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79-514: The unit's work involves randomized controlled trials , national surveillance programs and surveys and other research on maternal and infant health and care in the perinatal period (before, during and after birth). The early work of the NPEU in developing a register of perinatal trials and methods for synthesizing their results lay the foundations for the Cochrane Collaboration . The mission of

158-445: A mean cost of US$ 12 million per RCT. Nevertheless, the return on investment of RCTs may be high, in that the same study projected that the 28 RCTs produced a "net benefit to society at 10-years" of 46 times the cost of the trials program, based on evaluating a quality-adjusted life year as equal to the prevailing mean per capita gross domestic product . The conduct of an RCT takes several years until being published; thus, data

237-548: A lack of personal equipoise (e.g., a personal belief that an intervention is effective). Finally, Zelen's design , which has been used for some RCTs, randomizes subjects before they provide informed consent, which may be ethical for RCTs of screening and selected therapies, but is likely unethical "for most therapeutic trials." Although subjects almost always provide informed consent for their participation in an RCT, studies since 1982 have documented that RCT subjects may believe that they are certain to receive treatment that

316-499: A large sample population of non-smokers or non-drinkers in a particular occupation, the risk assessment may be biased towards finding a negative effect on health. A reduction in the potential for the occurrence and effect of confounding factors can be obtained by increasing the types and numbers of comparisons performed in an analysis. If measures or manipulations of core constructs are confounded (i.e. operational or procedural confounds exist), subgroup analysis may not reveal problems in

395-725: A national research institute by the Royal College of Obstetricians and Gynaecologists and the British Paediatric Association . The Department gave the unit the task of providing "information which can promote effective use of resources in the perinatal health services." From the beginning, the first NPEU Director, Iain Chalmers , was guided by the principles for evaluating effectiveness of health care described by Archie Cochrane in his book, Effectiveness and Efficiency: Random Reflections on Health Services . From its early days,

474-524: A prerequisite for publication. One way to classify RCTs is by study design . From most to least common in the healthcare literature, the major categories of RCT study designs are: An analysis of the 616 RCTs indexed in PubMed during December 2006 found that 78% were parallel-group trials, 16% were crossover, 2% were split-body, 2% were cluster, and 2% were factorial. RCTs can be classified as "explanatory" or "pragmatic." Explanatory RCTs test efficacy in

553-522: A procedure for a given study based on its advantages and disadvantages. This is a commonly used and intuitive procedure, similar to "repeated fair coin-tossing." Also known as "complete" or "unrestricted" randomization, it is robust against both selection and accidental biases. However, its main drawback is the possibility of imbalanced group sizes in small RCTs. It is therefore recommended only for RCTs with over 200 subjects. To balance group sizes in smaller RCTs, some form of "restricted" randomization

632-568: A register of trials in fertility as well as the basis for the development of the Cochrane Controlled Trials Register (CCTR) when the NPEU's Director left to establish the UK Cochrane Centre in 1992, from where the Cochrane Collaboration evolved in 1993. By 1989, the synthesis of the results of perinatal research led to the publication of major books. By 1990, ODPT included electronic syntheses called overviews, which were

711-540: A research setting with highly selected participants and under highly controlled conditions. In contrast, pragmatic RCTs (pRCTs) test effectiveness in everyday practice with relatively unselected participants and under flexible conditions; in this way, pragmatic RCTs can "inform decisions about practice." Another classification of RCTs categorizes them as "superiority trials", "noninferiority trials", and "equivalence trials", which differ in methodology and reporting. Most RCTs are superiority trials, in which one intervention

790-466: A trucking company owns a fleet of trucks made by two different manufacturers. Trucks made by one manufacturer are called "A Trucks" and trucks made by the other manufacturer are called "B Trucks." We want to find out whether A Trucks or B Trucks get better fuel economy. We measure fuel and miles driven for a month and calculate the MPG for each truck. We then run the appropriate analysis, which determines that there

869-459: Is a causal concept, and as such, cannot be described in terms of correlations or associations. The existence of confounders is an important quantitative explanation why correlation does not imply causation . Some notations are explicitly designed to identify the existence, possible existence, or non-existence of confounders in causal relationships between elements of a system. Confounders are threats to internal validity . Let's assume that

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948-473: Is a set of observed covariates that satisfies the Back-Door condition. Moreover, if Z is such a set, then the adjustment formula of Eq. (3) is valid. Pearl's do-calculus provides all possible conditions under which P ( y ∣ do ( x ) ) {\displaystyle P(y\mid {\text{do}}(x))} can be estimated, not necessarily by adjustment. According to Morabia (2011),

1027-405: Is a statistically significant trend that A Trucks are more fuel efficient than B Trucks. Upon further reflection, however, we also notice that A Trucks are more likely to be assigned highway routes, and B Trucks are more likely to be assigned city routes. This is a confounding variable. The confounding variable makes the results of the analysis unreliable. It is quite likely that we are just measuring

1106-550: Is always possible that a forgotten or unknown factor was not included or that factors interact complexly. Confounding by indication has been described as the most important limitation of observational studies. Randomized trials are not affected by confounding by indication due to random assignment . Confounding variables may also be categorised according to their source. The choice of measurement instrument (operational confound), situational characteristics (procedural confound), or inter-individual differences (person confound). Say one

1185-412: Is an important part of the scientific method . Reviewers examine the study results for potential problems with design that could lead to unreliable results (for example by creating a systematic bias ), evaluate the study in the context of related studies and other evidence, and evaluate whether the study can be reasonably considered to have proven its conclusions. To underscore the need for peer review and

1264-428: Is available, a placebo may be used in the control group so that participants are blinded to their treatment allocations. This blinding principle is ideally also extended as much as possible to other parties including researchers, technicians, data analysts, and evaluators. Effective blinding experimentally isolates the physiological effects of treatments from various psychological sources of bias . The randomness in

1343-476: Is best for them personally; that is, they do not understand the difference between research and treatment. Further research is necessary to determine the prevalence of and ways to address this " therapeutic misconception ". The RCT method variations may also create cultural effects that have not been well understood. For example, patients with terminal illness may join trials in the hope of being cured, even when treatments are unlikely to be successful. In 2004,

1422-399: Is called the Back-Door and requires that the chosen set Z "blocks" (or intercepts) every path between X and Y that contains an arrow into X. Such sets are called "Back-Door admissible" and may include variables which are not common causes of X and Y , but merely proxies thereof. Returning to the drug use example, since Z complies with the Back-Door requirement (i.e., it intercepts

1501-578: Is choosing a randomization procedure to generate an unpredictable sequence of allocations; this may be a simple random assignment of patients to any of the groups at equal probabilities, may be "restricted", or may be "adaptive." A second and more practical issue is allocation concealment , which refers to the stringent precautions taken to ensure that the group assignment of patients are not revealed prior to definitively allocating them to their respective groups. Non-random "systematic" methods of group assignment, such as alternating subjects between one group and

1580-438: Is designed well, conducted properly, and enrolls enough participants, an RCT may achieve sufficient control over these confounding factors to deliver a useful comparison of the treatments studied. An RCT in clinical research typically compares a proposed new treatment against an existing standard of care ; these are then termed the 'experimental' and 'control' treatments, respectively. When no such generally accepted treatment

1659-521: Is hypothesized to be superior to another in a statistically significant way. Some RCTs are noninferiority trials "to determine whether a new treatment is no worse than a reference treatment." Other RCTs are equivalence trials in which the hypothesis is that two interventions are indistinguishable from each other. The advantages of proper randomization in RCTs include: There are two processes involved in randomizing patients to different interventions. First

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1738-437: Is necessary to consider things other than design, such as heterogeneity, population, intervention or comparator. Two other lines of reasoning question RCTs' contribution to scientific knowledge beyond other types of studies: Like all statistical methods, RCTs are subject to both type I ("false positive") and type II ("false negative") statistical errors . Regarding Type I errors, a typical RCT will use 0.05 (i.e., 1 in 20) as

1817-403: Is on the study of smoking tobacco on human health. Smoking, drinking alcohol, and diet are lifestyle activities that are related. A risk assessment that looks at the effects of smoking but does not control for alcohol consumption or diet may overestimate the risk of smoking. Smoking and confounding are reviewed in occupational risk assessments such as the safety of coal mining. When there is not

1896-404: Is recommended that allocation concealment methods be included in an RCT's protocol , and that the allocation concealment methods should be reported in detail in a publication of an RCT's results; however, a 2005 study determined that most RCTs have unclear allocation concealment in their protocols, in their publications, or both. On the other hand, a 2008 study of 146 meta-analyses concluded that

1975-410: Is recommended. The major types of restricted randomization used in RCTs are: At least two types of "adaptive" randomization procedures have been used in RCTs, but much less frequently than simple or restricted randomization: "Allocation concealment" (defined as "the procedure for protecting the randomization process so that the treatment to be allocated is not known before the patient is entered into

2054-425: Is restricted from the medical community for long years and may be of less relevance at time of publication. It is costly to maintain RCTs for the years or decades that would be ideal for evaluating some interventions. Confounding factor In causal inference , a confounder is a variable that influences both the dependent variable and independent variable , causing a spurious association . Confounding

2133-433: Is studying the relation between birth order (1st child, 2nd child, etc.) and the presence of Down Syndrome in the child. In this scenario, maternal age would be a confounding variable: In risk assessments , factors such as age, gender, and educational levels often affect health status and so should be controlled. Beyond these factors, researchers may not consider or have access to data on other causal factors. An example

2212-436: Is the same as the association that would be measured in a controlled experiment , with x randomized . In principle, the defining equality P ( y ∣ do ( x ) ) = P ( y ∣ x ) {\displaystyle P(y\mid {\text{do}}(x))=P(y\mid x)} can be verified from the data generating model, assuming we have all the equations and probabilities associated with

2291-588: The Cochrane Collaboration . Beginning with a card file of references to perinatal trials and both manual and electronic searching for further trials, the NPEU developed first a book, the Classified Bibliography of Controlled Trials in Perinatal Medicine 1940–1984 , and then the Oxford Database of Perinatal Trials (ODPT). This process of developing a register of trials led to others establishing

2370-474: The International Committee of Medical Journal Editors (ICMJE) announced that all trials starting enrolment after July 1, 2005, must be registered prior to consideration for publication in one of the 12 member journals of the committee. However, trial registration may still occur late or not at all. Medical journals have been slow in adapting policies requiring mandatory clinical trial registration as

2449-414: The scientific literature . Not all RCTs are randomized controlled trials (and some of them could never be, as in cases where controls would be impractical or unethical to use). The term randomized controlled clinical trial is an alternative term used in clinical research; however, RCTs are also employed in other research areas, including many of the social sciences . The first reported clinical trial

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2528-507: The 1880s, and in education . The earliest experiments comparing treatment and control groups were published by Robert Woodworth and Edward Thorndike in 1901, and by John E. Coover and Frank Angell in 1907. In the early 20th century, randomized experiments appeared in agriculture, due to Jerzy Neyman and Ronald A. Fisher . Fisher's experimental research and his writings popularized randomized experiments. The first published Randomized Controlled Trial in medicine appeared in

2607-499: The 1948 paper entitled " Streptomycin treatment of pulmonary tuberculosis ", which described a Medical Research Council investigation. One of the authors of that paper was Austin Bradford Hill , who is credited as having conceived the modern RCT. Trial design was further influenced by the large-scale ISIS trials on heart attack treatments that were conducted in the 1980s. By the late 20th century, RCTs were recognized as

2686-399: The NPEU is "...to produce methodologically rigorous research evidence to improve the care provided to women and their families during pregnancy, childbirth, the newborn period and early childhood as well as promoting the effective use of resources by perinatal health services.” Since its inception, a key area of its activities has been undertaking and supporting randomized controlled trials of

2765-399: The NPEU was a leader in both randomized controlled trials to assess the effects of perinatal care, the retrieval of information, and the development and use of systematic reviews and meta-analyses to synthesize research results. The unit developed extensive national and international collaborations which were to form both the basis of its work and lay the foundations for the development of

2844-453: The adjustment set Z can introduce bias. A typical counterexample occurs when Z is a common effect of X and Y , a case in which Z is not a confounder (i.e., the null set is Back-door admissible) and adjusting for Z would create bias known as " collider bias" or " Berkson's paradox ." Controls that are not good confounders are sometimes called bad controls . In general, confounding can be controlled by adjustment if and only if there

2923-493: The analysis. Additionally, increasing the number of comparisons can create other problems (see multiple comparisons ). Peer review is a process that can assist in reducing instances of confounding, either before study implementation or after analysis has occurred. Peer review relies on collective expertise within a discipline to identify potential weaknesses in study design and analysis, including ways in which results may depend on confounding. Similarly, replication can test for

3002-543: The assessor or obtain an objective source of data for evaluation of outcomes." The types of statistical methods used in RCTs depend on the characteristics of the data and include: Regardless of the statistical methods used, important considerations in the analysis of RCT data include: The CONSORT 2010 Statement is "an evidence-based, minimum set of recommendations for reporting RCTs." The CONSORT 2010 checklist contains 25 items (many with sub-items) focusing on "individually randomised, two group, parallel trials" which are

3081-558: The assignment of participants to treatments reduces selection bias and allocation bias, balancing both known and unknown prognostic factors, in the assignment of treatments. Blinding reduces other forms of experimenter and subject biases . A well-blinded RCT is considered the gold standard for clinical trials. Blinded RCTs are commonly used to test the efficacy of medical interventions and may additionally provide information about adverse effects, such as drug reactions . A randomized controlled trial can provide compelling evidence that

3160-429: The assignments in order to reduce the bias. Although the principle of clinical equipoise ("genuine uncertainty within the expert medical community... about the preferred treatment") common to clinical trials has been applied to RCTs, the ethics of RCTs have special considerations. For one, it has been argued that equipoise itself is insufficient to justify RCTs. For another, "collective equipoise" can conflict with

3239-444: The confounding variable. Another choice is to quantify the amount of city driving and use that as a second independent variable. A third choice is to segment the study, first comparing MPG during city driving for all trucks, and then run a separate study comparing MPG during highway driving. Confounding is defined in terms of the data generating model. Let X be some independent variable , and Y some dependent variable . To estimate

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3318-406: The counterfactual language of Neyman (1935) and Rubin (1974). These were later supplemented by graphical criteria such as the Back-Door condition ( Pearl 1993; Greenland, Robins and Pearl 1999). Graphical criteria were shown to be formally equivalent to the counterfactual definition but more transparent to researchers relying on process models. In the case of risk assessments evaluating

3397-439: The danger of overgeneralizing conclusions, two Boston-area medical researchers performed a randomized controlled trial in which they randomly assigned either a parachute or an empty backpack to 23 volunteers who jumped from either a biplane or a helicopter. The study was able to accurately report that parachutes fail to reduce injury compared to empty backpacks. The key context that limited the general applicability of this conclusion

3476-415: The effect of X on Y , the statistician must suppress the effects of extraneous variables that influence both X and Y . We say that X and Y are confounded by some other variable Z whenever Z causally influences both X and Y . Let P ( y ∣ do ( x ) ) {\displaystyle P(y\mid {\text{do}}(x))} be the probability of event Y = y under

3555-418: The effects of drugs, surgical techniques, medical devices , diagnostic procedures , diets or other medical treatments. Participants who enroll in RCTs differ from one another in known and unknown ways that can influence study outcomes, and yet cannot be directly controlled. By randomly allocating participants among compared treatments, an RCT enables statistical control over these influences. Provided it

3634-734: The effects of perinatal care, now through the NPEU Clinical Trials Unit. The NPEU runs the UK Obstetric Surveillance System (UKOSS), which is a national system studying rare disorders of pregnancy. In 2011, the Policy Research Unit in Maternal Health and Care (PRUMC) was established at the NPEU. The NPEU was established in 1978 by the Department of Health at Oxford University , following a joint request for

3713-483: The equality P ( y ∣ do ( x ) ) = P ( y ∣ x ) {\displaystyle P(y\mid {\text{do}}(x))=P(y\mid x)} . Consider a researcher attempting to assess the effectiveness of drug X , from population data in which drug usage was a patient's choice. The data shows that gender ( Z ) influences a patient's choice of drug as well as their chances of recovery ( Y ). In this scenario, gender Z confounds

3792-449: The fact that highway driving results in better fuel economy than city driving. In statistics terms, the make of the truck is the independent variable, the fuel economy (MPG) is the dependent variable and the amount of city driving is the confounding variable. To fix this study, we have several choices. One is to randomize the truck assignments so that A trucks and B Trucks end up with equal amounts of city and highway driving. That eliminates

3871-601: The highest grade." However, a 2001 study published in Journal of the American Medical Association concluded that "discrepancies beyond chance do occur and differences in estimated magnitude of treatment effect are very common" between observational studies and RCTs. According to a 2014 (updated in 2024) Cochrane review, there is little evidence for significant effect differences between observational studies and randomized controlled trials. To evaluate differences it

3950-491: The highest-quality evidence available are: Notable RCTs with unexpected results that contributed to changes in clinical practice include: Many papers discuss the disadvantages of RCTs. Among the most frequently cited drawbacks are: RCTs can be expensive; one study found 28 Phase III RCTs funded by the National Institute of Neurological Disorders and Stroke prior to 2000 with a total cost of US$ 335 million, for

4029-519: The hypothesis being tested. This suggestion contrasted starkly with the prevalent Enlightenment -era attitude that scientific observation can only be objectively valid when undertaken by a well-educated, informed scientist. The first study recorded to have a blinded researcher was published in 1907 by W. H. R. Rivers and H. N. Webber to investigate the effects of caffeine. Randomized experiments first appeared in psychology , where they were introduced by Charles Sanders Peirce and Joseph Jastrow in

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4108-433: The hypothetical intervention X = x . X and Y are not confounded if and only if the following holds: for all values X = x and Y = y , where P ( y ∣ x ) {\displaystyle P(y\mid x)} is the conditional probability upon seeing X = x . Intuitively, this equality states that X and Y are not confounded whenever the observationally witnessed association between them

4187-562: The inability to control for variability of volunteers and human studies, confounding is a particular challenge. For these reasons, experiments offer a way to avoid most forms of confounding. In some disciplines, confounding is categorized into different types. In epidemiology , one type is "confounding by indication", which relates to confounding from observational studies . Because prognostic factors may influence treatment decisions (and bias estimates of treatment effects), controlling for known prognostic factors may reduce this problem, but it

4266-405: The magnitude and nature of risk to human health , it is important to control for confounding to isolate the effect of a particular hazard such as a food additive, pesticide , or new drug. For prospective studies, it is difficult to recruit and screen for volunteers with the same background (age, diet, education, geography, etc.), and in historical studies, there can be similar variability. Due to

4345-425: The model. This is done by simulating an intervention do ( X = x ) {\displaystyle {\text{do}}(X=x)} (see Bayesian network ) and checking whether the resulting probability of Y equals the conditional probability P ( y ∣ x ) {\displaystyle P(y\mid x)} . It turns out, however, that graph structure alone is sufficient for verifying

4424-526: The most common type of RCT. For other RCT study designs, " CONSORT extensions " have been published, some examples are: Two studies published in The New England Journal of Medicine in 2000 found that observational studies and RCTs overall produced similar results. The authors of the 2000 findings questioned the belief that "observational studies should not be used for defining evidence-based medical care" and that RCTs' results are "evidence of

4503-511: The null hypothesis in the respective statistical test . The failure to reject the null hypothesis would imply that the treatment shows no statistically significant effect on the treated in a given test. But as the sample size increases, the same RCT may be able to demonstrate a significant effect of the treatment, even if this effect is small. An RCT may be blinded, (also called "masked") by "procedures that prevent study participants, caregivers, or outcome assessors from knowing which intervention

4582-456: The one Back-Door path X ← Z → Y {\displaystyle X\leftarrow Z\rightarrow Y} ), the Back-Door adjustment formula is valid: In this way the physician can predict the likely effect of administering the drug from observational studies in which the conditional probabilities appearing on the right-hand side of the equation can be estimated by regression. Contrary to common beliefs, adding covariates to

4661-525: The other, can cause "limitless contamination possibilities" and can cause a breach of allocation concealment. However empirical evidence that adequate randomization changes outcomes relative to inadequate randomization has been difficult to detect. The treatment allocation is the desired proportion of patients in each treatment arm. An ideal randomization procedure would achieve the following goals: However, no single randomization procedure meets those goals in every circumstance, so researchers must select

4740-504: The precursor for the Cochrane Collaboration 's Cochrane Database of Systematic Reviews . In 2013, the NPEU was awarded a silver department Athena SWAN award for its commitment to advancing women's careers in science and medicine. Randomized controlled trials A randomized controlled trial (or randomized control trial ; RCT ) is a form of scientific experiment used to control factors not under direct experimental control. Examples of RCTs are clinical trials that compare

4819-490: The probability that the RCT will falsely find two equally effective treatments significantly different. Regarding Type II errors, despite the publication of a 1978 paper noting that the sample sizes of many "negative" RCTs were too small to make definitive conclusions about the negative results, by 2005-2006 a sizeable proportion of RCTs still had inaccurate or incompletely reported sample size calculations. Peer review of results

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4898-659: The relation between X and Y since Z is a cause of both X and Y : We have that because the observational quantity contains information about the correlation between X and Z , and the interventional quantity does not (since X is not correlated with Z in a randomized experiment). It can be shown that, in cases where only observational data is available, an unbiased estimate of the desired quantity P ( y ∣ do ( x ) ) {\displaystyle P(y\mid {\text{do}}(x))} , can be obtained by "adjusting" for all confounding factors, namely, conditioning on their various values and averaging

4977-719: The relationship between the environmental variables that possibly confound the analysis and the measured parameters can be studied. The information pertaining to environmental variables can then be used in site-specific models to identify residual variance that may be due to real effects. Depending on the type of study design in place, there are various ways to modify that design to actively exclude or control confounding variables: All these methods have their drawbacks: Artifacts are variables that should have been systematically varied, either within or across studies, but that were accidentally held constant. Artifacts are thus threats to external validity . Artifacts are factors that covary with

5056-406: The result. In the case of a single confounder Z , this leads to the "adjustment formula": which gives an unbiased estimate for the causal effect of X on Y . The same adjustment formula works when there are multiple confounders except, in this case, the choice of a set Z of variables that would guarantee unbiased estimates must be done with caution. The criterion for a proper choice of variables

5135-446: The results of RCTs with inadequate or unclear allocation concealment tended to be biased toward beneficial effects only if the RCTs' outcomes were subjective as opposed to objective . The number of treatment units (subjects or groups of subjects) assigned to control and treatment groups, affects an RCT's reliability. If the effect of the treatment is small, the number of treatment units in either group may be insufficient for rejecting

5214-666: The results of the study. Adequate allocation concealment should defeat patients and investigators from discovering treatment allocation once a study is underway and after the study has concluded. Treatment related side-effects or adverse events may be specific enough to reveal allocation to investigators or patients thereby introducing bias or influencing any subjective parameters collected by investigators or requested from subjects. Some standard methods of ensuring allocation concealment include sequentially numbered, opaque, sealed envelopes (SNOSE); sequentially numbered containers; pharmacy controlled randomization; and central randomization. It

5293-439: The results of unblinded RCTs tended to be biased toward beneficial effects only if the RCTs' outcomes were subjective as opposed to objective; for example, in an RCT of treatments for multiple sclerosis , unblinded neurologists (but not the blinded neurologists) felt that the treatments were beneficial. In pragmatic RCTs, although the participants and providers are often unblinded, it is "still desirable and often possible to blind

5372-481: The robustness of findings from one study under alternative study conditions or alternative analyses (e.g., controlling for potential confounds not identified in the initial study). Confounding effects may be less likely to occur and act similarly at multiple times and locations. In selecting study sites, the environment can be characterized in detail at the study sites to ensure sites are ecologically similar and therefore less likely to have confounding variables. Lastly,

5451-567: The standard method for "rational therapeutics" in medicine. As of 2004, more than 150,000 RCTs were in the Cochrane Library . To improve the reporting of RCTs in the medical literature, an international group of scientists and editors published Consolidated Standards of Reporting Trials (CONSORT) Statements in 1996, 2001 and 2010, and these have become widely accepted. Randomization is the process of assigning trial subjects to treatment or control groups using an element of chance to determine

5530-440: The study treatment causes an effect on human health. The terms "RCT" and "randomized trial" are sometimes used synonymously, but the latter term omits mention of controls and can therefore describe studies that compare multiple treatment groups with each other in the absence of a control group. Similarly, the initialism is sometimes expanded as "randomized clinical trial" or "randomized comparative trial", leading to ambiguity in

5609-442: The study") is important in RCTs. In practice, clinical investigators in RCTs often find it difficult to maintain impartiality. Stories abound of investigators holding up sealed envelopes to lights or ransacking offices to determine group assignments in order to dictate the assignment of their next patient. Such practices introduce selection bias and confounders (both of which should be minimized by randomization), possibly distorting

5688-437: The term "confounding" in causal inference by John Stuart Mill in 1843. Fisher introduced the word "confounding" in his 1935 book "The Design of Experiments" to refer specifically to a consequence of blocking (i.e., partitioning ) the set of treatment combinations in a factorial experiment , whereby certain interactions may be "confounded with blocks". This popularized the notion of confounding in statistics, although Fisher

5767-404: The terms "single-blind", "double-blind", and "triple-blind"; instead, reports of blinded RCT should discuss "If done, who was blinded after assignment to interventions (for example, participants, care providers, those assessing outcomes) and how." RCTs without blinding are referred to as "unblinded", "open", or (if the intervention is a medication) " open-label ". In 2008 a study concluded that

5846-440: The treatment and the outcome. Campbell and Stanley identify several artifacts. The major threats to internal validity are history, maturation, testing, instrumentation, statistical regression , selection, experimental mortality, and selection-history interactions. One way to minimize the influence of artifacts is to use a pretest-posttest control group design. Within this design, "groups of people who are initially equivalent (at

5925-455: The word confounding derives from the Medieval Latin verb "confundere", which meant "mixing", and was probably chosen to represent the confusion (from Latin: con=with + fusus=mix or fuse together) between the cause one wishes to assess and other causes that may affect the outcome and thus confuse, or stand in the way of the desired assessment. Greenland, Robins and Pearl note an early use of

6004-464: Was concerned with the control of heterogeneity in experimental units, not with causal inference. According to Vandenbroucke (2004) it was Kish who used the word "confounding" in the sense of "incomparability" of two or more groups (e.g., exposed and unexposed) in an observational study. Formal conditions defining what makes certain groups "comparable" and others "incomparable" were later developed in epidemiology by Greenland and Robins (1986) using

6083-491: Was conducted by James Lind in 1747 to identify a treatment for scurvy . The first blind experiment was conducted by the French Royal Commission on Animal Magnetism in 1784 to investigate the claims of mesmerism . An early essay advocating the blinding of researchers came from Claude Bernard in the latter half of the 19th century. Bernard recommended that the observer of an experiment should not have knowledge of

6162-596: Was received." Unlike allocation concealment, blinding is sometimes inappropriate or impossible to perform in an RCT; for example, if an RCT involves a treatment in which active participation of the patient is necessary (e.g., physical therapy ), participants cannot be blinded to the intervention. Traditionally, blinded RCTs have been classified as "single-blind", "double-blind", or "triple-blind"; however, in 2001 and 2006 two studies showed that these terms have different meanings for different people. The 2010 CONSORT Statement specifies that authors and editors should not use

6241-532: Was that the aircraft were parked on the ground, and participants had only jumped about two feet. RCTs are considered to be the most reliable form of scientific evidence in the hierarchy of evidence that influences healthcare policy and practice because RCTs reduce spurious causality and bias. Results of RCTs may be combined in systematic reviews which are increasingly being used in the conduct of evidence-based practice . Some examples of scientific organizations' considering RCTs or systematic reviews of RCTs to be

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