Statistical and econometric analysis of the treatment of HIV/AIDS

The epidemic of HIV/AIDS in the United States is constantly changing and evolving, starting from patient zero to now an estimated 650,000 to 900,000 Americans infected. The nature and course of HIV changed dramatically with the introduction of antiretrovirals. This discourse examines many different facets of HIV from the beginning where there wasn't any treatment for HIV until the present era of highly active antiretroviral therapy (HAART). By utilizing statistical analysis of clinical data, this paper examines where we were, where we are and projections as to where treatment of HIV/AIDS is headed.

Chapter Two describes the datasets that were used for the analyses. The primary database utilized was collected by myself from an outpatient HIV clinic. The data included dates from 1984 until the present. The second database was from the Multicenter AIDS Cohort Study (MACS) public dataset. The data from the MACS cover the time between 1984 and October 1992. Comparisons are made between both datasets.

Chapter Three discusses where we were. Before the first anti-HIV drugs (called antiretrovirals) were approved, there was no treatment to slow the progression of HIV. The first generation of antiretrovirals, reverse transcriptase inhibitors such as AZT (zidovudine), DDI (didanosine), DDC (zalcitabine), and D4T (stavudine) provided the first treatment for HIV. The first clinical trials showed that these antiretrovirals had a significant impact on increasing patient survival. The trials also showed that patients on these drugs had increased CD4+ T cell counts. Chapter Three examines the distributions of CD4 T cell counts. The results show that the estimated distributions of CD4 T cell counts are distinctly non-Gaussian. Thus distributional assumptions regarding CD4 T cell counts must be taken, into account when performing analyses with this marker. The results also show the estimated CD4 T cell distributions for each disease stage: asymptomatic, symptomatic and AIDS are non-Gaussian. Interestingly, the distribution of CD4 T cell counts for the asymptomatic period is significantly below that of the CD4 T cell distribution for the uninfected population suggesting that even in patients with no outward symptoms of HIV infection, there exists high levels of immunosuppression.

Chapter Four discusses where we are at present. HIV quickly grew resistant to reverse transcriptase inhibitors which were given sequentially as mono or dual therapy. As resistance grew, the positive effects of the reverse transcriptase inhibitors on CD4 T cell counts and survival dissipated. As the old era faded a new era characterized by a new class of drugs and new technology changed the way that we treat HIV-infected patients. Viral load assays were able to quantify the levels of HIV RNA in the blood. By quantifying the viral load, one now had a faster, more direct way to test antiretroviral regimen efficacy. Protease inhibitors, which attacked a different region of HIV than reverse transcriptase inhibitors, when used in combination with other antiretroviral agents were found to dramatically and significantly reduce the HIV RNA levels in the blood. Patients also experienced significant increases in CD4 T cell counts. For the first time in the epidemic, there was hope. It was hypothesized that with HAART, viral levels could be kept so low that the immune system as measured by CD4 T cell counts would be able to recover. If these viral levels could be kept low enough, it would be possible for the immune system to eradicate the virus. The hypothesis of immune reconstitution, that is bringing CD4 T cell counts up to levels seen in uninfected patients, is tested in Chapter Four. It was found that for these patients, there was not enough of a CD4 T cell increase to be consistent with the hypothesis of immune reconstitution.

In Chapter Five, the effectiveness of long-term HAART is analyzed. Survival analysis was conducted on 213 patients on long-term HAART. The primary endpoint was presence of an AIDS defining illness. A high level of clinical failure, or progression to an endpoint, was found.

Chapter Six yields insights into where we are going. New technology such as viral genotypic testing, that looks at the genetic structure of HIV and determines where mutations have occurred, has shown that HIV is capable of producing resistance mutations that confer multiple drug resistance. This section looks at resistance issues and speculates, ceterus parabis, where the state of HIV is going. This section first addresses viral genotype and the correlates of viral load and disease progression. A second analysis looks at patients who have failed their primary attempts at HAART and subsequent salvage therapy. It was found that salvage regimens, efforts to control viral replication through the administration of different combinations of antiretrovirals, were not effective in 90 percent of the population in controlling viral replication. Thus, primary attempts at therapy offer the best change of viral suppression and delay of disease progression. Documentation of transmission of drug-resistant virus suggests that the public health crisis of HIV is far from over. Drug resistant HIV can sustain the epidemic and hamper our efforts to treat HIV infection. The data presented suggest that the decrease in the morbidity and mortality due to HIV/AIDS is transient. Deaths due to HIV will increase and public health officials must prepare for this eventuality unless new treatments become available. These results also underscore the importance of the vaccine effort.

The final chapter looks at the economic issues related to HIV. The direct and indirect costs of treating HIV/AIDS are very high. For the first time in the epidemic, there exists treatment that can actually slow disease progression. The direct costs for HAART are estimated. It is estimated that the direct lifetime costs for treating each HIV infected patient with HAART is between $353,000 to $598,000 depending on how long HAART prolongs life. If one looks at the incremental cost per year of life saved it is only $101,000. This is comparable with the incremental costs per year of life saved from coronary artery bypass surgery.

Policy makers need to be aware that although HAART can delay disease progression, it is not a cure and HIV is not over. The results presented here suggest that the decreases in the morbidity and mortality due to HIV are transient. Policymakers need to be prepared for the eventual increase in AIDS incidence and mortality. Costs associated with HIV/AIDS are also projected to increase. The cost savings seen recently have been from the dramatic decreases in the incidence of AIDS defining opportunistic infections. As patients who have been on HAART the longest start to progress to AIDS, policymakers and insurance companies will find that the cost of treating HIV/AIDS will increase.

The search for gravitational waves from the coalescence of black hole binary systems in data from the LIGO and Virgo detectors. Or: A dark walk through a random forest

The LIGO and Virgo gravitational-wave observatories are complex and extremely sensitive strain detectors that can be used to search for a wide variety of gravitational waves from astrophysical and cosmological sources. In this thesis, I motivate the search for the gravitational wave signals from coalescing black hole binary systems with total mass between 25 and 100 solar masses. The mechanisms for formation of such systems are not well-understood, and we do not have many observational constraints on the parameters that guide the formation scenarios. Detection of gravitational waves from such systems — or, in the absence of detection, the tightening of upper limits on the rate of such coalescences — will provide valuable information that can inform the astrophysics of the formation of these systems. I review the search for these systems and place upper limits on the rate of black hole binary coalescences with total mass between 25 and 100 solar masses. I then show how the sensitivity of this search can be improved by up to 40% by the the application of the multivariate statistical classifier known as a random forest of bagged decision trees to more effectively discriminate between signal and non-Gaussian instrumental noise. I also discuss the use of this classifier in the search for the ringdown signal from the merger of two black holes with total mass between 50 and 450 solar masses and present upper limits. I also apply multivariate statistical classifiers to the problem of quantifying the non-Gaussianity of LIGO data. Despite these improvements, no gravitational-wave signals have been detected in LIGO data so far. However, the use of multivariate statistical classification can significantly improve the sensitivity of the Advanced LIGO detectors to such signals.

Some statistical aspects of the long-term gill net monitoring programme for pike Esox lucius in Windermere (English Lake District)

For more than 55 years, data have been collected on the population of pike Esox lucius in Windermere, first by the Freshwater Biological Association (FBA) and, since 1989, by the Institute of Freshwater Ecology (IFE) of the NERC Centre for Ecology and Hydrology. The aim of this article is to explore some methodological and statistical issues associated with the precision of pike gill net catches and catch-per-unit-effort (CPUE) data, further to those examined by Bagenal (1972) and especially in the light of the current deployment within the Windermere long-term sampling programme. Specifically, consideration is given to the precision of catch estimates from gill netting, including the effects of sampling different locations, the effectiveness of sampling for distinguishing between years, and the effects of changing fishing effort.

Neural and computational representations of decision variables

These studies explore how, where, and when representations of variables critical to decision-making are represented in the brain. In order to produce a decision, humans must first determine the relevant stimuli, actions, and possible outcomes before applying an algorithm that will select an action from those available. When choosing amongst alternative stimuli, the framework of value-based decision-making proposes that values are assigned to the stimuli and that these values are then compared in an abstract “value space” in order to produce a decision. Despite much progress, in particular regarding the pinpointing of ventromedial prefrontal cortex (vmPFC) as a region that encodes the value, many basic questions remain. In Chapter 2, I show that distributed BOLD signaling in vmPFC represents the value of stimuli under consideration in a manner that is independent of the type of stimulus it is. Thus the open question of whether value is represented in abstraction, a key tenet of value-based decision-making, is confirmed. However, I also show that stimulus-dependent value representations are also present in the brain during decision-making and suggest a potential neural pathway for stimulus-to-value transformations that integrates these two results.

More broadly speaking, there is both neural and behavioral evidence that two distinct control systems are at work during action selection. These two systems compose the “goal-directed system”, which selects actions based on an internal model of the environment, and the “habitual” system, which generates responses based on antecedent stimuli only. Computational characterizations of these two systems imply that they have different informational requirements in terms of input stimuli, actions, and possible outcomes. Associative learning theory predicts that the habitual system should utilize stimulus and action information only, while goal-directed behavior requires that outcomes as well as stimuli and actions be processed. In Chapter 3, I test whether areas of the brain hypothesized to be involved in habitual versus goal-directed control represent the corresponding theorized variables.

The question of whether one or both of these neural systems drives Pavlovian conditioning is less well-studied. Chapter 4 describes an experiment in which subjects were scanned while engaged in a Pavlovian task with a simple non-trivial structure. After comparing a variety of model-based and model-free learning algorithms (thought to underpin goal-directed and habitual decision-making, respectively), it was found that subjects’ reaction times were better explained by a model-based system. In addition, neural signaling of precision, a variable based on a representation of a world model, was found in the amygdala. These data indicate that the influence of model-based representations of the environment can extend even to the most basic learning processes.

Knowledge of the state of hidden variables in an environment is required for optimal inference regarding the abstract decision structure of a given environment and therefore can be crucial to decision-making in a wide range of situations. Inferring the state of an abstract variable requires the generation and manipulation of an internal representation of beliefs over the values of the hidden variable. In Chapter 5, I describe behavioral and neural results regarding the learning strategies employed by human subjects in a hierarchical state-estimation task. In particular, a comprehensive model fit and comparison process pointed to the use of "belief thresholding". This implies that subjects tended to eliminate low-probability hypotheses regarding the state of the environment from their internal model and ceased to update the corresponding variables. Thus, in concert with incremental Bayesian learning, humans explicitly manipulate their internal model of the generative process during hierarchical inference consistent with a serial hypothesis testing strategy.

Essays in Behavioral Decision Theory

This thesis studies decision making under uncertainty and how economic agents respond to information. The classic model of subjective expected utility and Bayesian updating is often at odds with empirical and experimental results; people exhibit systematic biases in information processing and often exhibit aversion to ambiguity. The aim of this work is to develop simple models that capture observed biases and study their economic implications.

In the first chapter I present an axiomatic model of cognitive dissonance, in which an agent's response to information explicitly depends upon past actions. I introduce novel behavioral axioms and derive a representation in which beliefs are directionally updated. The agent twists the information and overweights states in which his past actions provide a higher payoff. I then characterize two special cases of the representation. In the first case, the agent distorts the likelihood ratio of two states by a function of the utility values of the previous action in those states. In the second case, the agent's posterior beliefs are a convex combination of the Bayesian belief and the one which maximizes the conditional value of the previous action. Within the second case a unique parameter captures the agent's sensitivity to dissonance, and I characterize a way to compare sensitivity to dissonance between individuals. Lastly, I develop several simple applications and show that cognitive dissonance contributes to the equity premium and price volatility, asymmetric reaction to news, and belief polarization.

The second chapter characterizes a decision maker with sticky beliefs. That is, a decision maker who does not update enough in response to information, where enough means as a Bayesian decision maker would. This chapter provides axiomatic foundations for sticky beliefs by weakening the standard axioms of dynamic consistency and consequentialism. I derive a representation in which updated beliefs are a convex combination of the prior and the Bayesian posterior. A unique parameter captures the weight on the prior and is interpreted as the agent's measure of belief stickiness or conservatism bias. This parameter is endogenously identified from preferences and is easily elicited from experimental data.

The third chapter deals with updating in the face of ambiguity, using the framework of Gilboa and Schmeidler. There is no consensus on the correct way way to update a set of priors. Current methods either do not allow a decision maker to make an inference about her priors or require an extreme level of inference. In this chapter I propose and axiomatize a general model of updating a set of priors. A decision maker who updates her beliefs in accordance with the model can be thought of as one that chooses a threshold that is used to determine whether a prior is plausible, given some observation. She retains the plausible priors and applies Bayes' rule. This model includes generalized Bayesian updating and maximum likelihood updating as special cases.

Estresse no trabalho e pressão arterial: reflexões metodológicas sobre linearidade e operacionalização da exposição

O modelo demanda-controle proposto por Karasek caracteriza as situações de estresse no ambiente laboral que é definido pela alta exigência no trabalho resultante da combinação do efeito da demanda psicológica no trabalho (estressores) e moderadores do estresse, especialmente a capacidade de tomar decisões (controle). Existem diversas formas de operacionalizar a exposição (alta exigência no trabalho) descritas na literatura. No entanto, não há consenso sobre qual a melhor operacionalização. Outra questão negligenciada pela maioria dos autores é a forma funcional da curva exposição-resposta ou não linearidade da associação. Entre os desfechos avaliados em estudos sobre os efeitos do estresse no trabalho, usando o modelo demanda-controle, estão as doenças cardiovasculares, como a hipertensão arterial. Contudo, os resultados relatados parecem conflitantes sobre a associação entre o estresse no trabalho e a hipertensão arterial. Os objetivos deste trabalho são estudar a associação entre o estresse no trabalho e aumento da pressão arterial/hipertensão arterial usando as diferentes formas de operacionalização do estresse no trabalho e avaliar a curva exposição-resposta quanto à linearidade. O trabalho é um estudo seccional desenvolvido na população do Estudo Pró-Saúde que é composta por servidores públicos de uma universidade no Rio de Janeiro. Modelos de regressão usando diferentes distribuições foram usados para estimar a associação entre a alta exigência no trabalho e a pressão arterial/hipertensão arterial. Funções não lineares foram utilizadas para investigar a linearidade da associação entre a exposição e os desfechos. Os resultados sugerem que a relação entre a dimensão controle e a pressão arterial seja não linear. Foram observadas associações significativas entre alta exigência no trabalho e pressão arterial sistólica e diastólica para algumas formas de operacionalização da exposição, quando analisados separadamente. No entanto, quando analisadas de forma conjunta por meio do modelo de resposta bivariada não foi encontrada associação. Também não foi encontrada associação entre a alta exigência no trabalho e hipertensão arterial para nenhuma forma de operacionalização da exposição. Os modelos estatísticos com melhor ajuste foram aqueles em que a exposição foi operacionalizada por meio de quadrantes gerados pela mediana de cada uma das dimensões e de forma dicotômica com termo de interação entre demanda psicológica e controle. Neste estudo estas foram as formas mais adequadas de operacionalização. Os resultados também mostram que a associação entre a dimensão controle e a pressão arterial é não linear. Conclui-se que não há garantia de linearidade da associação entre estresse no trabalho e pressão arterial e que essa associação pode ser influenciada pela forma de operacionalização da exposição e do desfecho ou da estratégia de modelagem.