Illustrating the use of marginal structural

models in health economic evaluation of

time-varying treatments
Contents
Chapter 1 - Introduction..............................................................................................................................3
1.1. Economic Evaluation........................................................................................................................3
1.2. Economic evaluation studies based on individual patient data..........................................................5
1.2.1 Costs and Clinical...........................................................................................................................5
1.3 Type of economic evaluation.............................................................................................................6
1.3.1 Cost-Effectiveness Analysis.......................................................................................................6
1.3.2 Cost Utility Analysis...................................................................................................................7
1.3.3 Cost Benefit Analysis.................................................................................................................8
1.4. potential issues with time-dependent confounding in econ evaluation:............................................8
1.5. The appropriateness of MSMs to deal with time-dependent confounding in econ evaluation studies
................................................................................................................................................................. 9
1.6. Potential challenges with the use of MSMs in economic evaluation studies.....................................9
1.7. Aims and objectives:.......................................................................................................................10
Chapter 2 – Methods for Literature Review..............................................................................................10
2.1 Background......................................................................................................................................10
2.2. Identification of Point-Exposure Effects.........................................................................................12
2.2.1 Targeted effects of time-varying exposure................................................................................12
2.2.2 A hypothetical cohort................................................................................................................13
2.3. Inverse Probability Weighting........................................................................................................13
2.4. Inclusion criteria.............................................................................................................................14
2.5. Search strategy................................................................................................................................14
Table 1...................................................................................................................................................15
2.5.1. Identifying Guidance:..................................................................................................................15
2.5.2. Extracting Data:...........................................................................................................................15
2.6. Data extraction................................................................................................................................16
2.7. Analytical Framework........................................................................................................................17
Chapter 3 Quality assessment of the reviewed studies...............................................................................17
Chapter 4 – Results....................................................................................................................................19
Chapter 5 – Discussion..............................................................................................................................21
References.................................................................................................................................................22
Chapter 1 - Introduction
1.1. Economic Evaluation 
Economic assessment assesses the effectiveness of interventions to improve health care and
health outcomes and the distribution of money. Economic evaluation not only refers to decisions
regarding treatments or programmes that affect patients directly, such as drug therapies and
medical devices, but also to decisions on methods of application, which are explicitly designed to
inform health care providers and patients of the best available evidence for study and to improve
their use in their procedures.
Some health-care inefficiencies result from the over-use of unnecessary facilities, under-
utilization or medical mistakes. Given growing concern about care quality and expenditure
constraints, implementation strategies are being used to improve the delivery of services and the
results. Potentially effective strategies to promote service delivery can be as simple as funding
for clinical decision-making, education and financial incentives – and can be as nuanced as
comprehensive quality management and health care system improvements.
Economic assessments can guide decision-making about the effectiveness and the application of
capital to implementation strategies — strategies that are explicitly designed to educate and
improve the use in their activities of the best available data from analysis. These techniques are
becoming more common in healthcare, in particular given the growing questions about quality of
treatment and budget constraints. However, these issues have not been prompted to invest upon
some form of economic assessment in evaluation of the implementation strategies by health
authorities and other policymakers.
In recent years, the economic assessment of health programmes, evidenced by an increase in
literature, has become more relevant. It now reflects an approved medical assessment instrument.
Studies should be conducted from the standpoint of individual health care patients, service
professionals or society collectively, and scholars in many diverse disciplines, including
psychologists, medical experts and physicians, are now undertaking those studies. In terms of
their expenditures and implications, economic assessments can be described as 'compare an
overview of alternative action processes.
It addresses two main areas: firstly, the effects and implications of the services and, secondly,
strategies for the resource distribution. Although both physicians and the general population
often remain cynical, economic assessment attempts to decide if money can better help.
Economic assessment.
 Any economic research includes calculating both the health gains and the costs. Two
primary questions need to be answered:
 Is it worth the health procedure relative to the other stuff that we can do with the same
resources?
Do we think the health services should be used in this manner instead of in some other direction?
The benefits can be categorized into health gains and other secondary advantages (e.g.
development gains). health benefits can be classified into benefits. The cost can be subdivided
into immediate care costs (for example, NHS charges), direct non-medical spending (for
example, family expenditures, social services) and indirect costs or losses of efficiency (for
instance, treatment-related adjustments such as time-offs and quicker returns to employment).
The word 'opportunity cost' or the expense of a resource in its appropriate alternative use is
especially significant, since analyses tend to equate opportunity cost with health benefit arising
from the treatment being studied.
It is necessary to consider the context to the definition and some of the terminology often used
by those interested in delivering and receiving medical treatment entirely. Healthcare cannot
advance without a strong economic study, and solutions to current or new services may be found
by carrying out comprehensive evaluations. The consistency of the empirical data supporting
such an assessment is now regarded as a necessary tool for economic research.
There are some significant variations in the economic value of health care as opposed to other
commodities. The market includes options, and it is presumed that decisions are taken after
sufficient knowledge has been supplied to the customer. However, people in the health sector
also do not or cannot obtain the knowledge needed to make this decision. The idea that the
person delivering the details is also the individual receiving the care, which does not normally
exist anywhere, complicates this.
The idea that it is done as a result of the belief that health care services are obtained and people
are not always actively involved in the utilization of health care systems is another aspect that
makes healthcare distinctive. Later on, dentistry will vary from the rest of the field of healthcare.
Health care and state organisations must determine how their services are used across a wide
variety of very different medical procedures. This means that it is impossible to judge the value
of such health countries. There have been a variety of claims in regards to 'need' for healthcare
and/or 'right' to service. Gold indicated that two tiers of administration would be the only rational
means of allocating money. The first should be responsible for taking large decision, such as the
amount of money dedicated to health care, depending on the current political system. The second
tier, composed of local groups with a variety of health-related concerns, will be active in policy
decision-making and advice development.

1.2. Economic evaluation studies based on individual patient data.

To order to coordinate the diagnosis and avoid all accidental and deliberate injury, economic
evaluation assumes an even larger position. Policy makers and politicians typically require
details on the efficacy of an initiative in comparison to the costs to determine the importance of
an effort for resources. A literature analysis found that few methodologically accurate and
equivalent trials in the area of accident reduction were performed.
1.2.1 Costs and Clinical
Recently, clinical trials, especially for small and medium-sized biotech firms, have become quite
complicated. Several considerations are concerned, including changes in prices and legislative
standards, though not restricted to them. The prices of clinical studies soared by about 100
percent from 2008 to 2019, according to Tomasz Babinski, CEO of Transparency Life Sciences.
A research released in JAMA Internal Medicine in 2018 showed that there was a more than 100-
fold gap in clinical trial costs in 138 primary trials testing 59 experimental therapies FDA
approved between 2015 and 2016. They also noticed that an approximate expense of $12,2
million to $33,1 million for a central cluster of trials was. The sector has seen a lot of
restructuring and the development of giant CROs in the last five years. The rise of these giant
CROs has significantly changed market
conditions, requiring drug companies to change
their way of dealing with CROs. In the
preparation and monitoring of seller trials the
funding firms will be more cautious and alert. A
fair estimation of the costs of clinical research
would therefore encourage the preparation of
outsourcing for both large and small
pharmaceutical firms. Therefore, it is important to gain good comprehension by the sourcing
departments of the various cost factors and expense requirements of a clinical trial.
1.3 Type of economic evaluation
1.3.1 Cost-Effectiveness Analysis
The economic analysis (CEA) is a form of economic analysis which compares the relative costs
and results (effects) of different actions. The study of cost-effectiveness is different from the
cost-benefit analysis that provides the calculation of effect monetary worth. Cost-effective
research is often utilized as a way of monetizing clinical outcomes in the area of health care
facilities. In addition, the CEA is calculated in reference to a measure's health benefit (years of
existence, premature births avoided, years of sight gained) and the counting scheme is the costs
correlated with the health gain.
The definition of economic efficiency is used for organizing and controlling several various
forms of coordinated action. In many aspects of life, it is widely used. For starters, rival designs
are contrasted in acquisitions of military tanks not only for the purchasing price, but also for
factors including their area of action, top speed, firing rate, armor shield and guns' caliber and
armor penetration. When tank efficiency in these areas is comparable or only marginally better
than that of its rival, but considerably lower and simpler to manufacture, therefore military
designers will opt to be cheaper than their rivals.
A tool used to help recommendations that are to be provided for medical treatment is a cost-
effectiveness study. It is a method of comparing two or more alternatives' cost and efficiency.
These contrasts become helpful where traditional treatment is one of the options, as this helps the
decision-maker to determine if progress is stronger than the status quo. The cost-effectiveness
study attempts to assess whether a response 's benefit reflects its price. Cost-effectiveness
requires more than expense estimation and benefit management (Soini et al., 2017).
From a social point of view, costs should be estimated. Not only will the overall cost of a
procedure, but also its effect on clinical care and expenses borne by patients be taken into
consideration in the results of an action on any level.
In order to reflect the lower economic value of a later expense and the higher value of the benefit
realized sooner, costs and benefits should have been reduced at a 3 % annual rate.
If cost / benefit results during the test phase are not completely understood, simulations will be
used to measure cost / benefit over the whole lifespan of the individual.
The Task Force developed criteria for assessing the cost-effectiveness results' statistical
relevance. Pleases keep in mind that differences in expense and performance coupled with
covariance can influence sample size while cost-effectiveness is a key research hypothesis.
1.3.2 Cost Utility Analysis
The cost utility analysis (CUA) is an economic analysis in which the incremental costs
of a particular program are compared with incremental health improvements in the quality-
adjusted life years’ unit (QALYs). The cost utility analysis is an economic analysis. CUA is used
to evaluate the rate, to tell the quantity and quality of life in terms of services. Cost-utility
analyses are used to compare two distinct drugs or procedures that can have different benefits,
different from the cost-benefit analysis. In relation to the single form of health result, CUA
communicates its value for energy. The ICER is generally represented as an extra QALY fee in
this situation (Sloan & Hsieh, 2017).
Improved recovery period as well as increases in standard of living are taken into consideration
with this strategy. A rise in the quality of life(QoE), in a scale from 0 (dead) to one (perfect
quality of life) is represented as a utility. The cost-benefit calculations of cumulative usage
require an expense to be measured to equivalent factors of certain clinical procedures (e.g.
surgery or mammography screening) for the cost to receive safety benefits from drug use. It thus
provides a broader context for assessing the value for money of the use of a certain drug.
1.3.3 Cost Benefit Analysis
CUA is a special case of CEA in which the ICER numerator is an expense factor and the
denominator is usually determined by way of a metric defined as a QALY. The use of healthcare
techniques accounts for both survival and quality of life in a QALY. The QALY's QoE variable
is calculated using a tool known as a health utility and is hence used for the term CEA study. As
QALY is used to measure the
survival and the QoE
advantages of a medical
technology, QALY can serve
as a common measure for
comparing the benefits that
vary widely (Sloan & Hsieh,
2017).
1.4. potential issues with time-dependent confounding in econ evaluation:
A time-dependent confounder in epidemiology: (1) a covariate that varies in time and (2) a
confounder which is correlated with both exposure and outcomes and thus does not mediate
between exposure and outcome. In certain cases, synchronized uncertainty serves as a mediator
and jeopardizes the legitimacy of outcomes.
In figure a, the key variable of exposure (treatment) is defined as time-related uncertainty, where
C is a time dependent confounder, Y is the experimental outcomes in a hypothetical longitudinal
trial. C is a confuser since it is at all times related to effect Y and counselling X. Although Ct=1
is related to Ct=0, Ct=1 is not affected by Xt=0 treatment before, and thus also does not serve as
a mediator for the interaction of Y and X0.
1.5. The appropriateness of MSMs to deal with time-dependent confounding in econ
evaluation studies
Marginal structural models are a subset of mathematical models used in epidemiological causal
inference. The question of time-dependent uncertainty is dealt with by these models when
assessing the efficacy of the treatments by reverse weighting of probability for diagnosis. For
example, CD4 lymphocyte is being used for indication, is affected by medication, and affects
survival in the analysis of the role of zidovudine in AIDS-related mortality. Time-dependent
confounders are usually strongly pronounced when extended to other treatments as dosing or
signal, such as body weight or test values like aminotransferase alanine or bilirubin
(Vandecandelaere et al., 2016).
Certain variables also impact the connection between diagnosis and result. For example, age may
complicate the connection between treatment and effect by having beta blocker effects look
lesser if the therapy is done with beta blockers and outcomes are the death after myocarditis
infarction and the treated group is older than the treated group. When a procedure is not
distributed arbitrarily or more commonly in experimental trials of sensitivity and effect, such as
participation in a randomized controlled study, uncertainty may be addressed in order to achieve
an objective estimation of the interaction of concern (Torres, 2020).
1.6. Potential challenges with the use of MSMs in economic evaluation studies
There are a number of pitfalls as below:
1. Marginal dynamic structures from inverse likelihood weighting should be distinguished;
2. A marginal structural model is an equation which shows pre-specified causal estimate
assumptions, whereas the reverse likelihood weighting exposure models are a restriction to the
estimated distribution.
3. As a median conceptual model and an application likelihood model with specific reasons (with
reverse chance weighting), misinterpretation will contribute to differential bias;
4. Inverse probability weighting uses the identity assumptions for the g-formula and may be used
when the expectations are met for marginal structural models, even if the formula cannot be used
by them when the models are saturated.
Although some of these problems have already been discussed, we are seeking to explore them
in a particular way. Before entering those subtleties, using simple work-up examples without
depending on computerized packs would be helpful to grant the rationale of specialized causal
methods for time-varying exposures. Nevertheless, compared to point-exposure situations, these
pedagogical representations of exposures differ over time, providing counterfactual evidence that
describes causal effects and underlying factors, are not always present. At least four reasonable
numerical explanations are ideal for testing, they are based on the external causal information.
1.7. Aims and objectives:
The aim of this research is to investigate whether and how MSMs are used in econ evaluation
studies.
Chapter 2 – Methods for Literature Review
2.1 Aims and Objectives of the Research
This research aims at reviewing and analyzing the utilization of Marginal Structure Models in
Economic Evaluations. Increasingly, epidemiologists come across nuanced clinical evidence that
differ sensitivity and uncertainty in the surveillance process. If a previous exposure impacts the
confusers of future exposures, it may need specific computational techniques to quantify their
impact, likely with structural models for focused impact as all confusers are calculated correctly.
One popular approach to estimate such effects is reverse probability weighting, which can be
cast as a marginal structural model in an unambiguous way. While the principle is obviously
straightforward and program is easy to execute, misunderstandings exist.
Of example, marginal structural models may be incorrectly assimilated with inverse weighting of
probabilities, a marginal structural model cannot differentiate causal parameters for the
probability of disclosure from a nuisance model, and hence the complexities of variable selection
and model design cannot be differentiated between such distinct forms. In view of the nature and
measurements of the test, we will provide an incremental example of the generalized
standardization (known as the g-formulation) and inverse likelihood weighting, as well as the
definition of marginal structural models, especially for time variations, providing that the causes
are defined (Sloan & Hsieh, 2017).
In attempting to say anything significant about a certain causal relationship between exposure
and outcome, counterfactual models are one of the most widely accepted epidemiological
approaches. A contrary methodology not only formalizes the vocabulary of cause and effect but
often contributes to the explosion in the development of innovative analytical approaches,
including likelihood values (i.e. the possibility of exposures depending on the confounders
measured) and regression model-based methods of estimation (i.e., average risk, and a
multivariable-adjusted outcome modelling).
As a tool to estimate the effects of these time-variating exposure, marginal structural models
were introduced in 2000. A marginal theoretical model, in particular, is an algorithm for
displaying pre-specified hypotheses on the predicted causal effects (i.e. causal estimates). Thanks
to the variety of works by Robins and Hernán and others, marginal structural models were
commonly applicable to longitudinally dependent data on intuitive theory and simple to use
applications.
The influence of the procedure from the impact of the confounder can be accurately
differentiated by several means, including test design approaches (e.g. randomized controlled
studies) and observational techniques. The only way to manage uncertainty are randomized
clinical experiments, because both established and unknown (unmeasured) deceptive variables
counteract it. Nevertheless, it is not sufficient to perform randomized clinical trials for all study
problems, including post-marketing treatments or non-modifiable risk factors tests. In bio
statistical and epidemiological literatures, the success of retrospective research brought
significant exposure to uncertainty.
Marginal structural models are a subset of mathematical models used in epidemiological causal
inference. While much of the literature on marginal structural modeling focuses on counteracts
and causal impact, counterfactuals may be inaccurate to describe marginal structural models.
Ideally, a contrast of what really happens to a person receiving a certain medication should be
inferred with the true causality impact of a procedure (or exposure), if (unlike the fact) an
equivalent care had been provided.
Marginal structural models (MSMs) are primarily observational and an essential mathematical
method proposed by Robins in order to respond to changing conditions. MSMs are mostly but
not solely observational. Such models expand the possible effects paradigm suggested by Rubin
to provide quantitative evidence. The inverse likelihood of care weighted estimator (IPTW) is
one of the most popular and logical methods of estimating MSM 's parameters. The IPTW
mechanism allows all simple and time-varying confounders to be controlled for.
A weighting method provides every unit under survey with a weight that suits its opposite
feature, based on its prior exposure level background, its baseline and its time-varying
confounders. The numerator is determined by the probability of exposure in the stabilized
weights depending on the history of the previous exposure level and only on the baseline
confuses. Stabilized and non-stabilized weights (with numerators equal to one), particularly in
the presence of clear correlations between covariate and care, are advised to minimize the
heterogeneity generated from the dominant subjects in a sample.
The weight of each observed unit at each point multiplies the history of past weights. If the
underlying presume of constant unit patient frequency, accurate model weight trends, sequential
positivity and no unmeasured confounders are kept, the IPTW produces a pseudo-population,
under which the care assignment is like randomised and time limits guarantee that the prior
patient leave no longer influences them.
2.2. Identification of Point-Exposure Effects
Since several epidemiologists are acquainted with a single point or point-exposure possible result
system, here we only review briefly: new readers with common principles and ratings can relate
to Part 1 of Causal Inference: What if or quick introductions. Suppose exposure Ai, Yi, coronary
illness, etc., and a collection of coverable Li (i.e. present / previous states of wellbeing, unsafe
conduct, social support) exposure I = 1, ..., n) was detected. These exposures must not be
identified.
In the same population at the differences scale, the average causal effect of Exposure A on
outcome Y may be defined in E [Y 1] – E[Y0], comparing counteracted expectations (or the
potential risk for a binary outcome) for Y 1 and Y0. Suppose a hypothesis of 1240 participants,
with an exposure A mild risks rise (cause risk gap of 13.7 percent) by E[Y1] = 0.532 and E[Y1]
= 8 30/1240 = 0.669. Remember that, while Yi 0 or Yi1 may be identified while Yi under the
actual exposure status Ai, in a counterfactual context, either E [Y 0] nor E [Y 1] cannot be
explicitly identified in the results.
2.2.1 Targeted effects of time-varying exposure
When an event changes over time, it can be redefined to clarify the previous description of
impact. Consider a simple 2-point case. The L1i baseline confounders are calculated at time 1,
after which A1i exposure is started; then 2 confounder collection L2i is taken, exposure is
transferred to A2i, and finally Yi effects are assessed. The data are thus (L1i, A1i, L2i, A2i, Yi),
I = 1, ..., n. Remember that A1 and A2 can be the same exposure (e.g., antihypertension start /
stop drugs) or specific concurrent exposure.
The potential effect of time-varying exposure can be determined by the combination of joint
exposure interference (A1i, A2i): let a1, a2 represent the potential outcome that will be observed
when the A1i and A2i rates of exposure were set to a1 and a2, respectively. We presume that 0
(non exposed) or 1 (revealed) is revealed at each point, leading to 4 distinct outcomes – Yi 0,0,
Yi 0,1, Yi 1,0 and Yi 1,1 for each person i. Any contrast between counterfactual expectations E
[Ya1, a2]; e.g., E[Y1,1] – E[Y0,0] may be defined in the average causal impact of the result of
exposure. E [Y 1,0] – E [Y 0,0] may also be called, defined as the "direct control effect of A1
when A2 sets at 0.
2.2.2 A hypothetical cohort
Take a hypothetical cohort with empty L1 for simplicity. The situation arises when A1 is
randomized at the baseline, but no adherence or another subsequent exposure occurs, or when the
cohort is limited on the basis of measured variables L1. In either case the following picture does
not affect the different L1 values so let's ignore the basic confounders adjustment in our picture.
Table includes data distribution in the conceptual population of (A1i, L2i, A2i, Yi) with a
possible result not observed Yi a1, a2 (a1, a2 = 0,1). As in Table, the Yi results observed are
consistent with Yi a1, a2, which means (A1i, A2i) = (a1, a2) (He et al., 2019).
2.3. Inverse Probability Weighting
Inverse probability weighting (inverse probability weighting) is a statistical technique used to
calculate statistics standardized for pseudo populations different to the data collected. The
experiments are popular in implementation for a particular sample group and target community
(goal group). Researchers can be discouraged from specifically sampling the target population
such as expense, time and ethics. An alternate architecture technique, e.g. stratified sampling, is
an answer to this issue. If correctly implemented, weighing will theoretically increase
performance and reduce unweighted estimators' distortions (Soini et al., 2017).
The Horvitz – Thompson medium estimator is one very early weighted estimator. If the
probability of sampling, from which the target population is derived, is known, the opposite of
this probability is used to weigh the results. This methodology has become popular within
different structures in other areas of statistics. Weighted probabilities and weighted prediction
methods, in particular, are available and the bulk of the estimates are extracted from weighted
likelihood densities. Such implementations codify the principle of certain statistics and
estimators, for example neglected relational structures, the uniform mortality ratio, and
coarsened data EM algorithms (McIntosh et al., 2019).
Researchers often try to use retrospective evidence to measure the effect on the health result of
ongoing care over time within the pre-specified range; e.g. "always exercise for a minimum of 30
minutes a day That spectrum can be reached by multiple effective approaches. They take
symbolic actions into account in this report. Those are particular cases of spontaneous dynamical
interventions; techniques in which care is arbitrarily taken from a dispersion, which can depend
on the history of a topic.
More broadly, it can be mentioned that "for a subject, treatment at intervals (k) randomly is
allocated from the observed distributor at the interval k between those subjects with the same
care and background of uncertainty in the retrospective sample and (ii) treatment within the pre-
specified range (k)" for The distribution of the examined empirical results relies on a generic
operation.
A representative intervention is a particular case of a spontaneous complex intervention and is
not a deterministic process, but may rely on the history of an issue. We demonstrate in this paper
that, by common and easy reverse probability Weighting (IPW) procedures for deterministic
static (i.e. 'non-random' and 'not dynamic') care interventions on discrete, time changing services,
the risks raised by representative intervention in a time-variant constant care can be reliably
calculated.
2.4. Inclusion criteria
Criteria for inclusion shall be the criteria of an article to be considered for selection in a literature review.
Any therapies must be contrasted with experiments included and Studies conducted in the last 5 years
must have been included.

2.5. Search strategy

The centralized review of literature is recognised as a critical element of the structural examination
process. It requires systematic research which aims to create a concise study identification report that
makes it clear to readers what has been done to identify studies and how the results of the review are
reflected in the relevant evidence.

Marginal Structural Model*OR Health Economic Evaluation* OR Evaluation*OR Time

varying models*
Inverse Probability Weighting* OR Strategy*OR Actions* OR Plan*
Time dependent cofounding * OR Time varying Evaluation * OR MSM
Table 1
Table 1 represents the search queries that were applied to search the related valuable literature.

2.5.1. Identifying Guidance:

There have been listed nine guide materials. These manuals guide numerous forms of evaluations,
including: evaluations of programmes, clinical policy reviews, standard study reviews, social science
reviews and guideline analysis. Although these guide manuals also contain more recommendations for
other forms of institutional evaluations, we have concentrated on the central and specified goals of these
manuals with respect to the search for literature. Table 1 outlines: the text rules, an audited edition, their
central emphasis and a bibliographical index for the key recommendations for literary study.

In addition to the guidelines, the authors attempted to assemble a supportive data base (hereinafter
referred to as "studies") which would lead to current search practises. The authors first identified studies
in that field from their experience and then systematically referenced key studies at each key stage of the
quest process. A citer chase was performed through Google Scholar (forward citation chasing) and the
bibliography of references in each report. A quest was carried out in August 2017 for PubMed using the
institutional analysis methodology list. Search words used were AND system methods(sib) and 586
search results were returned (literature quest*[Title / Abstract]).

2.5.2. Extracting Data:

The related parts (chapters) of the literature quest were read and read again for the purpose of identifying
the main methodological steps, in order to expose the tacit sequence of literary searches within each
guidance text. In the overall process by which detailed knowledge is published, we identify a major
procedural stage as a distinct phase, and measures are taken that will lead to a completed literary quest in
group.

A table with the same terminology as stated in each guideline document has been extracted to the Chapter
or section subheading for each methodological point. The lead author (CC) then reads and re-reads these
material and outlines the specifics of the paragraphs of the text referred to under the headings. This table
was then checked using similarities and parallels to define specific instruction agreements and regions.
Consensus on various criteria was used to advise the collection of 'main moves' in the literature review
process. After deciding the main steps of literary study, we read back and read the sections concerning the
quest for literature, pointing out detailed information about the analytical structure of the quest for
literature at each key point. In order to recognise all commonalities and areas of special clarification, the
instructions were read again, first document-by-paper, and subsequently, in all the aforementioned texts.

This literature review appears to show in systematic studies the nature of a common literature searches
method paradigm. We call this paradigm the "conventional solution," since nine separate guideline
documents tend to be standard conventions. The above results show eight main steps in the quest for
structural literature. These main stages are constantly recorded in the nine guidelines which indicate a
consensus in the systematic reviews on the key phases of the search for literature and thus the literature
process as a whole.

We indicate consensus on the use of methods of literature search. All guidance papers separate main and
secondary methods of search. The first literature search tool, cited in each guiding text, is systematically
the bibliographic database analysis. While the guidance consistently encourages the use of alternate
methods of examination, there is no evidence that the different guidelines on the documents coherent
procedure. This may represent variations in the central emphasis of each study, for instance in the
description of efficacy trials or qualitative studies ( Soini et al., 2017).

Eight of the nine recommendations apply to literature review purposes. The general assumption was that
the literature review should be exhaustive and accurate, with a view to reproducing the procedure in a
straightforward manner. While this interpretation is directly related to mitigating partiality in just three
articles, it is evident that the complete literature study requires a "not lacking valid studies."

This analysis involves more study to decide if the traditional approach is acceptable. The dates of
publication of recommendations underlying the traditional method which determine if the procedure of an
article for current systemic searches in literature remains true. It can also be helpful to determine the
desirability of using the same literature approach model for looking for the validity of proof that is
generally proposed for the assessment of intervening efficacy.

2.6. Data extraction

In the first step, our research question or the aim we have in the study will affect the parameters that we
will use to extract the data. Following our parameters, we then have to list down our studies in an
organized manner. We will discover various consistent definitions in the studies which we will analyse
later, it will help in us in making conclusions and findings in the study. Having an independent reviewer
in our study would benefit us as a standard practice. Moving towards the end of the process this study
consistently checks and verifies that it has been searching in the right direction which could lead us to the
answers for our research objectives in the study.

2.7. Analytical Framework

Paper identified

N=540

After duplicates removed

Articles excluded N=150
N=390

Full articles excluded N=280

Exclusion reason
After screening for title and
abstract Not related to economic evaluation N=180

Not an intervention N=30

N=110
Only qualitative results N=50

Not in recent 10 years N=20

 Study included for analyses

N=15

Chapter 3 Quality assessment of the reviewed studies

This study will include various case studies from the valuable literature. It will analyses state of
the art techniques and theories used in the literature. The results show that mainly a small subset
of samples with very unusual estimates were responsible of the large variability of the truncated
treatment effect estimator. In fact, this was usually attributed to a few highly prominent findings
and exceedingly disproportionate quantities occurring as a result of peculiar forms of practise at
the time of a case. Therefore, before disclosing the IPTW estimation of a marginal model
systemic it is important to evaluate the influence of individual observations. Such outliers may
lead to IPTW estimates that are far from the true effect and can even change the effect 's course
in serious cases.
In short, both the IPTW and the MSM parameters must be specifically defined in order to allow a
cause-related explanation of the calculation.
In order to learn dynamic treatment responses over time, electronic health records provide a rich
source of information for machine learning methods. However, the presence of time-dependent
confusion hamperes any direct estimation, where action depends on time variables related to the
result of interest. Inspired by marginal structural models, a group of methods used in
epidemiology for adapting propensity weighting for time-based confidence, a sequence to
sequence architecture is introduced to predict a patient's desired response to several treatments
that are planned. They show our network's ability to reliably learn impartial treatment response
from observer data – also under change in the policy of patient assignments, and efficiency
improvements over standards, using simulations of a state-of-the-art Pharmacokinetic
Pharmacodynamics (PK PD) tumor growth model (Ozen et al., 2017).
Although heart disease has been decreasing significantly since the 1960s, the leading cause for
death remains heart disease in the United States and geographical disparities have increased in
heart disease mortality. State-level socioeconomic characteristics may be significant contributors
to geographic disparities in heart disease mortality. The study examined the association among
working-age people aged 35–64 years among those of a 'working age' in the USA between a
national minimum wage and death rates for heart diseases over the federal minimum wage. The
federal and state minimum wage average, inflation-adjusted statistics have been gathered from
the legal datasets and CDC Wonder has been issued annual state heart disease-death rates.
Although traditional regression models have been used to date for most minimum wages and
health analyses, we used marginal structural models to allow for potential temporal uncertainty.
Quasi-experimental, residual longitudinal equations accounting for population, year, and year   ×
  year fixed effects calculated the correlation between changes in the state-level minimum wage
over the federal minimum wage and heart disease death rates. The rise of the state minimum
wage over the federal minimum wage in models for working age people (35–64 years) was on
average ~6 less coronary deaths per 100,000 or the rate of death from a state heart disease that
was 3.5% less a year (He et al., 2019).
The underlying assumptions of conditional exchangeability, consistency, no interference and
positivity should be maintained for true causal interpretation. Furthermore, the correct model
description of the two weighting and outcome models requires not only the correct terms of the
model but also the right parametric form (e.g. linear vs quadratic). Therefore, caution is needed
in interpreting the estimation of the influence of plumpy'nut on weight gain as solely causal and
we can only satisfy the limitations addressed earlier today.
Many of these limitations also apply to all other multivariable model estimation studies.
Nevertheless, it is also a valuable demonstration of how outcomes will adjust in the event that
the MSM has been wrongly defined. In this respect, the ultimate result is modified just
marginally (boundary without a positive effect) but the distortion was very small. In other
situations, however, the bias may alter the findings considerably, and many other contexts may
have implications for our methodological findings. For starters, forced expiration (FEV) in
chronic asthma is much lower than mild asthma in extreme asthma. The power of regular asthma
drugs (similar to ART) may have a greater effect than moderate asthma on improving serious
asthma and the slower pitch of FEV improvement for lower-value patients is thus steeper.
Therefore, in addition to regular treatment, any study using MSMs to research the effect of co-
medication on FEV improvement will need to keep this in mind (Sloan & Hsieh, 2017).
Chapter 4 – Results
This research highlights a specific situation in which misrepresentation of the MSM model can
occur and affect the resulting calculation. Provided that such a specification is meaningless in
true randomization, it might not be instantly clear to those who use MSMs for repetitive
measurements the importance of accounting for associated slope and intercepting. Additional
simulation studies that evaluate more sophisticated specifications and variances of the model,
mean square error and coverage are required, but our initial findings indicate that since there
appears to be no effect assessment interaction in MSM (outcome) models when the interaction
does not exist, it might be advisable if such a word exists when MSMs are adapted to
(Barbulescu et al., 2020).
Security networks in African countries are developing as a policy mechanism for poverty
reduction and food insecurity. Rain safety nets have increased household food safety and the
variety of children's diets and health is not well known in sub-Saharan Africa. This paper
discusses the case of the Productive Safety Net (PSNP) programme in Ethiopia and demonstrates
the impact of safety nets on household food security and child nutrition. Previous tests have
demonstrated inconclusively that household food safety and baby feeding have been improved.
These research used methodological methods that are accurate for selection errors but neglected
the consequences of time-varying confusers that may contribute to incomplete estimates.
Although the household status of food safety is both the eligibility requirement and a target result
of the Initiative, it is likely to be endogenous to quantify PSNP's causal effect on household food
safety and child welfare due to selective biases and time-different confusions. The objective of
this paper is therefore to (1) analyse the effects of PSNP on household food safety, frequency of
food, diversity of child diets and children's anthropometry through the use of an approach of
marginal structural modelling taking into account both the selection factor and time-diversion
confounders.
Results suggest that, considering their beneficial influence on frequency of baby meals, PSNP
has not increased household food shortage, child health and child anthropometric. The amount of
meals eaten by a child in a PSNP household participation resulted in a unit benefit of 0.308. The
programme will benefit from a nutrition-specific and nutrition-sensitive initiative and combined
with other sector-level programming’s as a result of food insecurity and undernutrition on
physical and mental growth, the intergeneration cycle of poverty and the creation of human
resources (Torres, 2020).
In addition, while the average bootstrap-based SE's are usually very similar to that of robust SE,
bootstrap may best indicate uncertainty in "bad" samples in unstopped IPTW estimators, where
observations with the most severe weights have often occurred during the time that the irregular
treatment patterns have been observed. The bootstrap is therefore advisable to estimate the
variance of IPTW estimators, although this can only be a modest improvement in variability
estimates for truncated IPTW estimators over robust SE estimators in many applications
(Karpouzas et al., 2020).
Furthermore, in our numerical simulation we supposed that the treatment model was correctly
described in our data analysis, as was the marginal structural model Cox. In fact, however, some
unsaturated models can be miss-specified and can thus contribute to expected causal effects. A
non-parametrically based MSM (NPMSM) approach has been developed in Neugebauer and van
der Laan (2007) that requires no proper parametric model specification, but a work model that
can be voluntarily mis-specified. The NPMSM can be attractive when the parametric model is
not correctly defined with enough detail. A comprehensive approach needs to be adopted by
sourcing departments when calculating product expense. Stakeholders from both divisions are
necessary to participate. Because of a dynamic regulatory system, such expense metrics will
easily be misunderstood if operating teams are not consulted. Estimating data storage expenses,
for example, is quite challenging. Today, data protection is the priority of regulatory authorities.
This costs a ton each data point, so the following variables may or may not affect this. Patients
are also asked to complete four or five questionnaires throughout the recruiting process. This
may be interpreted meaningfully or not, but it does prolong the process of patient recruitment
(Karpouzas et al., 2020).

Further drawback of both the techniques used in our models and the other literary techniques of
weight truncation or stabilisation is that in the event of a technically agreed breach of positivity
they cannot eliminate a bias. In this case, there are no unusual treatment patterns, so that the
truncated estimates have a similar bias to those of non-truncated weights. This limit will also
exist if the positive expectation, which is more common in small samples, is essentially broken.
Chapter 5 – Discussion
In the presence of time-dependent confounders, marginal models of structural COx were used to
approximate the causal impact of time-dependent treatment on the survival test. These methods
are based on the assumption of positivity, which states that the propensity values are null and nil.
In longitudinal studies, practical violations of this assumption are common, leading to extreme
weights that could lead to misconceptions. The most prevalent method to monitor extreme
weights to date is truncation which consists of replacing outlying weights with less extreme ones.
The application of the methods to the MACS shows that the bias-variance correction of the
weight truncation methods can be added to reduce the high variance of the IPTW figures.
However, we note that the disproportionate reduction in weight will skew the effects of the
calculation. Unlike the fixed-level approach for cutting weights and MSE-based methods by a
user-specified proxy, there are no arbitrary criteria to the suggested two-fold cross-validation
system and may be a more reliable and more data-adaptable approach therefore (Soini et al.,
2017).
Petersen et al. (2012) reviewed alternative approaches for dealing with the violation of positivity
systematically and pointed out that most of these approaches are the balance between
impartiality and proximity to the initial goal of inference. Alternatively, covariates which cause
the most extreme weights must be eliminated, practical treatment rules must be established based
on measurable trends or the population of interest must be redefined. Many of these alternative
approaches depend on changing the target to a more easily identifiable parameter, which may be
the only possible solution for serious or theoretical violations of positivity.
As a method to determine the magnitude of the positivity violation, the suggested and tested
parametric bootstrap for a point-treatment analysis has been advocated. The collaborative guided
maximum likelihood estimator (C-TMLE), in which the model for the treatment process was
chosen in a data fit to refine the MSE for the target parameter, was created by van der Laan and
Gruber (2010). Statesman and van der Laan (2010) expanded the C-TMLE estimator to time-to -
event data, and their output has been compared to alternative methods to estimate causal effects
in practise under optimistic assumptions.
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