Use of unsupervised machine learning to characterise HIV predictors in sub-Saharan Africa.

INTRODUCTION: Significant regional variations in the HIV epidemic hurt effective common interventions in sub-Saharan Africa. It is crucial to analyze HIV positivity distributions within clusters and assess the homogeneity of countries. We aim at identifying clusters of countries based on socio-behavioural predictors of HIV for screening. METHOD: We used an agglomerative hierarchical, unsupervised machine learning, approach for clustering to analyse data for 146,733 male and 155,622 female respondents from 13 sub-Saharan African countries with 20 and 26 features, respectively, using Population-based HIV Impact Assessment (PHIA) data from the survey years 2015-2019. We employed agglomerative hierarchical clustering and optimal silhouette index criterion to identify clusters of countries based on the similarity of socio-behavioural characteristics. We analyse the distribution of HIV positivity with socio-behavioural predictors of HIV within each cluster. RESULTS: Two principal components were obtained, with the first describing 62.3% and 70.1% and the second explaining 18.3% and 20.6% variance of the total socio-behavioural variation in females and males, respectively. Two clusters per sex were identified, and the most predictor features in both sexes were: relationship with family head, enrolled in school, circumcision status for males, delayed pregnancy, work for payment in last 12 months, Urban area indicator, known HIV status and delayed pregnancy. The HIV positivity distribution with these variables was significant within each cluster. CONCLUSIONS /FINDINGS: The findings provide a potential use of unsupervised machine learning approaches for substantially identifying clustered countries based on the underlying socio-behavioural characteristics.

Use of machine learning techniques to identify HIV predictors for screening in sub-Saharan Africa.

AIM: HIV prevention measures in sub-Saharan Africa are still short of attaining the UNAIDS 90-90-90 fast track targets set in 2014. Identifying predictors for HIV status may facilitate targeted screening interventions that improve health care. We aimed at identifying HIV predictors as well as predicting persons at high risk of the infection. METHOD: We applied machine learning approaches for building models using population-based HIV Impact Assessment (PHIA) data for 41,939 male and 45,105 female respondents with 30 and 40 variables respectively from four countries in sub-Saharan countries. We trained and validated the algorithms on 80% of the data and tested on the remaining 20% where we rotated around the left-out country. An algorithm with the best mean f1 score was retained and trained on the most predictive variables. We used the model to identify people living with HIV and individuals with a higher likelihood of contracting the disease. RESULTS: Application of XGBoost algorithm appeared to significantly improve identification of HIV positivity over the other five algorithms by f1 scoring mean of 90% and 92% for males and females respectively. Amongst the eight most predictor features in both sexes were: age, relationship with family head, the highest level of education, highest grade at that school level, work for payment, avoiding pregnancy, age at the first experience of sex, and wealth quintile. Model performance using these variables increased significantly compared to having all the variables included. We identified five males and 19 females individuals that would require testing to find one HIV positive individual. We also predicted that 4·14% of males and 10.81% of females are at high risk of infection. CONCLUSION: Our findings provide a potential use of the XGBoost algorithm with socio-behavioural-driven data at substantially identifying HIV predictors and predicting individuals at high risk of infection for targeted screening.

Correlates of depression in bipolar disorder.

We analyse time series from 100 patients with bipolar disorder for correlates of depression symptoms. As the sampling interval is non-uniform, we quantify the extent of missing and irregular data using new measures of compliance and continuity. We find that uniformity of response is negatively correlated with the standard deviation of sleep ratings (ρ = -0.26, p = 0.01). To investigate the correlation structure of the time series themselves, we apply the Edelson-Krolik method for correlation estimation. We examine the correlation between depression symptoms for a subset of patients and find that self-reported measures of sleep and appetite/weight show a lower average correlation than other symptoms. Using surrogate time series as a reference dataset, we find no evidence that depression is correlated between patients, though we note a possible loss of information from sparse sampling.

A global analysis of the effectiveness of policy responses to COVID-19.

Governments implemented many non-pharmaceutical interventions (NPIs) to suppress the spread of COVID-19 with varying results. In this paper, country-level daily time series from Our World in Data facilitates a global analysis of the propagation of the virus, policy responses and human mobility patterns. High death counts and mortality ratios influence policy compliance levels. Evidence of long-term fatigue was found with compliance dropping from over 85% in the first half of 2020 to less than 40% at the start of 2021, driven by factors such as economic necessity and optimism coinciding with vaccine effectiveness. NPIs ranged from facial coverings to restrictions on mobility, and these are compared using an empirical assessment of their impact on the growth rate of case numbers. Masks are the most cost-effective NPI currently available, delivering four times more impact than school closures, and approximately double that of other mobility restrictions. Gathering restrictions were the second most effective. International travel controls and public information campaigns had negligible effects. Literacy rates and income support played key roles in maintaining compliance. A 10% increase in literacy rate was associated with a 3.2% increase in compliance, while income support of greater than half of previous earnings increased compliance by 4.8%.

Feedback control architecture and the bacterial chemotaxis network.

Bacteria move towards favourable and away from toxic environments by changing their swimming pattern. This response is regulated by the chemotaxis signalling pathway, which has an important feature: it uses feedback to 'reset' (adapt) the bacterial sensing ability, which allows the bacteria to sense a range of background environmental changes. The role of this feedback has been studied extensively in the simple chemotaxis pathway of Escherichia coli. However it has been recently found that the majority of bacteria have multiple chemotaxis homologues of the E. coli proteins, resulting in more complex pathways. In this paper we investigate the configuration and role of feedback in Rhodobacter sphaeroides, a bacterium containing multiple homologues of the chemotaxis proteins found in E. coli. Multiple proteins could produce different possible feedback configurations, each having different chemotactic performance qualities and levels of robustness to variations and uncertainties in biological parameters and to intracellular noise. We develop four models corresponding to different feedback configurations. Using a series of carefully designed experiments we discriminate between these models and invalidate three of them. When these models are examined in terms of robustness to noise and parametric uncertainties, we find that the non-invalidated model is superior to the others. Moreover, it has a 'cascade control' feedback architecture which is used extensively in engineering to improve system performance, including robustness. Given that the majority of bacteria are known to have multiple chemotaxis pathways, in this paper we show that some feedback architectures allow them to have better performance than others. In particular, cascade control may be an important feature in achieving robust functionality in more complex signalling pathways and in improving their performance.

Remote health diagnosis and monitoring in the time of COVID-19.

Coronavirus disease (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is rapidly spreading across the globe. The clinical spectrum of SARS-CoV-2 pneumonia requires early detection and monitoring, within a clinical environment for critical cases and remotely for mild cases, with a large spectrum of symptoms. The fear of contamination in clinical environments has led to a dramatic reduction in on-site referrals for routine care. There has also been a perceived need to continuously monitor non-severe COVID-19 patients, either from their quarantine site at home, or dedicated quarantine locations (e.g. hotels). In particular, facilitating contact tracing with proximity and location tracing apps was adopted in many countries very rapidly. Thus, the pandemic has driven incentives to innovate and enhance or create new routes for providing healthcare services at distance. In particular, this has created a dramatic impetus to find innovative ways to remotely and effectively monitor patient health status. In this paper, we present a review of remote health monitoring initiatives taken in 20 states during the time of the pandemic. We emphasize in the discussion particular aspects that are common ground for the reviewed states, in particular the future impact of the pandemic on remote health monitoring and consideration on data privacy.

Lamotrigine Therapy for Bipolar Depression: Analysis of Self-Reported Patient Data.

BACKGROUND: Depression in people with bipolar disorder is a major cause of long-term disability, possibly leading to early mortality and currently, limited safe and effective therapies exist. Although existing monotherapies such as quetiapine have limited proven efficacy and practical tolerability, treatment combinations may lead to improved outcomes. Lamotrigine is an anticonvulsant currently licensed for the prevention of depressive relapses in individuals with bipolar disorder. A double-blinded randomized placebo-controlled trial (comparative evaluation of Quetiapine-Lamotrigine [CEQUEL] study) was conducted to evaluate the efficacy of lamotrigine plus quetiapine versus quetiapine monotherapy in patients with bipolar type I or type II disorders. OBJECTIVE: Because the original CEQUEL study found significant depressive symptom improvements, the objective of this study was to reanalyze CEQUEL data and determine an unbiased classification accuracy for active lamotrigine versus placebo. We also wanted to establish the time it took for the drug to provide statistically significant outcomes. METHODS: Between October 21, 2008 and April 27, 2012, 202 participants from 27 sites in United Kingdom were randomly assigned to two treatments; 101: lamotrigine, 101: placebo. The primary variable used for estimating depressive symptoms was based on the Quick Inventory of Depressive Symptomatology-self report version 16 (QIDS-SR16). The original CEQUEL study findings were confirmed by performing t test and linear regression. Multiple features were computed from the QIDS-SR16 time series; different linear and nonlinear binary classifiers were trained to distinguish between the two groups. Various feature-selection techniques were used to select a feature set with the greatest explanatory power; a 10-fold cross-validation was used. RESULTS: From weeks 10 to 14, the mean difference in QIDS-SR16 ratings between the groups was -1.6317 (P=.09; sample size=81, 77; 95% CI -0.2403 to 3.5036). From weeks 48 to 52, the mean difference was -2.0032 (P=.09; sample size=54, 48; 95% CI -0.3433 to 4.3497). The coefficient of variation (σ/µ) and detrended fluctuation analysis (DFA) exponent alpha had the greatest explanatory power. The out-of-sample classification accuracy for the 138 participants who reported more than 10 times after week 12 was 62%. A consistent classification accuracy higher than the no-information benchmark was obtained in week 44. CONCLUSIONS: Adding lamotrigine to quetiapine treatment decreased depressive symptoms in patients with bipolar disorder. Our classification model suggested that lamotrigine increased the coefficient of variation in the QIDS-SR16 scores. The lamotrigine group also tended to have a lower DFA exponent, implying a substantial temporal instability in the time series. The performance of the model over time suggested that a trial of at least 44 weeks was required to achieve consistent results. The selected model confirmed the original CEQUEL study findings and helped in understanding the temporal dynamics of bipolar depression during treatment. TRIAL REGISTRATION: EudraCT Number 2007-004513-33; https://www.clinicaltrialsregister.eu/ctr-search/trial/2007-004513-33/GB (Archived by WebCite at http://www.webcitation.org/73sNaI29O).

Exploiting nonlinear recurrence and fractal scaling properties for voice disorder detection.

BACKGROUND: Voice disorders affect patients profoundly, and acoustic tools can potentially measure voice function objectively. Disordered sustained vowels exhibit wide-ranging phenomena, from nearly periodic to highly complex, aperiodic vibrations, and increased "breathiness". Modelling and surrogate data studies have shown significant nonlinear and non-Gaussian random properties in these sounds. Nonetheless, existing tools are limited to analysing voices displaying near periodicity, and do not account for this inherent biophysical nonlinearity and non-Gaussian randomness, often using linear signal processing methods insensitive to these properties. They do not directly measure the two main biophysical symptoms of disorder: complex nonlinear aperiodicity, and turbulent, aeroacoustic, non-Gaussian randomness. Often these tools cannot be applied to more severe disordered voices, limiting their clinical usefulness. METHODS: This paper introduces two new tools to speech analysis: recurrence and fractal scaling, which overcome the range limitations of existing tools by addressing directly these two symptoms of disorder, together reproducing a "hoarseness" diagram. A simple bootstrapped classifier then uses these two features to distinguish normal from disordered voices. RESULTS: On a large database of subjects with a wide variety of voice disorders, these new techniques can distinguish normal from disordered cases, using quadratic discriminant analysis, to overall correct classification performance of 91.8 +/- 2.0%. The true positive classification performance is 95.4 +/- 3.2%, and the true negative performance is 91.5 +/- 2.3% (95% confidence). This is shown to outperform all combinations of the most popular classical tools. CONCLUSION: Given the very large number of arbitrary parameters and computational complexity of existing techniques, these new techniques are far simpler and yet achieve clinically useful classification performance using only a basic classification technique. They do so by exploiting the inherent nonlinearity and turbulent randomness in disordered voice signals. They are widely applicable to the whole range of disordered voice phenomena by design. These new measures could therefore be used for a variety of practical clinical purposes.

Comparison of predictability of epileptic seizures by a linear and a nonlinear method.

The performance of traditional linear (variance based) methods for the identification and prediction of epileptic seizures are contrasted with "modern" methods from nonlinear time series analysis. We note several flaws of design in demonstrations claiming to establish the efficacy of nonlinear techniques; in particular, we examine published evidence for precursor identification. We perform null hypothesis tests using relevant surrogate data to demonstrate that decreases in the correlation density prior to and during seizure may simply reflect increases in the variance.

A dynamical model for generating synthetic electrocardiogram signals.

A dynamical model based on three coupled ordinary differential equations is introduced which is capable of generating realistic synthetic electrocardiogram (ECG) signals. The operator can specify the mean and standard deviation of the heart rate, the morphology of the PQRST cycle, and the power spectrum of the RR tachogram. In particular, both respiratory sinus arrhythmia at the high frequencies (HFs) and Mayer waves at the low frequencies (LFs) together with the LF/HF ratio are incorporated in the model. Much of the beat-to-beat variation in morphology and timing of the human ECG, including QT dispersion and R-peak amplitude modulation are shown to result. This model may be employed to assess biomedical signal processing techniques which are used to compute clinical statistics from the ECG.

Mood dynamics in bipolar disorder.

The nature of mood variation in bipolar disorder has been the subject of relatively little research because detailed time series data has been difficult to obtain until recently. However some papers have addressed the subject and claimed the presence of deterministic chaos and of stochastic nonlinear dynamics. This study uses mood data collected from eight outpatients using a telemonitoring system. The nature of mood dynamics in bipolar disorder is investigated using surrogate data techniques and nonlinear forecasting. For the surrogate data analysis, forecast error and time reversal asymmetry statistics are used. The original time series cannot be distinguished from their linear surrogates when using nonlinear test statistics, nor is there an improvement in forecast error for nonlinear over linear forecasting methods. Nonlinear sample forecasting methods have no advantage over linear methods in out-of-sample forecasting for time series sampled on a weekly basis. These results can mean that either the original series have linear dynamics, the test statistics for distinguishing linear from nonlinear behaviour do not have the power to detect the kind of nonlinearity present, or the process is nonlinear but the sampling is inadequate to represent the dynamics. We suggest that further studies should apply similar techniques to more frequently sampled data.

Novel speech signal processing algorithms for high-accuracy classification of Parkinson's disease.

There has been considerable recent research into the connection between Parkinson's disease (PD) and speech impairment. Recently, a wide range of speech signal processing algorithms (dysphonia measures) aiming to predict PD symptom severity using speech signals have been introduced. In this paper, we test how accurately these novel algorithms can be used to discriminate PD subjects from healthy controls. In total, we compute 132 dysphonia measures from sustained vowels. Then, we select four parsimonious subsets of these dysphonia measures using four feature selection algorithms, and map these feature subsets to a binary classification response using two statistical classifiers: random forests and support vector machines. We use an existing database consisting of 263 samples from 43 subjects, and demonstrate that these new dysphonia measures can outperform state-of-the-art results, reaching almost 99% overall classification accuracy using only ten dysphonia features. We find that some of the recently proposed dysphonia measures complement existing algorithms in maximizing the ability of the classifiers to discriminate healthy controls from PD subjects. We see these results as an important step toward noninvasive diagnostic decision support in PD.

Forecasting depression in bipolar disorder.

Bipolar disorder is characterized by recurrent episodes of mania and depression and affects about 1% of the adult population. The condition can have a major impact on an individual's ability to function and is associated with a long-term risk of suicide. In this paper, we report on the use of self-rated mood data to forecast the next week's depression ratings. The data used in the study have been collected using SMS text messaging and comprises one time series of approximately weekly mood ratings for each patient. We find a wide variation between series: some exhibit a large change in mean over the monitored period and there is a variation in correlation structure. Almost half of the time series are forecast better by unconditional mean than by persistence. Two methods are employed for forecasting: exponential smoothing and Gaussian process regression. Neither approach gives an improvement over a persistence baseline. We conclude that the depression time series from patients with bipolar disorder are very heterogeneous and that this constrains the accuracy of automated mood forecasting across the set of patients. However, the dataset is a valuable resource and work remains to be done that might result in clinically useful information and tools.

Nonlinear speech analysis algorithms mapped to a standard metric achieve clinically useful quantification of average Parkinson's disease symptom severity.

The standard reference clinical score quantifying average Parkinson's disease (PD) symptom severity is the Unified Parkinson's Disease Rating Scale (UPDRS). At present, UPDRS is determined by the subjective clinical evaluation of the patient's ability to adequately cope with a range of tasks. In this study, we extend recent findings that UPDRS can be objectively assessed to clinically useful accuracy using simple, self-administered speech tests, without requiring the patient's physical presence in the clinic. We apply a wide range of known speech signal processing algorithms to a large database (approx. 6000 recordings from 42 PD patients, recruited to a six-month, multi-centre trial) and propose a number of novel, nonlinear signal processing algorithms which reveal pathological characteristics in PD more accurately than existing approaches. Robust feature selection algorithms select the optimal subset of these algorithms, which is fed into non-parametric regression and classification algorithms, mapping the signal processing algorithm outputs to UPDRS. We demonstrate rapid, accurate replication of the UPDRS assessment with clinically useful accuracy (about 2 UPDRS points difference from the clinicians' estimates, p<0.001). This study supports the viability of frequent, remote, cost-effective, objective, accurate UPDRS telemonitoring based on self-administered speech tests. This technology could facilitate large-scale clinical trials into novel PD treatments.

A graphical user interface for a method to infer kinetics and network architecture (MIKANA).

One of the main challenges in the biomedical sciences is the determination of reaction mechanisms that constitute a biochemical pathway. During the last decades, advances have been made in building complex diagrams showing the static interactions of proteins. The challenge for systems biologists is to build realistic models of the dynamical behavior of reactants, intermediates and products. For this purpose, several methods have been recently proposed to deduce the reaction mechanisms or to estimate the kinetic parameters of the elementary reactions that constitute the pathway. One such method is MIKANA: Method to Infer Kinetics And Network Architecture. MIKANA is a computational method to infer both reaction mechanisms and estimate the kinetic parameters of biochemical pathways from time course data. To make it available to the scientific community, we developed a Graphical User Interface (GUI) for MIKANA. Among other features, the GUI validates and processes an input time course data, displays the inferred reactions, generates the differential equations for the chemical species in the pathway and plots the prediction curves on top of the input time course data. We also added a new feature to MIKANA that allows the user to exclude a priori known reactions from the inferred mechanism. This addition improves the performance of the method. In this article, we illustrate the GUI for MIKANA with three examples: an irreversible Michaelis-Menten reaction mechanism; the interaction map of chemical species of the muscle glycolytic pathway; and the glycolytic pathway of Lactococcus lactis. We also describe the code and methods in sufficient detail to allow researchers to further develop the code or reproduce the experiments described. The code for MIKANA is open source, free for academic and non-academic use and is available for download (Information S1).

Accurate telemonitoring of Parkinson's disease progression by noninvasive speech tests.

Tracking Parkinson's disease (PD) symptom progression often uses the unified Parkinson's disease rating scale (UPDRS) that requires the patient's presence in clinic, and time-consuming physical examinations by trained medical staff. Thus, symptom monitoring is costly and logistically inconvenient for patient and clinical staff alike, also hindering recruitment for future large-scale clinical trials. Here, for the first time, we demonstrate rapid, remote replication of UPDRS assessment with clinically useful accuracy (about 7.5 UPDRS points difference from the clinicians' estimates), using only simple, self-administered, and noninvasive speech tests. We characterize speech with signal processing algorithms, extracting clinically useful features of average PD progression. Subsequently, we select the most parsimonious model with a robust feature selection algorithm, and statistically map the selected subset of features to UPDRS using linear and nonlinear regression techniques that include classical least squares and nonparametric classification and regression trees. We verify our findings on the largest database of PD speech in existence (approximately 6000 recordings from 42 PD patients, recruited to a six-month, multicenter trial). These findings support the feasibility of frequent, remote, and accurate UPDRS tracking. This technology could play a key part in telemonitoring frameworks that enable large-scale clinical trials into novel PD treatments.

A model invalidation-based approach for elucidating biological signalling pathways, applied to the chemotaxis pathway in R. sphaeroides.

BACKGROUND: Developing methods for understanding the connectivity of signalling pathways is a major challenge in biological research. For this purpose, mathematical models are routinely developed based on experimental observations, which also allow the prediction of the system behaviour under different experimental conditions. Often, however, the same experimental data can be represented by several competing network models. RESULTS: In this paper, we developed a novel mathematical model/experiment design cycle to help determine the probable network connectivity by iteratively invalidating models corresponding to competing signalling pathways. To do this, we systematically design experiments in silico that discriminate best between models of the competing signalling pathways. The method determines the inputs and parameter perturbations that will differentiate best between model outputs, corresponding to what can be measured/observed experimentally. We applied our method to the unknown connectivities in the chemotaxis pathway of the bacterium Rhodobacter sphaeroides. We first developed several models of R. sphaeroides chemotaxis corresponding to different signalling networks, all of which are biologically plausible. Parameters in these models were fitted so that they all represented wild type data equally well. The models were then compared to current mutant data and some were invalidated. To discriminate between the remaining models we used ideas from control systems theory to determine efficiently in silico an input profile that would result in the biggest difference in model outputs. However, when we applied this input to the models, we found it to be insufficient for discrimination in silico. Thus, to achieve better discrimination, we determined the best change in initial conditions (total protein concentrations) as well as the best change in the input profile. The designed experiments were then performed on live cells and the resulting data used to invalidate all but one of the remaining candidate models. CONCLUSION: We successfully applied our method to chemotaxis in R. sphaeroides and the results from the experiments designed using this methodology allowed us to invalidate all but one of the proposed network models. The methodology we present is general and can be applied to a range of other biological networks.

Suitability of dysphonia measurements for telemonitoring of Parkinson's disease.

We present an assessment of the practical value of existing traditional and non-standard measures for discriminating healthy people from people with Parkinson's disease (PD) by detecting dysphonia. We introduce a new measure of dysphonia, Pitch Period Entropy (PPE), which is robust to many uncontrollable confounding effects including noisy acoustic environments and normal, healthy variations in voice frequency. We collected sustained phonations from 31 people, 23 with PD. We then selected 10 highly uncorrelated measures, and an exhaustive search of all possible combinations of these measures finds four that in combination lead to overall correct classification performance of 91.4%, using a kernel support vector machine. In conclusion, we find that non-standard methods in combination with traditional harmonics-to-noise ratios are best able to separate healthy from PD subjects. The selected non-standard methods are robust to many uncontrollable variations in acoustic environment and individual subjects, and are thus well-suited to telemonitoring applications.