In a blind or blinded experiment, information which may influence the participants of the experiment is withheld until after the experiment is complete. Good blinding can reduce or eliminate experimental biases that arise from a participants' expectations, observer's effect on the participants, observer bias, confirmation bias, and other sources. A blind can be imposed on any participant of an experiment, including subjects, researchers, technicians, data analysts, and evaluators. In some cases, while blinding would be useful, it is impossible or unethical. For example, it is not possible to blind a patient to their treatment in a physical therapy intervention. A good clinical protocol ensures that blinding is as effective as possible within ethical and practical constraints.
During the course of an experiment, a participant becomes unblinded if they deduce or otherwise obtain information that has been masked to them. For example, a patient who experiences a side effect may correctly guess their treatment, becoming unblinded. Unblinding is common in blinded experiments, particularly in pharmacological trials. In particular, trials on pain medication and antidepressants are poorly blinded. Unblinding that occurs before the conclusion of a study is a source of experimental error, as the bias that was eliminated by blinding is re-introduced. The CONSORT reporting guidelines recommend that all studies assess and report unblinding. In practice, very few studies do so. [1]
Blinding is an important tool of the scientific method, and is used in many fields of research. In some fields, such as medicine, it is considered essential. [2] In clinical research, a trial that is not a blinded trial is called an open trial.
The first known blind experiment was conducted by the French Royal Commission on Animal Magnetism in 1784 to investigate the claims of mesmerism as proposed by Charles d'Eslon, a former associate of Franz Mesmer. In the investigations, the researchers (physically) blindfolded mesmerists and asked them to identify objects that the experimenters had previously filled with "vital fluid". The subjects were unable to do so.[ citation needed ]
In 1817, the first blind experiment recorded to have occurred outside of a scientific setting compared the musical quality of a Stradivarius violin to one with a guitar-like design. A violinist played each instrument while a committee of scientists and musicians listened from another room so as to avoid prejudice. [3] [4]
An early example of a double-blind protocol was the Nuremberg salt test of 1835 performed by Friedrich Wilhelm von Hoven, Nuremberg's highest-ranking public health official, [5] as well as a close friend of Friedrich Schiller. [6] This trial contested the effectiveness of homeopathic dilution. [5]
In 1865, Claude Bernard published his Introduction to the Study of Experimental Medicine, which advocated for the blinding of researchers. [7] Bernard's recommendation that an experiment's observer should not know the hypothesis being tested contrasted starkly with the prevalent Enlightenment-era attitude that scientific observation can only be objectively valid when undertaken by a well-educated, informed scientist. [8] The first study recorded to have a blinded researcher was conducted in 1907 by W. H. R. Rivers and H. N. Webber to investigate the effects of caffeine. [9] The need to blind researchers became widely recognized in the mid-20th century. [10]
A number of biases are present when a study is insufficiently blinded. Patient-reported outcomes can be different if the patient is not blinded to their treatment. [11] Likewise, failure to blind researchers results in observer bias. [12] Unblinded data analysts may favor an analysis that supports their existing beliefs (confirmation bias). These biases are typically the result of subconscious influences, and are present even when study participants believe they are not influenced by them. [13]
In medical research, the terms single-blind, double-blind and triple-blind are commonly used to describe blinding. These terms describe experiments in which (respectively) one, two, or three parties are blinded to some information. Most often, single-blind studies blind patients to their treatment allocation, double-blind studies blind both patients and researchers to treatment allocations, and triple-blinded studies blind patients, researcher, and some other third party (such as a monitoring committee) to treatment allocations. However, the meaning of these terms can vary from study to study. [14]
CONSORT guidelines state that these terms should no longer be used because they are ambiguous. For instance, "double-blind" could mean that the data analysts and patients were blinded; or the patients and outcome assessors were blinded; or the patients and people offering the intervention were blinded, etc. The terms also fail to convey the information that was masked and the amount of unblinding that occurred. It is not sufficient to specify the number of parties that have been blinded. To describe an experiment's blinding, it is necessary to report who has been blinded to what information, and how well each blind succeeded. [15]
"Unblinding" occurs in a blinded experiment when information becomes available to one from whom it has been masked. In clinical studies, unblinding may occur unintentionally when a patient deduces their treatment group. Unblinding that occurs before the conclusion of an experiment is a source of bias. Some degree of premature unblinding is common in blinded experiments. [16] When a blind is imperfect, its success is judged on a spectrum with no blind (or complete failure of blinding) on one end, perfect blinding on the other, and poor or good blinding between. Thus, the common view of studies as blinded or unblinded is an example of a false dichotomy. [17]
Success of blinding is assessed by questioning study participants about information that has been masked to them (e.g. did the participant receive the drug or placebo?). In a perfectly blinded experiment, the responses should be consistent with no knowledge of the masked information. However, if unblinding has occurred, the responses will indicate the degree of unblinding. Since unblinding cannot be measured directly, but must be inferred from participants' responses, its measured value will depend on the nature of the questions asked. As a result, it is not possible to measure unblinding in a way that is completely objective. Nonetheless, it is still possible to make informed judgments about the quality of a blind. Poorly blinded studies rank above unblinded studies and below well-blinded studies in the hierarchy of evidence. [18]
Post-study unblinding is the release of masked data upon completion of a study. In clinical studies, post-study unblinding serves to inform subjects of their treatment allocation. Removing a blind upon completion of a study is never mandatory, but is typically performed as a courtesy to study participants. Unblinding that occurs after the conclusion of a study is not a source of bias, because data collection and analysis are both complete at this time. [19]
Premature unblinding is any unblinding that occurs before the conclusion of a study. In contrast with post-study unblinding, premature unblinding is a source of bias. A code-break procedure dictates when a subject should be unblinded prematurely. A code-break procedure should only allow for unblinding in cases of emergency. Unblinding that occurs in compliance with code-break procedure is strictly documented and reported. [20]
Premature unblinding may also occur when a participant infers from experimental conditions information that has been masked to them. A common cause for unblinding is the presence of side effects (or effects) in the treatment group. In pharmacological trials, premature unblinding can be reduced with the use of an active placebo, which conceals treatment allocation by ensuring the presence of side effects in both groups. [21] However, side effects are not the only cause of unblinding; any perceptible difference between the treatment and control groups can contribute to premature unblinding.[ citation needed ]
A problem arises in the assessment of blinding because asking subjects to guess masked information may prompt them to try to infer that information. Researchers speculate that this may contribute to premature unblinding. [22] Furthermore, it has been reported that some subjects of clinical trials attempt to determine if they have received an active treatment by gathering information on social media and message boards. While researchers counsel patients not to use social media to discuss clinical trials, their accounts are not monitored. This behavior is believed to be a source of unblinding. [23] CONSORT standards and good clinical practice guidelines recommend the reporting of all premature unblinding. [24] [25] In practice, unintentional unblinding is rarely reported. [1]
Bias due to poor blinding tends to favor the experimental group, resulting in inflated effect size and risk of false positives. [24] Success or failure of blinding is rarely reported or measured; it is implicitly assumed that experiments reported as "blind" are truly blind. [1] Critics have pointed out that without assessment and reporting, there is no way to know if a blind succeeded. This shortcoming is especially concerning given that even a small error in blinding can produce a statistically significant result in the absence of any real difference between test groups when a study is sufficiently powered (i.e. statistical significance is not robust to bias). As such, many statistically significant results in randomized controlled trials may be caused by error in blinding. [26] Some researchers have called for the mandatory assessment of blinding efficacy in clinical trials. [18]
Blinding is considered essential in medicine, [27] but is often difficult to achieve. For example, it is difficult to compare surgical and non-surgical interventions in blind trials. In some cases, sham surgery may be necessary for the blinding process. A good clinical protocol ensures that blinding is as effective as possible within ethical and practical constrains.
Studies of blinded pharmacological trials across widely varying domains find evidence of high levels of unblinding. Unblinding has been shown to affect both patients and clinicians. This evidence challenges the common assumption that blinding is highly effective in pharmacological trials. Unblinding has also been documented in clinical trials outside of pharmacology. [28]
A 2018 meta-analysis found that assessment of blinding was reported in only 23 out of 408 randomized controlled trials for chronic pain (5.6%). The study concluded upon analysis of pooled data that the overall quality of the blinding was poor, and the blinding was "not successful." Additionally, both pharmaceutical sponsorship and the presence of side effects were associated with lower rates of reporting assessment of blinding. [29]
Studies have found evidence of extensive unblinding in antidepressant trials: at least three-quarters of patients were able to correctly guess their treatment assignment. [30] Unblinding also occurs in clinicians. [31] Better blinding of patients and clinicians reduces effect size. Researchers concluded that unblinding inflates effect size in antidepressant trials. [32] [33] [34] Some researchers believe that antidepressants are not effective for the treatment of depression and only outperform placebos due to systematic error. These researchers argue that antidepressants are just active placebos. [35] [36]
While the possibility of blinded trials on acupuncture is controversial, a 2003 review of 47 randomized controlled trials found no fewer than four methods of blinding patients to acupuncture treatment: 1) superficial needling of true acupuncture points, 2) use of acupuncture points which are not indicated for the condition being treated, 3) insertion of needles outside of true acupuncture points, and 4) the use of placebo needles which are designed not to penetrate the skin. The authors concluded that there was "no clear association between type of sham intervention used and the results of the trials." [37]
A 2018 study on acupuncture which used needles that did not penetrate the skin as a sham treatment found that 68% of patients and 83% of acupuncturists correctly identified their group allocation. The authors concluded that the blinding had failed, but that more advanced placebos may someday offer the possibility of well-blinded studies in acupuncture. [38]
It is standard practice in physics to perform blinded data analysis. After data analysis is complete, one is allowed to unblind the data. A prior agreement to publish the data regardless of the results of the analysis may be made to prevent publication bias. [13]
Social science research is particularly prone to observer bias, so it is important in these fields to properly blind the researchers. In some cases, while blind experiments would be useful, they are impractical or unethical. Blinded data analysis can reduce bias, but is rarely used in social science research. [39]
In a police photo lineup, an officer shows a group of photos to a witness and asks the witness to identify the individual who committed the crime. Since the officer is typically aware of who the suspect is, they may (subconsciously or consciously) influence the witness to choose the individual that they believe committed the crime. There is a growing movement in law enforcement to move to a blind procedure in which the officer who shows the photos to the witness does not know who the suspect is. [40] [41]
Auditions for symphony orchestras take place behind a curtain so that the judges cannot see the performer. Blinding the judges to the gender of the performers has been shown to increase the hiring of women. [42] Blind tests can also be used to compare the quality of musical instruments. [43] [44]
Antidepressants are a class of medications used to treat major depressive disorder, anxiety disorders, chronic pain, and addiction.
A placebo can be roughly defined as a sham medical treatment. Common placebos include inert tablets, inert injections, sham surgery, and other procedures.
A randomized controlled trial 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 or other medical treatments.
Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments and known interventions that warrant further study and comparison. Clinical trials generate data on dosage, safety and efficacy. They are conducted only after they have received health authority/ethics committee approval in the country where approval of the therapy is sought. These authorities are responsible for vetting the risk/benefit ratio of the trial—their approval does not mean the therapy is 'safe' or effective, only that the trial may be conducted.
An open-label trial, or open trial, is a type of clinical trial in which information is not withheld from trial participants. In particular, both the researchers and participants know which treatment is being administered. This contrasts with a double-blinded trial, where information is withheld both from the researchers and the participants to reduce bias.
A scientific control is an experiment or observation designed to minimize the effects of variables other than the independent variable. This increases the reliability of the results, often through a comparison between control measurements and the other measurements. Scientific controls are a part of the scientific method.
Clinical study design is the formulation of trials and experiments, as well as observational studies in medical, clinical and other types of research involving human beings. The goal of a clinical study is to assess the safety, efficacy, and / or the mechanism of action of an investigational medicinal product (IMP) or procedure, or new drug or device that is in development, but potentially not yet approved by a health authority. It can also be to investigate a drug, device or procedure that has already been approved but is still in need of further investigation, typically with respect to long-term effects or cost-effectiveness.
In causal inference, a confounder is a variable that influences both the dependent variable and independent variable, causing a spurious association. Confounding 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.
Agomelatine, sold under the brand names Valdoxan and Thymanax, among others, is an atypical antidepressant most commonly used to treat major depressive disorder and generalized anxiety disorder. One review found that it is as effective as other antidepressants with similar discontinuation rates overall but fewer discontinuations due to side effects. Another review also found it was similarly effective to many other antidepressants.
In a randomized experiment, allocation concealment hides the sorting of trial participants into treatment groups so that this knowledge cannot be exploited. Adequate allocation concealment serves to prevent study participants from influencing treatment allocations for subjects. Studies with poor allocation concealment are prone to selection bias.
In natural and social science research, a protocol is most commonly a predefined procedural method in the design and implementation of an experiment. Protocols are written whenever it is desirable to standardize a laboratory method to ensure successful replication of results by others in the same laboratory or by other laboratories. Additionally, and by extension, protocols have the advantage of facilitating the assessment of experimental results through peer review. In addition to detailed procedures, equipment, and instruments, protocols will also contain study objectives, reasoning for experimental design, reasoning for chosen sample sizes, safety precautions, and how results were calculated and reported, including statistical analysis and any rules for predefining and documenting excluded data to avoid bias.
In homeopathy, arsenicum album (Arsenic. alb.) is a solution prepared by diluting aqueous arsenic trioxide generally until there is little amounts of Arsenic remaining in individual doses. It is used by homeopaths to treat a range of symptoms that include digestive disorders and, as an application of the Law of Similars, has been suggested by homeopathy as a treatment for arsenic poisoning. Since the arsenic oxide in a homeopathic preparation is normally non-existent, it is considered generally safe, although cases of arsenic poisoning from poorly prepared homeopathic treatments sold in India have been reported. When properly prepared, however, the extreme dilutions, typically to at least 1 in 1024, or 12C in homeopathic notation, mean that a pill would not contain even a molecule of the original arsenic used. While Anisur Khuda-Bukhsh's unblinded studies have claimed an effect on reducing arsenic toxicity, they do not recommend its large-scale use, and studies of homeopathic remedies have been shown to generally have problems that prevent them from being considered unambiguous evidence. There is no known mechanism for how arsenicum album could remove arsenic from a body, and there is insufficient evidence for it to be considered effective medicine (for any condition) by the scientific community.
Esketamine, also known as (S)-ketamine or S(+)-ketamine, is the S(+) enantiomer of ketamine. It is a dissociative hallucinogen drug used as a general anesthetic and as an antidepressant for treatment of depression. It is sold under the brand names Spravato, Ketanest, among others. Esketamine is the active enantiomer of ketamine in terms of NMDA receptor antagonism and is more potent than racemic ketamine.
The Jadad scale, sometimes known as Jadad scoring or the Oxford quality scoring system, is a procedure to assess the methodological quality of a clinical trial by objective criteria. It is named after Canadian-Colombian physician Alex Jadad who in 1996 described a system for allocating such trials a score of between zero and five (rigorous). It is the most widely used such assessment in the world, and as of 2022, its seminal paper has been cited in over 23,000 scientific works.
Placebo-controlled studies are a way of testing a medical therapy in which, in addition to a group of subjects that receives the treatment to be evaluated, a separate control group receives a sham "placebo" treatment which is specifically designed to have no real effect. Placebos are most commonly used in blinded trials, where subjects do not know whether they are receiving real or placebo treatment. Often, there is also a further "natural history" group that does not receive any treatment at all.
The Emperor's New Drugs – Exploding the Antidepressant Myth is a 2009 book by Irving Kirsch, arguing that the chemical imbalance theory of depression is wrong and that antidepressants have little or no direct effect on depression but, because of their common or serious side-effects, they are powerful active placebos.
Brilaroxazine, also known as oxaripiprazole, is an investigational atypical antipsychotic which is under development by Reviva Pharmaceuticals for the treatment of neuropsychiatric and inflammatory disorders. It has currently completed the first of two phase III clinical trials for schizophrenia. Reviva Pharmaceuticals also intends to investigate brilaroxazine for the treatment of bipolar disorder, major depressive disorder, attention deficit hyperactivity disorder (ADD/ADHD), psychosis/agitation associated with Alzheimer's disease, Parkinson's disease psychosis, as well as the inflammatory disorders pulmonary arterial hypertension (PAH), idiopathic pulmonary fibrosis (IPF), and psoriasis. The FDA granted brilaroxazine orphan drug designation for the treatment of PAH and IPF.
Dextromethorphan/bupropion (DXM/BUP), sold under the brand name Auvelity, is a combination medication for the treatment of major depressive disorder (MDD). Its active components are dextromethorphan (DXM) and bupropion. Patients who stayed on the medication had an average of 11% greater reduction in depressive symptoms than placebo in an FDA approval trial. It is taken as a tablet by mouth.
A code-break procedure is a set of rules which determine when planned unblinding should occur in a blinded experiment. FDA guidelines recommend that sponsors of blinded trials include a code-break procedure in their standard operating procedure. A code-break procedure should only allow a participant to be unblinded before the conclusion of a trial in the event of an emergency. Code-break usually refers to the unmasking of treatment allocation, but can refer to any form of unblinding.
Psychoplastogens are a group of small molecule drugs that produce rapid and sustained effects on neuronal structure and function, intended to manifest therapeutic benefit after a single administration. Several existing psychoplastogens have been identified and their therapeutic effects demonstrated; several are presently at various stages of development as medications including Ketamine, MDMA, Scopolamine, and the serotonergic psychedelics, including LSD, psilocin, DMT, and 5-MeO-DMT. Compounds of this sort are being explored as therapeutics for a variety of brain disorders including depression, addiction, and PTSD. The ability to rapidly promote neuronal changes via mechanisms of neuroplasticity was recently discovered as the common therapeutic activity and mechanism of action.
Shortly after the start of the Cold War [...] double-blind reviews became the norm for conducting scientific medical research, as well as the means by which peers evaluated scholarship, both in science and in history.
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