Multi-stream Longitudinal Data Analysis using Deep Learning

Longitudinal healthcare data encompasses all tasks where patients information are collected at multiple follow-up times. Analyzing this data is critical in addressing many real world problems in healthcare such as disease prediction and prevention. In this thesis, technical challenges in analyzing longitudinal administrative claims data are addressed and novel deep learning based models are proposed for multi-stream data analysis and disease prediction tasks. These algorithms and frameworks are assessed mainly on substance use disorders prediction tasks and specifically designed to tackled these disorders. Substance use disorder is a public health crisis costing the US an estimated $740 billion annually in healthcare, lost workplace productivity, and crime. Early identification and engagement of individuals at risk of developing a substance use disorder is a critical unmet need in healthcare which can be achieved by producing automatic artificial intelligence based tools trained using big healthcare data. In fact, healthcare data can be harnessed together with artificial intelligence and machine learning to advance our understanding of factors that increase the propensity for developing different diseases as well as those that aid in the treatment of these disorders. Here in, a disease prediction framework is first proposed based on recurrent neural networks. This framework includes three components: 1) data pre-processing, 2) disease prediction using long short term memory models, and 3) hypothesis exploration by varying the models and the inputs. This framework is assessed using two use cases: substance use disorder prediction and mild cognitive impairment prediction. Experimental results show that this proposed model can efficiently analyze patients\u27 data and creates efficient disease prediction tools. Second, the limitationsof current deep learning models including long short term memory models in claimsdata analysis are detected and addressed, and a novel model based on the transformer models is proposed. In fact, leveraging the real-world longitudinal claims data, a novel multi-stream transformer model is proposed for predicting opioid use disorder as an important case of substance use disorders. This model is designed to simultaneously analyze multiple types of data streams, such as medications, diagnoses, procedures and demographics, by attending to segments within and across these data streams. The proposed model tested on the IBM MarketScan data showed significantly better performance than the traditional models and recently developed deep learning models

Adolescent D-amphetamine treatment in a rodent model of ADHD: pro-cognitive effects during adolescence and cocaine abuse risk during adulthood

Attention-deficit/hyperactivity disorder (ADHD) is comorbid with cocaine abuse. Whereas initiating ADHD medication in childhood does not alter later cocaine abuse risk, initiating medication during adolescence may increase risk. Preclinical work in the Spontaneously Hypertensive Rat (SHR) model of ADHD found that adolescent methylphenidate increased cocaine self-administration in adulthood, suggesting a need to identify alternatively efficacious medications for teens with ADHD. We examined effects of adolescent d-amphetamine treatment on strategy set shifting performance during adolescence and on cocaine self-administration and reinstatement of cocaine-seeking behavior (cue reactivity) during adulthood in male SHR, Wistar- Kyoto (inbred control), and Wistar (outbred control) rats. During the set shift phase, adolescent SHR needed more trials and had a longer latency to reach criterion, made more regressive errors and trial omissions, and exhibited slower and more variable lever press reaction times. d- Amphetamine improved performance only in SHR by increasing choice accuracy and decreasing errors and latency to criterion. In adulthood, SHR self-administered more cocaine, made more cocaine-seeking responses, and took longer to extinguish lever responding than control strains. Adolescent d-amphetamine did not alter cocaine self-administration in adult rats of any strain, but reduced cocaine seeking during the first of seven reinstatement test sessions in adult SHR. These findings highlight utility of SHR in modeling cognitive dysfunction and comorbid cocaine abuse in ADHD. Unlike methylphenidate, d-amphetamine improved several aspects of flexible learning in adolescent SHR and did not increase cocaine intake or cue reactivity in adult SHR. Thus, adolescent d-amphetamine was superior to methylphenidate in this ADHD model

Adolescent D-amphetamine treatment in a rodent model of ADHD: pro-cognitive effects in adolescence without an impact on cocaine cue reactivity in adulthood

Attention-deficit/hyperactivity disorder (ADHD) is comorbid with cocaine abuse. Whereas initiating ADHD medication in childhood does not alter later cocaine abuse risk, initiating medication during adolescence may increase risk. Preclinical work in the Spontaneously Hypertensive Rat (SHR) model of ADHD found that adolescent methylphenidate increased cocaine self-administration in adulthood, suggesting a need to identify alternatively efficacious medications for teens with ADHD. We examined effects of adolescent d-amphetamine treatment on strategy set shifting performance during adolescence and on cocaine self-administration and reinstatement of cocaine-seeking behavior (cue reactivity) during adulthood in male SHR, Wistar-Kyoto (inbred control), and Wistar (outbred control) rats. During the set shift phase, adolescent SHR needed more trials and had a longer latency to reach criterion, made more regressive errors and trial omissions, and exhibited slower and more variable lever press reaction times. d-Amphetamine improved performance only in SHR by increasing choice accuracy and decreasing errors and latency to criterion. In adulthood, SHR self-administered more cocaine, made more cocaine-seeking responses, and took longer to extinguish lever responding than control strains. Adolescent d-amphetamine did not alter cocaine self-administration in adult rats of any strain, but reduced cocaine seeking during the first of seven reinstatement test sessions in adult SHR. These findings highlight utility of SHR in modeling cognitive dysfunction and comorbid cocaine abuse in ADHD. Unlike methylphenidate, d-amphetamine improved several aspects of flexible learning in adolescent SHR and did not increase cocaine intake or cue reactivity in adult SHR. Thus, adolescent d-amphetamine was superior to methylphenidate in this ADHD model.R01 DA011716 - NIDA NIH HHS; DA011716 - NIDA NIH HH

Stimulant drug effects on attention deficit/hyperactivity disorder: a review of the effects of age and sex of patients

Objective: As dopamine functioning varies by sex and age it might be expected that the effects of methylphenidate or amfetamine, the psychostimulants used for the treatment of Attention Deficit /Hyperactivity Disorder (ADHD), will also be moderated by these factors. Here we review the published literature on whether stimulant effects in ADHD symptoms vary by age and sex. Method: We searched for studies published from 1989 until October 2009. Databases searched included U. S. National Library of Medicine (PubMed), Medline, EMBASE, PsycINFO and ISI Web of Knowledge. Firstly, we reviewed the effects of stimulant drugs on male and female patients and also patients of pre-school, middle childhood, adolescence and adulthood. Secondly, we reviewed studies that directly tested the moderating effect of age and sex on stimulant treatment outcome. Results: Randomised controlled trials confirm that stimulant medication is efficacious for, and well tolerated by, males and females and patients across the age range; although preschoolers appear to have a less beneficial response and more side effects. Few studies that specifically examined the moderating effect of age and/or sex were identified. For sex, no effects on overall response were found, although one study reported that sex moderated methylphenidate pharmacodynamics. The few effects found for age were small and inconsistent. Conclusions: The available evidence suggests that stimulant medication, when appropriately administered, has efficacy as an ADHD treatment for both sexes and across all ages. There are currently too few published papers examining the effects of sex and age to draw strong conclusions about moderation. Further studies of the pharmacodynamics of stimulants on symptoms measured using objective tests in the laboratory or classroom setting need to be undertaken

Testing ADHD, executive functioning, and stimulant medication as predictors of psychotic symptoms in children

Executive dysfunction has been associated with psychotic experiences. One of the syndromes most associated with executive dysfunction difficulties in childhood is ADHD. However, stimulant ADHD medications are known to increase psychotic-like symptoms in some circumstances. These interrelated factors make it difficult to tease apart which of these most predict psychotic experiences. Using cross sectional data analysis, this thesis looks into the extent of how executive dysfunction, ADHD, and stimulant medication each independently predict psychotic symptoms in 9-10-year-old children. Part 1 is a conceptual paper based on a review of related literature. The primary aim was to understand the natures of ADHD, executive dysfunction, and stimulant medications. It further investigates their associations and potential mechanisms for psychotic experiences. Part 2 is an empirical paper, which reports a study on predictors of psychotic experiences in children. The study aimed to examine to what extent a diagnosis of ADHD, stimulant medication, and executive dysfunction each independently predict psychotic symptoms in children after controlling for potential confounders. Findings indicate that ADHD was not associated with psychotic experiences. On the other hand, both stimulant medication and executive dysfunction showed a significant relationship with psychotic experiences, even after controlling for confounders. Stimulant medication did not moderate the relationship between executive dysfunction and psychotic experiences. Clinical implications and future recommendations are further discussed. Part 3 is a critical appraisal of the study of the literature review and the empirical study. It includes personal reflections on the research processes from a clinical and research perspective

Neurocognitive resilience in children born late and moderate preterm (LAMP): Predictors of outcomes in attention, working memory, and executive functioning

This study sought to broaden the findings of the current research on the relationship between late and moderate preterm (LAMP) birth and long-term neurocognitive outcomes—specifically those related to attention-deficit/hyperactivity disorder (ADHD). The purpose of this study was to better understand the relationship between gestational age (GA) and ADHD by (a) comparing prevalence of diagnosis between term-born and LAMP children, (b) comparing ADHD behavioral symptom severity between term-born and LAMP children, (c) and by examining neurocognitive status between term-born children and LAMP children (with and without ADHD diagnoses). The study also examined other factors that contribute to the relationship between GA and ADHD, including consideration of other risk factors and potential symptom-mitigating factors. The final sample for this study included 169 patients between the ages of 8 and 12 years who had completed an outpatient neuropsychological evaluation. GA was not related to ADHD diagnostic status, but lower GA predicted high ADHD-related symptom severity as indicated by caregiver report on the Conners-3. Though LAMP children did not differ from their term-born peers across measures of neurocognitive functioning, lower GA showed a marginally significant negative relationship with overall neurocognitive functioning (WISC-V FSIQ). Risk factors such as family history of ADHD and in-utero exposure to substances were consistently significantly related to ADHD symptom severity, and cumulative risk negatively impacted overall cognitive functioning, attention, working memory, and executive functioning. Adaptive skills and social skills were found to mitigate ADHD symptomatology as indicated by caregiver report on the BASC-3, though total symptom mitigating factors did not influence cognitive outcomes. Lastly, moderation analyses showed that gestational age interacts with birthweight at a marginally significant level in predicting overall cognitive functioning

The relationship between the main symptoms of ADHD and alcohol, cannabis and nicotine

Attention Deficit Hyperactivity Disorder (ADHD) is a neurodevelopmental disorder that starts in early childhood and continues throughout the lifetime. The main symptoms of ADHD are inattention and hyperactivity/impulsivity. Even though substance misuse is one of the main comorbid conditions of ADHD, it has been an exclusion criterion in most studies of ADHD. The limited number of studies on ADHD and substance misuse measured ADHD as a whole, but in this thesis, the two main symptoms of ADHD have been divided to investigate the relationship between each symptom and developing alcohol, cannabis, and nicotine use. Studies show that individuals with ADHD and comorbid substance misuse become drug addicted at a younger age, use higher amounts of drugs, relapse is more common among them and ADHD medication treatments are less effective in them. There are common personality traits and impairments in individuals with the symptoms of ADHD and those who use alcohol, cannabis and nicotine. The studies of this thesis investigated the role of different facets of Executive Functions (EF), facets of impulsivity, emotional regulation, bipolar disorder and sleep quality in the relationship between each ADHD symptom and alcohol, cannabis, and nicotine use in typically developing participants. The results of Study 1 showed that hyperactivity/impulsivity explained additional variance after accounting for the facets of EF. Study 2 showed that inattention explained additional variance over and above the facets of impulsivity. Additionally, in studies 3, 4 and 5, emotional regulation, bipolar disorder and sleep quality were partial mediators between each ADHD symptom and some alcohol, cannabis and nicotine use scores, which are presented in detail in the next chapters

NEUROCOGNITION IN INDIVIDUALS AT HIGH FAMILIAL RISK FOR MAJOR DEPRESSIVE DISORDER

Neurocognitive deficits may qualify as vulnerability markers in individuals at risk for developing MDD. We examined the extent to which characteristic neurocognitive difficulties in MDD may be apparent in early to late adolescence in the offspring of a parent with MDD, as well as the extent to which other factors, such as a history of comorbid diagnoses (e.g., ADHD), a history of MDD, and a current depressive episode, might confound to these differences. Offspring of patients with MDD (n=184) and a healthy normative sample (n=88) were compared on measures assessing attention, working memory, impulse control, and visual memory. The two groups were compared using ANCOVA, including an estimate of intellectual ability as a covariate, examining the effect of offspring status on neuropsychological performance. Offspring had significantly lower working memory and visual memory performance than did the normative sample, even after adjustment for IQ differences. Offspring with current depression, a history of comorbid ADHD or comorbid PTSD had significantly lower attention and working memory performance than did other unaffected offspring. Offspring with past depressive episodes and those who had never been depressed did not differ in current neuropsychological performance. When offspring with ADHD, PTSD, or current depression were removed from the analysis, however, and scores were adjusted for IQ differences, offspring of a parent with MDD continued to differ from individuals in the normative sample in working memory, at all levels of estimated intelligence. Offspring of patients with MDD exhibited working memory weaknesses at all levels of basic estimated intellectual ability. Modest working memory deficiencies may be a risk factor for, or potential genetic marker of, susceptibility to MDD

The developmental course of attention-deficit/hyperactivity disorder : persistence, remission and emergence of symptoms from childhood to adulthood

Attention-deficit/Hyperactivity Disorder (ADHD) is a common neurodevelopmental disorder that affects children, adolescents and adults. Several adverse outcomes have been consistently associated with a diagnosis of ADHD at any point in life. In this thesis, we were dedicated to the study of the course of ADHD from childhood to adulthood focusing on three perspectives. First, we discuss the age at onset of ADHD. Historically, ADHD has first been identified and described in children. Prospective clinical studies of children with ADHD found that the disorder might persist throughout adulthood, and the concept of adult ADHD remained tied to a childhood-onset disorder. Diagnostic manuals included age at onset in childhood as a core criterion for a valid ADHD diagnosis in adolescence and adulthood. However, recent studies challenged the validity of this criterion, suggesting that many ADHD cases in adulthood might have had a late onset. In this thesis, we present our contribution to the field with original data from a longitudinal birth cohort in Brazil and a theoretical discussion on the evidence so far available on the matter. Second, our research tried to parse out children who are at high risk for either persisting with ADHD throughout adolescence (for those already affected) or developing ADHD during their development into young adulthood. While many risk factors are already known, the literature is heterogeneous, findings are sometimes contradictory, and there is little clinical translation from the evidence. We reviewed and meta-analyzed the evidence available on risk factors for ADHD persistence, providing summary estimates for several known risk factors. We then developed and validated a multivariable risk calculator that aggregated several of these risk factors into one accurate individualized risk prediction. This tool is intended for research and clinical use, and available on-line. Third, we investigated the relative immaturity effect, by which children who are born later in the school calendar year present are more frequently diagnosed with ADHD. We did so by reviewing and meta-analyzing the evidence available, and by analyzing data from three large community-based cohorts placed in Brazil. The effect of relative immaturity is a conceptual demonstration of the importance of developmental adaptations in the genesis or worsening of ADHD symptoms, which might influence its emergence along childhood, adolescence and adulthood.O Transtorno de Déficit de Atenção/Hiperatividade (TDAH) é um transtorno comum do neurodesenvolvimento que afeta crianças, adolescentes e adultos. O diagnóstico de TDAH estão consistentemente associados com desfechos adversos em qualquer idade. Nesta tese, nós nos dedicamos ao estudo do curso do TDAH da infância até a idade adulta, focando em três perspectivas. Primeiro, discutimos a idade de início do TDAH. Historicamente, o TDAH foi identificado e descrito pela primeira vez em crianças. Estudos clínicos prospectivos de crianças com TDAH descobriram que o transtorno pode persistir até a idade adulta, e o conceito de TDAH adulto permaneceu conectado a um transtorno de início na infância. Manuais diagnósticos incluíram idade de início na infância como um critério central para um diagnóstico válido de TDAH na adolescência e idade adulta. Entretanto, estudos recentes desafiaram a validade empírica deste critério, sugerindo que muitos casos de TDAH na idade adulta podem ter um início tardio. Nesta tese, apresentamos nossa contribuição nesta área com dados originais de uma coorte de nascimento no Brasil, e uma discussão teórica a respeito da evidência disponível sobre o assunto. Na segunda perspectiva, nossa pesquisa tentou identificar crianças que estão em risco para persistir com TDAH ao longo da adolescência (para aquelas já afetadas pelo transtorno) ou desenvolver TDAH ao longo do seu desenvolvimento até o início da idade adulta. Embora diversos fatores de risco sejam conhecidos, a literatura é heterogênea, os achados são por vezes contraditórios, e existe pouca tradução da evidência para a clínica. Nós revisamos e meta-analisamos a evidência disponível em fatores de risco para a persistência de TDAH, produzindo assim estimativas sumarizadas de risco para diversos fatores conhecidos. Em um segundo estudo, desenvolvemos e validamos uma calculadora de risco multivariada que agrega vários destes fatores em uma predição de risco individualizada e acurada. Esta ferramenta está disponível gratuitamente on-line, e pode ser usada em contextos clínicos e de pesquisa. Na terceira perspectiva, investigamos o efeito da imaturidade relativa, pelo qual crianças que nasceram mais tarde no ano letivo são mais frequentemente diagnosticadas com TDAH. Nós revisamos e meta-analisamos a evidência disponível, e analisando dados de três grandes coortes comunitárias no Brasil. O efeito da imaturidade relativa é uma demonstração conceitual da importância de adaptações desenvolvimentais na gênese de sintomas de TDAH, que podem influenciar sua emergência ao longo da infância, adolescência ou idade adulta