On Variational Data Assimilation in Continuous Time

Variational data assimilation in continuous time is revisited. The central techniques applied in this paper are in part adopted from the theory of optimal nonlinear control. Alternatively, the investigated approach can be considered as a continuous time generalisation of what is known as weakly constrained four dimensional variational assimilation (WC--4DVAR) in the geosciences. The technique allows to assimilate trajectories in the case of partial observations and in the presence of model error. Several mathematical aspects of the approach are studied. Computationally, it amounts to solving a two point boundary value problem. For imperfect models, the trade off between small dynamical error (i.e. the trajectory obeys the model dynamics) and small observational error (i.e. the trajectory closely follows the observations) is investigated. For (nearly) perfect models, this trade off turns out to be (nearly) trivial in some sense, yet allowing for some dynamical error is shown to have positive effects even in this situation. The presented formalism is dynamical in character; no assumptions need to be made about the presence (or absence) of dynamical or observational noise, let alone about their statistics.Comment: 28 Pages, 12 Figure

Episodic medication adherence in adolescents and young adults with perinatally acquired HIV: a within-participants approach

Due to the success of antiretroviral (ART) medications, young people living with perinatally acquired HIV (PHIV+) are now surviving into adolescence and young adulthood. Understanding factors influencing ART non-adherence in this group is important in developing effective adherence interventions. Most studies of ART adherence in HIV-positive populations assess differences in adherence levels and adherence predictors between participants, over a period of time (global adherence). Many individuals living with HIV, however, including PHIV+ young people, take medication inconsistently. To investigate this pattern of adherence, a within-participants design, focussing on specific episodes of adherence and non-adherence, is suitable (episodic adherence). A within-participants design was used with 29 PHIV+ young people (17 female, median age 17 years, range 14–22 years), enrolled in the UK Adolescents and Adults Living with Perinatal HIV cohort study. Participants were eligible if they could identify one dose of medication taken and one dose they had missed in the previous two months. For each of the two episodes (one adherent, one non-adherent), behavioural factors (whom they were with, location, routine, day, reminders) and psychological factors at the time of the episode (information about medication, adherence motivation, perceived behavioural skills to adhere to medication – derived from the Information-Motivation-Behavioural Skills (IMB) Model – and affect) were assessed in a questionnaire. Non-adherence was significantly associated with weekend days (Friday to Sunday versus Monday to Thursday, p = .001), lack of routine (p = .004), and being out of the home (p = .003), but not with whom the young person was with or whether they were reminded to take medication. Non-adherence was associated with lower levels of behavioural skills (p < .001), and lower positive affect (p = .005). Non-adherence was not significantly associated with negative affect, information about ART, or ART motivation. The use of situationally specific strategies to enhance adherence in young people who take their medication inconsistently is proposed

Sensitivity And Out-Of-Sample Error in Continuous Time Data Assimilation

Data assimilation refers to the problem of finding trajectories of a prescribed dynamical model in such a way that the output of the model (usually some function of the model states) follows a given time series of observations. Typically though, these two requirements cannot both be met at the same time--tracking the observations is not possible without the trajectory deviating from the proposed model equations, while adherence to the model requires deviations from the observations. Thus, data assimilation faces a trade-off. In this contribution, the sensitivity of the data assimilation with respect to perturbations in the observations is identified as the parameter which controls the trade-off. A relation between the sensitivity and the out-of-sample error is established which allows to calculate the latter under operational conditions. A minimum out-of-sample error is proposed as a criterion to set an appropriate sensitivity and to settle the discussed trade-off. Two approaches to data assimilation are considered, namely variational data assimilation and Newtonian nudging, aka synchronisation. Numerical examples demonstrate the feasibility of the approach.Comment: submitted to Quarterly Journal of the Royal Meteorological Societ

An adapted algorithm for patient engagement in care for young people living with perinatal HIV in England

BACKGROUND: Evidence suggests that engagement in care (EIC) may be worse in young people living with perinatal HIV (YPLPHIV) compared to adults or children living with HIV. We took a published EIC algorithm for adults with HIV, which takes patients’ clinical scenarios into account, and adapted it for use in YPLPHIV in England, to measure their EIC. METHODS: The adult algorithm predicts when in the next 6 months the next clinic visit should be scheduled, based on routinely collected clinical indicators at the current visit. We updated the algorithm based on the latest adult guidelines at the time, and modified it for young people in paediatric care using the latest European paediatric guidelines. Paediatric/adolescent HIV consultants from the UK reviewed and adapted the resulting flowcharts. The adapted algorithm was applied to the Adolescent and Adults Living with Perinatal HIV (AALPHI) cohort in England. Data for 12 months following entry into AALPHI were used to predicted visits which were then compared to appointment attendances, to measure whether young people were in care in each month. Proxy markers (e.g. dates of CD4 counts, viral loads (VL)) were used to indicate appointment attendance. RESULTS: Three hundred sixteen patients were in AALPHI, of whom 41% were male, 82% of black African ethnicity and 58% born abroad. At baseline (time of AALPHI interview) median [IQR] age was 17 [15–18] years, median CD4 was 597 [427, 791] cells/µL and 69% had VL ≤50c/mL. 10 patients were dropped due to missing data. 306 YPLPHIV contributed 3,585 person months of follow up across the 12 month study in which a clinic visit was recorded for 1,204 months (38/1204 dropped due to missing data). The remaining 1,166 months were classified into 3 groups: Group-A: on ART, VL ≤ 50c/mL—63%(734/1,166) visit months, Group-B: on ART, VL > 50c/mL—27%(320/1,166) Group-C: not on ART-10%(112/1,166). Most patients were engaged in care with 87% (3,126/3,585) of months fulfilling the definition of engaged in care. CONCLUSIONS: The adapted algorithm allowed the varying clinical scenarios of YPLPHIV to be taken into account when measuring EIC. However availability of good quality surveillance data is crucial to ensure that EIC can be measured well

Towards precision medicine for pain: diagnostic biomarkers and repurposed drugs

We endeavored to identify objective blood biomarkers for pain, a subjective sensation with a biological basis, using a stepwise discovery, prioritization, validation, and testing in independent cohorts design. We studied psychiatric patients, a high risk group for co-morbid pain disorders and increased perception of pain. For discovery, we used a powerful within-subject longitudinal design. We were successful in identifying blood gene expression biomarkers that were predictive of pain state, and of future emergency department (ED) visits for pain, more so when personalized by gender and diagnosis. MFAP3, which had no prior evidence in the literature for involvement in pain, had the most robust empirical evidence from our discovery and validation steps, and was a strong predictor for pain in the independent cohorts, particularly in females and males with PTSD. Other biomarkers with best overall convergent functional evidence for involvement in pain were GNG7, CNTN1, LY9, CCDC144B, and GBP1. Some of the individual biomarkers identified are targets of existing drugs. Moreover, the biomarker gene expression signatures were used for bioinformatic drug repurposing analyses, yielding leads for possible new drug candidates such as SC-560 (an NSAID), and amoxapine (an antidepressant), as well as natural compounds such as pyridoxine (vitamin B6), cyanocobalamin (vitamin B12), and apigenin (a plant flavonoid). Our work may help mitigate the diagnostic and treatment dilemmas that have contributed to the current opioid epidemic

Exploiting the UMLS Metathesaurus for extracting and categorizing concepts representing signs and symptoms to anatomically related organ systems

AbstractObjectiveTo develop a method to exploit the UMLS Metathesaurus for extracting and categorizing concepts found in clinical text representing signs and symptoms to anatomically related organ systems. The overarching goal is to classify patient reported symptoms to organ systems for population health and epidemiological analyses.Materials and methodsUsing the concepts’ semantic types and the inter-concept relationships as guidance, a selective portion of the concepts within the UMLS Metathesaurus was traversed starting from the concepts representing the highest level organ systems. The traversed concepts were chosen, filtered, and reviewed to obtain the concepts representing clinical signs and symptoms by blocking deviations, pruning superfluous concepts, and manual review. The mapping process was applied to signs and symptoms annotated in a corpus of 750 clinical notes.ResultsThe mapping process yielded a total of 91,000 UMLS concepts (with approximately 300,000 descriptions) possibly representing physical and mental signs and symptoms that were extracted and categorized to the anatomically related organ systems. Of 1864 distinct descriptions of signs and symptoms found in the 750 document corpus, 1635 of these (88%) were successfully mapped to the set of concepts extracted from the UMLS. Of 668 unique concepts mapped, 603 (90%) were correctly categorized to their organ systems.ConclusionWe present a process that facilitates mapping of signs and symptoms to their organ systems. By providing a smaller set of UMLS concepts to use for comparing and matching patient records, this method has the potential to increase efficiency of information extraction pipelines

Episodic medication adherence in adolescents and young adults with perinatally acquired HIV:a within participants approach

Due to the success of antiretroviral (ART) medications, young people living with perinatally acquired HIV (PHIV+) are now surviving into adolescence and young adulthood. Understanding factors influencing ART non-adherence in this group is important in developing effective adherence interventions. Most studies of ART adherence in HIV-positive populations assess differences in adherence levels and adherence predictors between participants, over a period of time (global adherence). Many individuals living with HIV, however, including PHIV+ young people, take medication inconsistently. To investigate this pattern of adherence, a within-participants design, focussing on specific episodes of adherence and non-adherence, is suitable (episodic adherence). A within-participants design was used with 29 PHIV+ young people (17 female, median age 17 years, range 14–22 years), enrolled in the UK Adolescents and Adults Living with Perinatal HIV cohort study. Participants were eligible if they could identify one dose of medication taken and one dose they had missed in the previous two months. For each of the two episodes (one adherent, one non-adherent), behavioural factors (whom they were with, location, routine, day, reminders) and psychological factors at the time of the episode (information about medication, adherence motivation, perceived behavioural skills to adhere to medication – derived from the Information-Motivation-Behavioural Skills (IMB) Model – and affect) were assessed in a questionnaire. Non-adherence was significantly associated with weekend days (Friday to Sunday versus Monday to Thursday, p = .001), lack of routine (p = .004), and being out of the home (p = .003), but not with whom the young person was with or whether they were reminded to take medication. Non-adherence was associated with lower levels of behavioural skills (p < .001), and lower positive affect (p = .005). Non-adherence was not significantly associated with negative affect, information about ART, or ART motivation. The use of situationally specific strategies to enhance adherence in young people who take their medication inconsistently is proposed

Experiences of transition to adult care and readiness to self-manage care in young people with perinatal HIV in England

Background: There are few data on young people’s own experiences of transferring from paediatric to adult care, or readiness to self-manage care. Methods: A total of 132 young people living with perinatal HIV, aged 14–25 years, answered questions about transition experiences. Results: Of the participants, 45 (34%), with a median age of 16 (interquartile range [IQR] 16–17), were in paediatric care, of whom 89% reported that transition discussions had begun, at median age 15 (IQR 14–16) years. Young people in adult care were more likely than those in paediatric care to self manage appointments (90% vs 42% respectively, P < 0.001), and know their antiretroviral therapy (ART) drugs (55% vs 37%, P = 0.033). Knowledge of most recent CD4 T cell count/VL was slightly better for those in adult care (48% vs 31%, P = 0.059); naming side effects of ART was similar (71% vs 60%, P = 0.119). Conclusions: Transition discussions occurred before movement from paediatric to adult care. Further education around ART, potential side effects, and CD4 T cell count/viral load knowledge is required

Short- and Long-term Immunological and Virological Outcome in HIV-Infected Infants According to the Age at Antiretroviral Treatment Initiation

The clinical benefit of antiretroviral therapy in infants is established. In this cohort collaboration, we compare immunological and virological response to treatment started before or after 3 months of age. Early initiation provides a better short-term response, although evolution after 12 months of age is similar in both group

Arterial Stiffness in a Cohort of Young People Living With Perinatal HIV and HIV Negative Young People in England

Background: Antiretroviral therapy (ART) has increased life expectancy and consequently the risk of cardiovascular disease (CVD) in adults living with HIV. We investigated the levels and predictors of arterial stiffness in young people (YP) living with perinatal HIV (PHIV) and HIV negative YP in the Adolescents and Adults Living with Perinatal HIV (AALPHI) study. Methods: AALPHI was a prospective study evaluating the impact of HIV infection and exposure to ART on YP living with PHIV (aged 13-21 years) who had known their HIV status for at least 6 months, and HIV negative YP (aged 13-23 years) who either had a sibling, friend or parent living with HIV. Participants were enrolled from HIV clinics and community services in England. Two hundred and thirteen PHIV and 65 HIV negative YP (42% siblings of PHIV) had pulse wave velocity (PWV) measurements taken (Vicorder software) from the supra-sternal notch to the middle of the thigh cuff, at their second interview in the study between 2015 and 2017. Average PWV was calculated from the three closest readings (≥3 and ≤ 12 m/s) within 0.6 m/s of each other. Linear regression examined predictors of higher (worse) PWV, including age, sex, HIV status and height as a priori, ethnicity, born outside UK/Ireland, alcohol/nicotine/drug use, weight, waist-to-hip-ratio, mean arterial pressure (MAP), caffeine 2 h before PWV and nicotine on day of PWV. A separate PHIV model included CD4, viral load, years taking ART and ART regimen. Findings: One hundred and twenty eight (60%) PHIV and 45 (69%) HIV negative YP were female (p = 0.18), with median (IQR) age 18 (16, 20) and 18 (16, 21) years (p = 0.48) respectively. Most PHIV were taking a combination of three ART drugs from two classes. There was a trend toward higher (worse) mean PWV in the PHIV group than the HIV negative group [unvariable analysis 6.15 (SD 0.83) m/s vs. 5.93 (0.70) m/s, respectively, unadjusted p = 0.058], which was statistically significant in the multivariable analysis [adjusted p (ap) = 0.020]. In multivariable analysis being male (ap = 0.002), older age (ap < 0.001), higher MAP (ap < 0.001) and nicotine use on day of measurement (ap = 0.001) were also predictors of higher PWV. The predictors were the same in the PHIV model. Interpretation: By late adolescence PHIV had worse PWV in comparison to HIV negative peers, and traditional risk factors for CVD (higher arterial pressure, being male and older age) were associated with higher PWV values. Regular detailed monitoring of cardiovascular risk factors should become standard of care for every young person with PHIV worldwide