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53-420: The CAM consists of a short and long form. The CAM short form assesses four features: 1. acute onset or fluctuating course, 2. inattention, 3. disorganized thinking, and 4. altered level of consciousness. The CAM-long form includes the short-form features and adds disorientation, memory impairment, perceptual disturbances, psychomotor agitation or retardation, and altered sleep-wake cycle. These features are based on

106-445: 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

159-548: 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

212-528: 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

265-522: 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

318-540: 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

371-545: A sensitivity of 82%, 95% CI 69-91%; and specificity of 99%, 95% CI 87-100%. A large high-quality STARD-compliant diagnostic randomized controlled trial published in 2019 comparing the CAM with the 4AT delirium detection tool found that the CAM had lower sensitivity than the 4AT, with the two tools showing similar specificity. Though some studies show good performance of the CAM in research settings, large scale studies of detection of delirium in real-world clinical practice show that

424-499: A study in several ways ‍ — ‍ in the observer-expectancy effect, the experimenter may subtly communicate their expectations for the outcome of the study to the participants, causing them to alter their behavior to conform to those expectations. Such observer bias effects are near-universal in human data interpretation under expectation and in the presence of imperfect cultural and methodological norms that promote or enforce objectivity. The classic example of experimenter bias

477-621: Is a form of scientific experiment used to control factors not under direct experimental control. Examples of RCTs are clinical trials that compare 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

530-412: 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

583-428: 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

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636-476: 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,

689-578: 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

742-438: 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

795-474: 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

848-437: 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

901-404: 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

954-410: 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

1007-404: 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. Observer-expectancy effect The observer-expectancy effect is a form of reactivity in which a researcher 's cognitive bias causes them to subconsciously influence

1060-480: Is that of " Clever Hans ", an Orlov Trotter horse claimed by his owner von Osten to be able to do arithmetic and other tasks. As a result of the large public interest in Clever Hans, philosopher and psychologist Carl Stumpf , along with his assistant Oskar Pfungst , investigated these claims. Ruling out simple fraud, Pfungst determined that the horse could answer correctly even when von Osten did not ask

1113-484: 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

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1166-414: 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

1219-507: 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

1272-506: 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

1325-423: The 9 features of delirium from DSM-III-R. Each feature is scored as present or absent. Delirium is considered present based on the CAM diagnostic algorithm: presence of (acute onset or fluctuating course -AND‐ inattention) ‐AND EITHER‐ (disorganized thinking or altered level of consciousness) (Table 1). Detailed training and scoring instructions are available here. In the original study, the 3-5-minute CAM assessment

1378-712: The CAM shows a lower sensitivity (as judged by positive score rates in relation to estimated delirium rates) of around 30-40%. The table below describes delirium assessment tools based on the CAM, their scoring, and available translations. Additional information (for example: administration and instrument validity) may be found here . CAM – Short All settings All settings All settings All settings All settings All settings All settings ICU Emergency Department Emergency Department Emergency Department Nursing Home Randomized controlled trial A randomized controlled trial (or randomized control trial ; RCT )

1431-543: 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

1484-558: 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

1537-429: 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

1590-439: 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

1643-423: The data collected from Group B. The researchers suggested that experimenters gave subtle but clear cues with which the subjects complied . Double blind techniques may be employed to combat bias by causing the experimenter and subject to be ignorant of which condition data flows from. It might be thought that, due to the central limit theorem of statistics, collecting more independent measurements will improve

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1696-618: 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

1749-499: 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

1802-519: 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

1855-536: 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

1908-511: 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

1961-525: 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

2014-666: The participants of an experiment. Confirmation bias can lead to the experimenter interpreting results incorrectly because of the tendency to look for information that conforms to their hypothesis, and overlook information that argues against it. It is a significant threat to a study's internal validity , and is therefore typically controlled using a double-blind experimental design . It may include conscious or unconscious influences on subject behavior including creation of demand characteristics that influence subjects, and altered or selective recording of experimental results themselves. The experimenter may introduce cognitive bias into

2067-493: 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

2120-482: The questioner in detail, and showed that as the horse's taps approached the right answer, the questioner's posture and facial expression changed in ways that were consistent with an increase in tension, which was released when the horse made the final, correct tap. This provided a cue that the horse had learned to use as a reinforced cue to stop tapping. Experimenter-bias also influences human subjects. As an example, researchers compared performance of two groups given

2173-413: The questions. However, the horse was unable to answer correctly when either it could not see the questioner, or if the questioner themselves was unaware of the correct answer: When von Osten knew the answers to the questions, Hans answered correctly 89% of the time. However, when von Osten did not know the answers, Hans guessed only 6% of questions correctly. Pfungst then proceeded to examine the behaviour of

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2226-446: 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

2279-666: 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

2332-439: 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

2385-424: The same task (rating portrait pictures and estimating how successful each individual was on a scale of −10 to 10), but with different experimenter expectations. In one group, ("Group A"), experimenters were told to expect positive ratings while in another group, ("Group B"), experimenters were told to expect negative ratings. Data collected from Group A was a significant and substantially more optimistic appraisal than

2438-575: 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

2491-440: 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

2544-442: 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

2597-404: 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

2650-501: 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

2703-596: 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

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2756-532: 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

2809-477: Was validated against a >90 minute assessment by reference standard geriatric psychiatrists using DSM-III-R, and found to have a sensitivity and specificity of 94-100% and 90-95%, respectively, for identification of delirium. In a systematic review of 7 high quality studies involving >1000 patients, CAM was found to have a sensitivity of 94%, 95% CI 91-97%; and specificity of 89%, 95% CI 85-94%. A 2013 systematic review of 22 studies involving >2400 patients found

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