Dynamic regime marginal structural mean models for estimation of optimal dynamic treatment regimes, Part I: main content

Dynamic treatment regimes are set rules for sequential decision making based on patient covariate history. Observational studies are well suited for the investigation of the effects of dynamic treatment regimes because of the variability in treatment decisions found in them. This variability exists because different physicians make different decisions in the face of similar patient histories. In this article we describe an approach to estimate the optimal dynamic treatment regime among a set of enforceable regimes. This set is comprised by regimes defined by simple rules based on a subset of past information. The regimes in the set are indexed by a Euclidean vector. The optimal regime is the one that maximizes the expected counterfactual utility over all regimes in the set. We discuss assumptions under which it is possible to identify the optimal regime from observational longitudinal data. Murphy et al. (2001) developed efficient augmented inverse probability weighted estimators of the expected utility of one fixed regime. Our methods are based on an extension of the marginal structural mean model of Robins (1998, 1999) which incorporate the estimation ideas of Murphy et al. (2001). Our models, which we call dynamic regime marginal structural mean models, are specially suitable for estimating the optimal treatment regime in a moderately small class of enforceable regimes of interest. We consider both parametric and semiparametric dynamic regime marginal structural models. We discuss locally efficient, double-robust estimation of the model parameters and of the index of the optimal treatment regime in the set. In a companion paper in this issue of the journal we provide proofs of the main results.

Dynamic regime marginal structural mean models for estimation of optimal dynamic treatment regimes, Part II: proofs of results

In this companion article to "Dynamic Regime Marginal Structural Mean Models for Estimation of Optimal Dynamic Treatment Regimes, Part I: Main Content" [Orellana, Rotnitzky and Robins (2010), IJB, Vol. 6, Iss. 2, Art. 7] we present (i) proofs of the claims in that paper, (ii) a proposal for the computation of a confidence set for the optimal index when this lies in a finite set, and (iii) an example to aid the interpretation of the positivity assumption.

Development of a biocidal treatment regime to inhibit biological growths on cultural heritage: BIODAM

Existing chemical treatments to prevent biological damage to monuments often involve considerable amounts of potentially dangerous and even poisonous biocides. The scientific approach described in this paper aims at a drastic reduction in the concentration of biocide applications by a polyphasic approach of biocides combined with cell permeabilisers, polysaccharide and pigment inhibitors and a photodynamic treatment. A variety of potential agents were screened to determine the most effective combination. Promising compounds were tested under laboratory conditions with cultures of rock deteriorating bacteria, algae, cyanobacteria and fungi. A subsequent field trial involved two sandstone types with natural biofilms. These were treated with multiple combinations of chemicals and exposed to three different climatic conditions. Although treatments proved successful in the laboratory, field trials were inconclusive and further testing will be required to determine the most effective treatment regime. While the most effective combination of chemicals and their application methodology is still being optimised, results to date indicate that this is a promising and effective treatment for the control of a wide variety of potentially damaging organisms colonising stone substrates

Estimating Dynamic Treatment Effects from Project STAR (Working Paper 36)

This paper considers the analysis of data from randomized trials which offer a sequence of interventions and suffer from a variety of problems in implementation. In experiments that provide treatment in multiple periods (T>1), subjects have up to 2^{T}-1 counterfactual outcomes to be estimated to determine the full sequence of causal effects from the study. Traditional program evaluation and non-experimental estimators are unable to recover parameters of interest to policy makers in this setting, particularly if there is non-ignorable attrition. We examine these issues in the context of Tennessee's highly influential randomized class size study, Project STAR. We demonstrate how a researcher can estimate the full sequence of dynamic treatment effects using a sequential difference in difference strategy that accounts for attrition due to observables using inverse probability weighting M-estimators. These estimates allow us to recover the structural parameters of the small class effects in the underlying education production function and construct dynamic average treatment effects. We present a complete and different picture of the effectiveness of reduced class size and find that accounting for both attrition due to observables and selection due to unobservable is crucial and necessary with data from Project STAR

Estimation and extrapolation of optimal treatment and testing strategies

We review recent developments in the estimation of an optimal treatment strategy or regime from longitudinal data collected in an observational study. We also propose novel methods for using the data obtained from an observational database in one health-care system to determine the optimal treatment regime for biologically similar subjects in a second health-care system when, for cultural, logistical, or financial reasons, the two health-care systems differ (and will continue to differ) in the frequency of, and reasons for, both laboratory tests and physician visits. Finally, we propose a novel method for estimating the optimal timing of expensive and/or painful diagnostic or prognostic tests. Diagnostic or prognostic tests are only useful in so far as they help a physician to determine the optimal dosing strategy, by providing information on both the current health state and the prognosis of a patient because, in contrast to drug therapies, these tests have no direct causal effect on disease progression. Our new method explicitly incorporates this no direct effect restriction.

A lattice dynamical treatment for the total potential energy of single-walled carbon nanotubes and its applications: relaxed equilibrium structure, elastic properties, and vibrational modes of ultra-narrow tubes

In this paper, we propose a lattice dynamic treatment for the total potential energy of single-walled carbon nanotubes (SWCNTs) which is, apart from a parameter for the nonlinear effects, extracted from the vibrational energy of the planar graphene sheet. The energetics, elasticity and lattice dynamics are treated in terms of the same set of force constants, independently of the tube structures. Based upon this proposal, we have investigated systematically the relaxed lattice configuration for narrow SWCNTs, the strain energy, the Young's modulus and Poisson ratio, and the lattice vibrational properties with respect to the relaxed equilibrium tubule structure. Our calculated results for various physical quantities are nicely in consistency with existing experimental measurements. In particular, we verified that the relaxation effect makes the bond length longer and the frequencies of various optical vibrational modes softer. Our calculation provides evidence that the Young's modulus of an armchair tube exceeds that of the planar graphene sheet, and that the large diameter limits of the Young's modulus and Poisson ratio are in agreement with the experimental values of graphite; the calculated radial breathing modes for ultra-narrow tubes with diameters ranging between 2 and 5 angstrom coincide with the experimental results and the existing ab initio calculations with satisfaction. For narrow tubes with a diameter of 20 angstrom, the calculated frequencies of optical modes in the tubule's tangential plane, as well as those of radial breathing modes, are also in good agreement with the experimental measurements. In addition, our calculation shows that various physical quantities of relaxed SWCNTs can actually be expanded in terms of the chiral angle defined for the corresponding ideal SWCNTs.

Static and dynamic degradation of sintered calcium phosphate ceramics

The chemical compositions of calcium phosphate materials are similar to that of bone making them very attractive for use in the repair of critical size bone defects. The bioresorption of calcium phosphate occurs principally by dissolution. To determine the impact of composition and flow conditions on dissolution rates, calcium phosphate tablets were prepared by slip casting of ceramic slips with different ratios of hydroxyapatite (HA) and ß-tricalcium phosphate (ß-TCP). Dissolution was evaluated at pH4 using both a static and dynamic flow regime. Both the composition of the HA:ß-TCP tablet and flow regime noticeably influenced the rate of dissolution; the 50:50 HA:ß-TCP composition demonstrating the greatest level of dissolution, and, exposure of the ceramic specimens to dynamic conditions producing the highest rate of dissolution. Understanding the impact of phase composition and flow condition with respect to the dissolution of calcium phosphate will aid in the development and improvement of materials for bone substitution.

Oral treatment of chickens with Lactobacillus reuteri LM1 reduces Brachyspira pilosicoli-induced pathology

Avian intestinal spirochaetosis (AIS) results from the colonization of the caeca and colon of poultry by pathogenic Brachyspira, notably Brachyspira pilosicoli. Following the ban on the use of antibiotic growth promoters in the European Union in 2006, the number of cases of AIS has increased, which, alongside emerging antimicrobial resistance in Brachyspira, has driven renewed interest in alternative intervention strategies. Lactobacillus-based probiotics have been shown to protect against infection with common enteric pathogens in livestock. Our previous studies have shown that Lactobacillus reuteri LM1 antagonizes aspects of the pathobiology of Brachyspira in vitro. Here, we showed that L. reuteri LM1 mitigates the clinical symptoms of AIS in chickens experimentally challenged with B. pilosicoli. Two groups of 15 commercial laying hens were challenged experimentally by oral gavage with B. pilosicoli B2904 at 18 weeks of age; one group received unsupplemented drinking water and the other received L. reuteri LM1 in drinking water from 1 week prior to challenge with Brachyspira and thereafter for the duration of the study. This treatment regime was protective. Specifically, B. pilosicoli was detected by culture in fewer birds, bird weights were higher, faecal moisture contents were significantly lower (P<0.05) and egg production as assessed by egg weight and faecal staining score was improved (P<0.05). Also, at post-mortem examination, significantly fewer B. pilosicoli were recovered from treated birds (P<0.05), with only mild–moderate histopathological changes observed. These data suggest that L. reuteri LM1 may be a useful tool in the control of AIS.

Peri-interventional antibiotic prophylaxis only vs continuous low-dose antibiotic treatment in patients with JJ stents: a prospective randomised trial analysing the effect on urinary tract infections and stent-related symptoms

To evaluate the antibiotic treatment regime in patients with indwelling JJ stents, the benefits and disadvantages of a peri-interventional antibiotic prophylaxis were compared with those of a continuous low-dose antibiotic treatment in a prospective randomised trial.

Dynamic decision-making based on NFR for managing software variability and configuration selection

Due to dynamic variability, identifying the specific conditions under which non-functional requirements (NFRs) are satisfied may be only possible at runtime. Therefore, it is necessary to consider the dynamic treatment of relevant information during the requirements specifications. The associated data can be gathered by monitoring the execution of the application and its underlying environment to support reasoning about how the current application configuration is fulfilling the established requirements. This paper presents a dynamic decision-making infrastructure to support both NFRs representation and monitoring, and to reason about the degree of satisfaction of NFRs during runtime. The infrastructure is composed of: (i) an extended feature model aligned with a domain-specific language for representing NFRs to be monitored at runtime; (ii) a monitoring infrastructure to continuously assess NFRs at runtime; and (iii) a exible decision-making process to select the best available configuration based on the satisfaction degree of the NRFs. The evaluation of the approach has shown that it is able to choose application configurations that well fit user NFRs based on runtime information. The evaluation also revealed that the proposed infrastructure provided consistent indicators regarding the best application configurations that fit user NFRs. Finally, a benefit of our approach is that it allows us to quantify the level of satisfaction with respect to NFRs specification.

Effect of broadcast baiting on abundance patterns of red imported fire ants (Hymenoptera: Formicidae) and key local ant genera at long-term monitoring sites in Brisbane, Australia

In 2001, the red imported fire ant (Solenopsis invicta Buren) was identified in Brisbane, Australia. An eradication program involving broadcast bait treatment with two insect growth regulators and a metabolic inhibitor began in September of that year and is currently ongoing. To gauge the impacts of these treatments on local ant populations, we examined long-term monitoring data and quantified abundance patterns of S. invicta and common local ant genera using a linear mixed-effects model. For S. invicta, presence in pitfalls reduced over time to zero on every site. Significantly higher numbers of S. invicta workers were collected on high-density polygyne sites, which took longer to disinfest compared with monogyne and low-density polygyne sites. For local ants, nine genus groups of the 10 most common genera analyzed either increased in abundance or showed no significant trend. Five of these genus groups were significantly less abundant at the start of monitoring on high-density polygyne sites compared with monogyne and low-density polygyne sites. The genus Pheidole significantly reduced in abundance over time, suggesting that it was affected by treatment efforts. These results demonstrate that the treatment regime used at the time successfully removed S. invicta from these sites in Brisbane, and that most local ant genera were not seriously impacted by the treatment. These results have important implications for current and future prophylactic treatment efforts, and suggest that native ants remain in treated areas to provide some biological resistance to S. invicta.

Effect of Broadcast Baiting on Abundance Patterns of Red Imported Fire Ants (Hymenoptera: Formicidae) and Key Local Ant Genera at Long-Term Monitoring Sites in Brisbane, Australia

In 2001, the red imported fire ant (Solenopsis invicta Buren) was identified in Brisbane, Australia. An eradication program involving broadcast bait treatment with two insect growth regulators and a metabolic inhibitor began in September of that year and is currently ongoing. To gauge the impacts of these treatments on local ant populations, we examined long-term monitoring data and quantified abundance patterns of S. invicta and common local ant genera using a linear mixed-effects model. For S. invicta, presence in pitfalls reduced over time to zero on every site. Significantly higher numbers of S. invicta workers were collected on high-density polygyne sites, which took longer to disinfest compared with monogyne and low-density polygyne sites. For local ants, nine genus groups of the 10 most common genera analyzed either increased in abundance or showed no significant trend. Five of these genus groups were significantly less abundant at the start of monitoring on high-density polygyne sites compared with monogyne and low-density polygyne sites. The genus Pheidole significantly reduced in abundance over time, suggesting that it was affected by treatment efforts. These results demonstrate that the treatment regime used at the time successfully removed S. invicta from these sites in Brisbane, and that most local ant genera were not seriously impacted by the treatment. These results have important implications for current and future prophylactic treatment efforts, and suggest that native ants remain in treated areas to provide some biological resistance to S. invicta.

Parenting a child with haemophilia while living in a non-metropolitan area

The experience of living in a non-metropolitan area and parenting a child with haemophilia is relatively unknown. Using Interpretive Phenomenological Analysis (IPA), the following study explored the experiences of seven parents, from which four themes emerged: ‘bearing the brunt of diagnosis’ captures the impact of the diagnosis; ‘if you can’t help me, who can?’ reveals experiences with the health system; ‘tackling the challenge of treatment’ encompasses difficulties in adhering to the treatment regime; ‘I need you to understand’ reflects desires for others support and understanding. These themes should be considered when developing support systems and interventions for parents living in non-metropolitan areas.

Analysis of the temperature-induced transition to current self-oscillations in doped GaAs/AlAs superlattices

We observed the decrease of the hysteresis effect and the transition from the stable to the dynamic domain regime in doped superlattices with increasing temperature. The current-voltage characteristics and the behaviours of the domain boundary are dominated by the temperature-dependent lineshape of the electric field dependence of the drift velocity (V(F)), As the peak-valley ratio in the V(F) curve decreases with increasing temperature, the hysteresis will diminish and temporal current self-oscillations will occur. The simulated calculation, which takes the difference in V(F) curves into consideration, gives a good agreement with the experimental results.

Biosensor-based detection of reduced sex hormone-binding globulin binding capacities in response to growth-promoter administrations

Growth-promoting agents are illicitly used during animal rearing processes and the detection of their use is limited by new compounds and dosing practices that limit the efficiency of current testing which is based on residue analysis by liquid chromatography–tandem mass spectrometry (LC–MS/MS) and gas chromatography–mass spectrometry (GC–MS) methodology. An alternative approach is to use indirect biological evidence as a screening tool to identify growth-promoter treated animals thus improving the effectiveness of residue testing through the targeted sampling of these animals. Sex hormone-binding globulin (SHBG) is a glycoprotein which binds and controls the levels of sex-hormones within the circulation. Using a biosensor assay based on measurement of binding to an immobilised 1a-dihydrotestosterone (1a-DHT) derivative, reduced SHBG binding capacities were detected in growth-promoter treated animals. During the course of a veal treatment regime based on repeated oestradiol benzoate, nortestosterone decanoate and dexamethasone administrations, treated male and female calves were shown to have significantly lower SHBG capacities. To assess the effectiveness of using SHBG binding capacities as a biomarker of treatment and to investigate the role of individual growth-promoter components to the SHBG capacity lowering effects, adult heifer animals were subjected to repeated doses of nortestosterone decanoate. These animals also demonstrated a reduction in SHBG capacity levels at Day 39 of the study, in contrast to oestradiol benzoate treated adult steers who were found to have unaltered levels. These findings suggest that the measurement of SHBG binding capacities using a biosensor assay has potential in the identification of illegally treated animals, particularly those exposed to androgens.