.

Ecological Validity of Walking Capacity Tests in Multiple Sclerosis

Background Ecological validity implicates in how far clinical assessments refer to real life. Short clinical gait tests up to ten meters and 2- or 6-Minutes Walking Tests (2MWT/6MWT) are used as performance-based outcomes in Multiple Sclerosis (MS) studies and considered as moderately associated with real life mobility. Objective To investigate the ecological validity of 10 Meter Walking Test (10mWT), 2MWT and 6MWT. Methods Persons with MS performed 10mWT, 6MWT including 2MWT and 7 recorded days by accelerometry. Ecological validity was assumed if walking tests represented a typical walking sequence in real-life and correlations with accelerometry parameters were strong. Results In this cohort (n=28, medians: age=45, EDSS=3.2, disease duration=9 years), uninterrupted walking of 2 or 6 minutes occurred not frequent in real life (2.61 and 0.35 sequences/day). 10mWT correlated only with slow walking speed quantiles in real life. 2MWT and 6MWT correlated moderately with most real life walking parameters. Conclusion Clinical gait tests over a few meters have a poor ecological validity while validity is moderate for 2MWT and 6MWT. Mobile accelerometry offers the opportunity to control and improve the ecological validity of MS mobility outcomes.

Fampridine and real-life walking in multiple sclerosis: Low predictive value of clinical test for habitual short-term changes

BACKGROUND Fampridine improves walking speed in patients with multiple sclerosis (MS) in performance-based tests. The impact on habitual mobility and its correlation with clinical tests has not been analysed. OBJECTIVE To investigate the association between clinical response criteria and habitual mobility in MS patients starting a fampridine treatment. METHODS During a four-week baseline-to-treatment study, we assessed in 28 patients (median EDSS 4.75, range 4-6.5) walking tests as the Timed-25-Foot-Walk (T25FW) and mobility questionnaires at day 0, 14 (start of treatment) and 28. Habitual steps and distance per day, total activity and walking speed was measured by accelerometry over four weeks. Beside improvement in real-life mobility, we investigated if such measures differed between non-responders and responders defined by a 20% improvement in clinical tests. RESULTS All clinical test, patient reported outcomes and total activity improved significantly (p<0.05). 46% improved (any change >0) in three of four real-life measures. Change of the T25FW predicted only an increase of distance per day. Subjective rating of patients performed better by predicting distance and walking speed changes correctly. CONCLUSION Fampridine might improve walking in daily life of MS, but clinical tests are weak predictors. Accelerometry opens a new perspective on mobility measurment, but the current data do not show a consistent effect on non-performance based accelerometry outcomes.

Combined MRI lesions and relapses as a surrogate for disability in MS.

Submissions to Writ e Click this week highlight a common difficulty: how to relate conclusions from research to clinical practice and vice versa. Dr. Ebers and colleagues debate with authors Sormani and De Stefano about the article “Combined MRI lesions and relapses as a surrogate for disability in MS,” with a sticking point over the difference between surrogacy and correlation. They agree in calling for another look at the outcomes used in multiple sclerosis trials. Drs. Kent and Mandava, in reference to “Predicting outcome of IV thrombolysis-treated ischemic stroke patients: The DRAGON score,” point out the …

On the Measurement of the Disease Status in Clinical Trials: Lessons from Multiple Sclerosis

There are two fundamentally different approaches in the assessment of the disease status of a patient: the pathophysiological approach and the phenomenological approach.