Confounding by Indication, Confounding Variables, Covariates, and Independent Variables: Knowing What These Terms Mean and When to Use Which Term.

The terms independent variables, covariates, confounding variables, and confounding by indication are often imprecisely used in the context of regression. Independent variables are the full set of variables whose influence on the outcome is studied. Covariates are the independent variables that are included not because they are of interest but because their influence on the outcome can be adjusted for, leaving a more precise understanding of how the single remaining independent variable influences the outcome. Confounding variables are variables that are associated with both independent variables and outcomes; so, the relationship identified between independent variables and outcomes may be due to the confounding variable rather than to the independent variable. Potential confounders should be identified, measured, and adjusted for in regression, just as other covariates are. Confounding by indication occurs when the presence of the independent variable is driven by the confounding variable. Confounding by indication is a special kind of confounding; a confounding variable is a special kind of covariate; and a covariate is a special kind of independent variable in regression analysis. These terms and concepts are explained with the help of examples.

Physical Exercise and Health, 5: Sedentary Time, Independent of Health-Related Physical Activity, as a Risk Factor for Adverse Physical Health and Mental Health Outcomes.

Medical and neuropsychiatric benefits associated with physical exercise and activity are well recognized. It is less well known that time spent in sedentary behaviors, such as television-viewing or sitting at a desk, are associated with adverse health outcomes even after taking into consideration health-related physical activity. Although sedentary behaviors have become common in daily life, people tend to substantially underestimate how sedentary they actually are. The average person spends nearly 10 hours per day in a sedentary state, during leisure activities or work; sedentariness is even greater in persons with major mental illness such as psychosis. This article explains what sedentariness is, why sedentary behaviors are common in daily life, and how sedentariness is defined and assessed. Sedentariness is an important concept in its own right; it is not merely an absence of health-related physical activity. Sedentariness is associated with adverse outcomes in children and adolescents, adults, and older adults. Examples are provided of associations between sedentariness and adverse medical outcomes such as the metabolic syndrome, cardiovascular disease, stroke, and all cause mortality. Examples are also provided of associations between sedentariness and adverse mental health outcomes such as anxiety, depression, and dementia. Importantly, the adverse associations are independent of health-related physical activity; however, higher levels of physical activity may attenuate or offset the adverse effects of sedentariness. It is hoped that this article will encourage readers to reduce sedentary behaviors with a view to improve long-term physical and mental health.

Physical Exercise and Health, 6: Sedentary Time, Independent of Health-Related Physical Activity, as a Risk Factor for Dementia in Older Adults.

Sedentary behaviors are leisurely behaviors that occur during waking hours performed while lying down or seated; examples are relaxing, conversing, using a smartphone, watching television, traveling in private or public transport, and thinking or working at a desk. Sedentary behaviors are common in everyday life; the average person spends 9-10 h/d sedentary. Findings from meta-analyses show that higher levels of physical activity are associated with a reduced risk of dementia and that near-absence of moderate to vigorous physical activity is associated with an increased risk of dementia. Sedentariness is a clearly defined construct that is more than just low levels of physical activity. Sedentariness, therefore, merits independent study. In this context, a recent cohort study, conducted in elderly subjects (mean age, 67 years) who were followed for a mean of 6.7 years, found that sedentariness, independent of current levels of moderate to vigorous physical activity, was associated in a dose-dependent fashion with the risk of incident dementia; the finding held true when reverse causation was addressed through the exclusion of subjects who developed dementia within 4 years of follow-up. The adjusted 10-year risk of dementia rose from about 8% with sedentariness at 10 h/d to about 23% with sedentariness at 15 h/d; the difference is clinically meaningful. Limitations of studies in the field are that residual confounding cannot be excluded, and that no randomized controlled trials exist upon which guidance may be based. Nevertheless, it could be prudent to decrease sedentary behaviors if only because these have also been associated with other adverse physical and mental health outcomes. Additional subjects explained in this article include reverse causation and how it may be dealt with during research design and data analysis, individual participant data meta-analysis, and making sense of results that are reported in terms of "per 1,000 person-years."

Physical Exercise and Health, 3: The Health Care Professional and Patient's Guide to Understanding What to Do, How, and Why-Part 1.

Physical activity and exercise are associated with important short- and long-term health benefits. It does not take much effort to reap these benefits; every little bit of activity counts, including activities that are performed as part of daily life. Everybody can exercise, even those with existing medical conditions, and even those with existing cardiac or orthopedic conditions; all that is necessary is to tailor the exercise to individual capacity with appropriate dos and don'ts. This article, addressed to health care professionals, their patients, and the general public, provides practical guidance on exercise, mostly in the form of points and short paragraphs, so that the reader can easily understand and assimilate what to do, how, and why. The article explains what the health benefits of exercise are; how much exercise one ideally needs to perform for optimal health outcomes; what targets to set for exercise; what effects exercise has on muscles, bones, and the heart; and how these effects are beneficial. The article offers suggestions on how to create time and opportunity for exercise, how to motivate oneself for exercise, and how to avoid boredom and discouragement. Most important of all, this article provides a detailed discussion on exercise-related risks, especially orthopedic risks, and how to avoid these risks. Protecting the knee joint from injury receives particular attention. Practical guidance on what to actually do appears in the next article in the series.

Physical Exercise and Health, 4: The Health Care Professional and Patient's Guide to Understanding What to Do, How, and Why-Part 2.

This article is the fourth in a series on physical exercise and health. The article addresses health care professionals, patients, and the public and provides practical guidance on how to exercise with emphasis on understanding what to do, how, and why. Subjects covered include how cardiorespiratory, muscle-strengthening, load-bearing, balancing, and other exercises benefit the heart, strengthen muscles and bones, improve balance and stability, and reduce the risk of falls and fractures while providing both current and long-term gains related to health, mobility, independence, and quality of life. Examples are provided for each type of exercise. Guidance is provided on how to perform the exercises, how to organize an exercise session from warming up and loosening exercises to cooling down and stretching exercises, what to do during different kinds of exercise sessions, how to organize sessions across the course of a week, at what level of exercise to start, how to gradually increase the intensity of exercise, what targets to aim for, and how to avoid exercise-related injury. The use of exercise equipment, interval training, long continuous exercise, isometric exercise, the role of the mind in exercise, and other subjects are briefly discussed. Model exercise sessions and model programs for the week are also presented. It is hoped that this series of articles will help readers change their attitudes toward exercise, start exercising, and benefit from longer and healthier lives.

Ketamine for Depression-Knowns, Unknowns, Possibilities, Barriers, and Opportunities.

This Viewpoint discusses ketamine and its new and experimentally investigated on- and off-label indications that span different medical disciplines.

Physical Exercise and Health, 1: An Overview of Terminology, Guidance, Benefits, and Risks.

Regular physical activity in any form is important for health; nevertheless, more than a quarter of adults and more than four-fifths of adolescents do not meet recommended thresholds for exercise. This article outlines the magnitude of the global problem. It discusses terms such as physical activity, aerobic exercise, muscle strengthening exercise, weight-bearing exercise, sitting time, and sedentariness. It presents and explains current guidance on physical activity, averaged across a week, for adults as well as special populations, including adolescents, the elderly, and pregnant women. It notes that immediate, short-term, and long-term benefits of exercise have been identified in thousands of randomized controlled trials (RCTs) and cohort studies, and pooled in hundreds of meta-analyses, for a wide range of neuropsychiatric and medical conditions. It explains the strengths and limitations of the RCT and cohort study data as well as explains how some of the limitations can and have been addressed. It demonstrates how the Bradford Hill criteria can be applied to support the credibility of the research findings. It outlines immediate as well as long-term risks associated with exercise, as well as factors associated with these risks. In summary, the benefits of exercise outweigh the harms, especially when exercise is performed in moderation and within the individual's comfort zone. Although any physical activity is better than none, individuals should attempt to reach the currently recommended thresholds for exercise. There is little additional benefit associated with exceeding the guidance, and there may be immediate as well as long-term risks associated with overexercising. Finally, sitting time and sedentariness are constructs that are independent of physical activity; greater sitting time and greater sedentariness are both associated with poorer health outcomes and should therefore be discouraged at the same time that physical activity is encouraged.

Physical Exercise and Health, 2: Benefits Associated With Different Levels and Patterns of Activity.

Physical activity and leisure time exercise are associated with well-documented health benefits. Cohort studies and meta-analyses of such studies show that the benefits of physical activity are dose-dependent, arise at even low levels of activity, improve sharply from low to higher levels of activity, peak at very high levels of activity, and plateau thereafter. The benefits are apparent regardless of how the activity is accrued, from vigorous movements in very short intervals during everyday activities across the course of a day to vigorous, "weekend warrior" exercise, accumulated mostly during 1-2 days in a week. An earlier article in this column discussed terminology, guidance, benefits, and risks in the context of exercise and health. This article states and explains the guidance about exercise for adults and for special populations such as the elderly, discusses general limitations of cohort studies, examines how many steps of walking a day suffice to improve health outcomes and at what level a ceiling is reached, considers at what speed these steps need to accrue, examines the benefits of exercise patterns such as vigorous intermittent lifestyle physical activity and weekend warrior workouts, discusses a study that examined different combinations of exercise, and explains the reasons behind the paradox that fitter persons need to perform apparently harder workouts to meet the exercise guidance. Some niche issues are also discussed, such as a role for isometric exercise, the use of caffeinated and energy beverages before exercise, the use of target heart rate as a measure of exercise intensity, how to grade an exercise session that varies in intensity, and the importance of load-bearing, stability, balancing, and flexibility exercises. It must be understood that exercise is a lifetime commitment that provides benefits that pills cannot. Health care professionals need to recommend activity and discourage sedentariness in all patients whom they see.

Prevalence and predictors of QTc prolongation in patients seen in a clozapine clinic in a real-world setting in Australia.

BACKGROUND: Many antipsychotic drugs have been associated with QTc prolongation, which is a risk factor for sudden death. We studied the prevalence and predictors of QTc prolongation in treatment-resistant schizophrenia patients who were receiving clozapine in a real-world setting. METHODS: Data were extracted from the records of all schizophrenia patients aged 18-65 years, enrolled in a clozapine clinic in metropolitan Australia during October 2020 to April 2022, for whom ECG data were available. RESULTS: There were 104 eligible patients. The mean age of the sample was 42 years. The sample was 56 % male. About a third of patients were receiving antipsychotic and antidepressant drugs in addition to clozapine. The mean (standard deviation) QTc was 437.0 (24.8) ms in men and 445.8 (28.5) ms in women. QTc prolongation was present in 36.5 % of the sample. In univariate analysis, higher heart rate and higher clozapine levels were significantly associated with QTc prolongation; in multivariable logistic regression analysis, nonsignificant statistical trends were observed for male sex, higher heart rate, and higher serum clozapine level. CONCLUSIONS: QTc prolongation may be common in schizophrenia patients who receive clozapine in real world settings; this is a matter of much concern. Potential predictors of QTc prolongation need to be identified and these predictors and their interactions require to be explored in studies with greater statistical power.

Real World Studies: What They Are and What They Are Not.

Patients are filtered by rigorously defined study selection criteria for recruitment into research; this is necessary to improve signal detection, improve internal validity, reduce study-related risks, and meet ethical standards. Research patients are assessed and managed in ways that differ from usual practice. So, neither patients nor the treatment environment resembles everyday patients treated in everyday practice. This diminishes the generalizability of study findings; that is, their external validity. There is, therefore, an increasing trend to conduct "real-world studies." In this context, "real-world patients" are those who are not filtered by restrictive study selection criteria, and "real-world settings" are those in which patients are managed with few study-related guidelines and restrictions. The elephant in the room is that the glamour associated with such real-world studies is an illusion. This is because real-world patients in one real-world setting can differ widely from real-world patients in another real-world setting. So, even in real-world studies, we can only generalize study findings to the population from which the sample was drawn and the setting in which the sample was managed. As a final note, many assessments in research, such as computerized or pen-and-paper neuropsychological tests, are not real-world measures as are, for example, measures of activities of daily living or quality of life.

Cholinesterase Inhibitors for Delusions and Hallucinations in Alzheimer Disease and Parkinson Disease: Questionably Significant Benefits.

Delusions and hallucinations are common in Alzheimer disease (AD) and Parkinson disease (PD), especially in the later stages of illness. Antipsychotic drugs are effective in treating these psychotic symptoms but are associated with an increased risk of serious adverse events, including mortality. There is therefore a need to explore other treatment approaches. In this context, a recent individual patient data meta-analysis of 17 randomized controlled trials (RCTs) conducted in AD (12 RCTs) and PD (5 RCTs) found that the cholinesterase inhibitor (ChEI) drugs donepezil, rivastigmine, and galantamine attenuated the severity of both delusions and hallucinations in both AD and PD. Most of these trials were 24 weeks in duration. The effect sizes, expressed as standardized mean differences (SMDs), were, however, small, lying in the -0.08 to -0.14 range. These values are so small as to be perhaps clinically insignificant. When analyses were restricted to data from patients who actually had delusions and hallucinations at baseline, all effect sizes became larger, lying in the -0.13 to -0.39 range; however, after correcting for multiple hypothesis testing, only the finding for delusions in PD remained statistically significant. The meta-analysis did not provide information on what the best doses were, how long it took for improvement to become evident, and what proportion of patients showed remission from psychotic symptoms. Whereas the signal identified in this meta-analysis merits examination in appropriately designed RCTs, the findings of the meta-analysis may not much change current treatment strategies because patients with dementia would probably anyway receive a ChEI. Therefore, if psychotic symptoms persist for 24 weeks despite optimally dosed ChEI treatment, and if behavioral and psychosocial interventions do not help, clinicians may need to consider the potential benefits vs risks of other drugs, such as atypical antipsychotics and pimavanserin, in a shared decision-making process.

How to Use Percentiles to Better Understand Standardized Mean Difference (SMD) as a Measure of Effect Size.

The standardized mean difference (SMD) is the difference between the means of a variable, expressed not in its original unit but in the unit of standard deviation (SD). SMDs of 0.2, 0.5, and 0.8 are conventionally considered to be small, medium, and large, respectively. The reader, however, obtains no real world understanding of an SMD from these adjectives. This article suggests a solution: SMDs and their 95% confidence intervals can be better understood if they are converted into percentile scores. The procedure is explained, step by step, with reference to a meta-analysis that found that cholinesterase inhibitors (ChEIs) significantly attenuated delusions and hallucinations in Alzheimer disease and Parkinson disease with SMDs that ranged from -0.08 to -0.14. After conversion of these SMDs to percentile scores, the reader is shown that the average patient in the ChEI treatment arms would have improved by just 3 to 7 percentile places relative to the average patient in the placebo arms. So, whereas the findings were statistically significant, they would perhaps be so small as to be clinically unobservable in the average patient. All that the reader needs to do to convert an SMD into a percentile score is to locate a table that presents area under the normal curve, understand how the table presents what it does, look up the SMD value in the table, and obtain the percentile score from the value in the table. The entire procedure is very easily understood and takes less than a minute, starting from locating the table through an online search to obtaining the percentile score for the SMD.