a b s t r a c tCurrently, there are no established objective biomarkers for the diagnosis or monitoring of schizophrenia. It has been previously reported that there are notable qualitative s in the speech of schizophrenics. The objective of this study was to determine whether a quantitative acoustic and temporal analysis of speech may be a potential biomarker for schizophrenia.In this study, 39 schizophrenic patients and 18 controls were digitally recorded reading aloud an emotionally neutral text passage from a children's story. Temporal, energy and vocal pitch features were automatically extracted from the recordings. A classifier based on linear discriminant analysis was employed to e between controls and schizophrenic subjects. Processing the recordings with the algorithm developed demonstrated that it is possible to schizophrenic patients and controls with a classification accuracy of 79.4% (specificity = 83.6%, sensitivity = 75.2%) based on speech pause related parameters extracted from recordings carried out in standard office (non-studio) environments.Acoustic and temporal analysis of speech may represent a potential tool for the objective analysis in schizophrenia.

Written permission has been obtained from all persons named in the acknowledgment.Author Contributions: EM, SOD and SR were primarily involved in patient recruitment. SD, VR, IK and RBR were primarily involved in the audio analysis required for this manuscript. FB was primarily involved in the statistical analysis for this manuscript. BC, and MCM were involved in data collection and data analysis for this manuscript. IS, JS and RWC were involved in all aspects required for this manuscript including patient recruitment, data management, data analysis and were the primary leads in the design of the work. All co-authors were involved in writing and editing this manuscript. Methods:We attached a digital audio device (INCA TM ) to a dry powder inhaler. This recorded when the inhaler was used and analysis of the audio data indicated if the inhaler had been used correctly. These aspects of inhaler use were combined to calculate adherence over time, as an AUC measure. Over a 3 month period a cohort of asthma patients were studied. Adherence to a twice-daily inhaler preventer therapy using this device and clinical measures were assessed. Measurements and Results:Recordings from 239 patients with severe asthma were analysed.Average Adherence, based on the dose counter was 84.4%, whereas the ratio of expected to observed accumulated AUC, Actual Adherence, was 61.8% (p<0.01). Of all adherence measures, only adherence calculated as AUC reflected changes in asthma quality of life, beta agonist reliever use and PEF, over the three months (p<0.05 compared to other measures of adherence). Conclusion:Adherence that incorporates the interval between doses and inhaler technique, and calculated as AUC, is more reflective of changes in quality of life and lung function than the currently used measures of adherence. Electronic monitors are considered to be the gold standard for objectively quantifying adherence (1). Most studies using electronic recording devices have reported adherence as the mean adherence or, the Mean Daily Dose, over the study period (2) (3) (4) The aim of this study was to test the hypothesis that by including the time of use, the interval between doses and accounting for inhaler technique, we could quantify adherence as an Area Under the Curve (AUC) and, furthermore, determine whether adherence calculated using AUC was more reflective of patient outcomes than current methods of assessing adherence. Some of the results of this study have been previously reported in the form of an abstract(18). Methods

IntroductionIn clinical practice, it is difficult to distinguish between patients with refractory asthma from those with poorly controlled asthma, where symptoms persist due to poor adherence, inadequate inhaler technique or comorbid diseases. We designed an audio recording device which, when attached to an inhaler, objectively identifies the time and technique of inhaler use, thereby assessing both aspects of adherence. This study will test the hypothesis that feedback on these two aspects of adherence when passed on to patients improves adherence and helps clinicians distinguish refractory from difficult-to-control asthma.MethodsThis is a single, blind, prospective, randomised, clinical trial performed at 5 research centres. Patients with partially controlled or uncontrolled severe asthma who have also had at least one severe asthma exacerbation in the prior year are eligible to participate. The effect of two types of nurse-delivered education interventions to promote adherence and inhaler technique will be assessed. The active group will receive feedback on their inhaler technique and adherence from the new device over a 3-month period. The control group will also receive training in inhaler technique and strategies to promote adherence, but no feedback from the device. The primary outcome is the difference in actual adherence, a measure that incorporates time and technique of inhaler use between groups at the end of the third month. Secondary outcomes include the number of patients who remain refractory despite good adherence, and differences in the components of adherence after the intervention. Data will be analysed on an intention-to-treat and a per-protocol basis. The sample size is 220 subjects (110 in each group), and loss to follow-up is estimated at 10% which will allow results to show a 10% difference (0.8 power) in adherence between group means with a type I error probability of 0.05.Trial registration numberNCT01529697; Pre-results.

BackgroundPoor adherence to inhaled medication may lead to inadequate symptom control in patients with respiratory disease. In practice it can be difficult to identify poor adherence. We designed an acoustic recording device, the INCA® (INhaler Compliance Assessment) device, which, when attached to an inhaler, identifies and records the time and technique of inhaler use, thereby providing objective longitudinal data on an individual’s adherence to inhaled medication. This study will test the hypothesis that providing objective, personalised, visual feedback on adherence to patients in combination with a tailored educational intervention in a community pharmacy setting, improves adherence more effectively than education alone.Methods/designThe study is a prospective, cluster randomised, parallel-group, multi-site study conducted over 6 months. The study is designed to compare current best practice in care (i.e. routine inhaler technique training) with the use of the INCA® device for respiratory patients in a community pharmacy setting. Pharmacies are the unit of randomisation and on enrolment to the study they will be allocated by the lead researcher to one of the three study groups (intervention, comparator or control groups) using a computer-generated list of random numbers. Given the nature of the intervention neither pharmacists nor participants can be blinded. The intervention group will receive feedback from the acoustic recording device on inhaler technique and adherence three times over a 6-month period along with inhaler technique training at each of these times. The comparator group will also receive training in inhaler use three times over the 6-month study period but no feedback on their habitual performance. The control group will receive usual care (i.e. the safe supply of medicines and advice on their use). The primary outcome is the rate of participant adherence to their inhaled medication, defined as the proportion of correctly taken doses of medication at the correct time relative to the prescribed interval. Secondary outcomes include exacerbation rates and quality of life measures. Differences in the timing and technique of inhaler use as altered by the interventions will also be assessed. Data will be analysed on an intention-to-treat and a per-protocol basis. Sample size has been calculated with reference to comparisons to be made between the intervention and comparator clusters and indicates 75 participants per cluster. With an estimated 10 % loss to follow-up we will be able to show a 20 % difference between the population means of the intervention and comparator groups with a power of 0.8. The Type I error probability associated with the test of the null hypothesis is 0.05.DiscussionThis clinical trial will establish whether providing personalised feedback to individuals on their inhaler use improves adherence. It may also be possible to enhance the role of pharmacists in clinical care by identifying patients in whom alteration of either therapy or inhaler device is appropriate.Registration...

Asthma is chronic airways disease characterized by recurrent attacks of breathlessness and wheezing. Adherence to medication regimes is a common failing for asthmatic patients and there exists a requirement to monitor such patients' adherence. The detection of inhalations from recordings of inhaler use can provide empirical evidence about patients' adherence to their asthma medication regime. Manually listening to recordings of inhaler use is a tedious and time consuming process and thus an algorithm which can automatically and accurately carry out this task would be of great value. This study employs a recording device attached to a commonly used dry powder inhaler to record the acoustic signals of patients taking their prescribed medication. An algorithm was developed to automatically detect and accurately demarcate inhalations from the acoustic signals. This algorithm was tested on a dataset of 255 separate recordings of inhaler use in real world environments. The dataset was obtained from 12 asthma outpatients who attended a respiratory clinic over a three month period. Evaluation of the algorithm on this dataset achieved sensitivity of 95%, specificity of 94% and an accuracy of 89% in detecting inhalations compared to manual inhalation detection.