The last observation carried forward (LOCF) method is not suitable for processing the data for which of the following RCTs with intention to treat analysis?
D. In most drug trials, patients drop-out because of non-efficacy or adverse events. If we think that a number of participants drop-out because of non-efficacy, dropping them out of the analysis would project a favorable outcome for the drug in question. Hence the LOCF method takes the last observation and utilizes it in the analysis. For illustration, we take two subjects, in a trial of antidepressants.
Subject 1, improves significantly over the 4 weeks, his MADRS score has dropped to 1 from a baseline of 30, while Subject 2 dropped out of the study in the second week, due to non-efficacy. If we remove subject 2 from the analysis, the mean score at the end would be 1 (an whopping improvement of 29 points on the MADRS), while if we carry forward his last observation score (week 2) of 30 to the end and took the mean of the two scores (15.05), the drop is only 15 points from the mean baseline score of 30.
Trials of Alzheimer’s disease interventions are different, since we do not expect (although we most definitely would like to see) improvement in the cognitive score, but a rather slow decline in scores over time, in spite of the medications, due to the progressive nature of the illness. If a patient drops out early because of the experience of adverse effects, carrying forward his score to the endpoint analysis will falsely project a favorable outcome. Again to illustrate, let us consider a trial of cholinesterase inhibitors.
Subject 1 experienced a decline of 19 points over 4 weeks, while the second subject dropped out the fi rst week, when his MMSE had not declined. If we carry forward his last observation of 20, it will look like there was no deterioration at all, and the difference in the mean scores over time would be diluted to 10, rather than a drop of 19.
As a corollary, the reason for drop-out is another important issue. In trials of Alzheimer’s disease interventions, early drop-outs are most probably due to adverse effects, while late drop-outs are due to non-efficacy. This can again project a favorable outcome for the drug.
Reference:
All of the following measures can be used to decrease the heterogeneity in a meta-analysis except:
E. There are a number of ways to manage heterogeneity. The easiest way would be to avoid it. This includes using strict inclusion criteria to include studies that are as similar as possible. In case of continuous variables, one of the ways would be to transform the data so that all data look similar and are less heterogeneous. Meta regression is a collection of statistical procedures to assess heterogeneity, in which the effect size of study is regressed on one or several covariates, with a value defined for each study. The fixed-effect model of meta-analysis as reported in this question, considers the variability between the studies as exclusively due to random variation. The random-effects model assumes a different underlying effect for each study and takes this into consideration as an additional source of variation. The effects of the studies are assumed to be randomly distributed and the central point of this distribution is the focus of the combined (pooled) effect estimate. If there were some types of studies that were likely to be quite different from the others, a subgroup analysis may be done. And finally, one could exclude the studies that contribute a great deal to the heterogeneity. Locating unpublished studies may help reduce publication bias but will not have any predictable and constant effect on the degree of heterogeneity.
References:
Both odds ratios and relative risk are often used as outcome measures in published studies.
Which of the following statement is true regarding these measures?
C. Odds are the probability of an event occurring divided by the probability of the event not occurring. An odds ratio is the odds of the event in one group (e.g. intervention group) divided by the odds in another group (e.g. control group). Odds ratios tend to exaggerate the true relative risk to some degree. But this exaggeration is kept minimal and even negligible if the probability of the studied outcome is low (empirically, less than 10%); in such cases the odds ratio approximates the true relative risk. As the event becomes more common the odds ratio no longer remains a useful proxy for the relative risk. It is suggested that the use of odds ratios should probably be limited to case-control studies and logistic regression examining dichotomous variables. As risk refers to the probability of an event occurring at a time point, in other words it is the same as the incidence rate. The inherent cross-sectional nature of a case–control study (where ‘existing cases’ are recruited) does not allow one to study ‘new’ incidences. Hence we cannot measure risk, and so relative risk, from case–control designs.
Which one of the following clinical question can be correctly addressed by a case–control design?
E. Choice A refers to a clinical question related to therapeutic intervention – RCTs are best suited to answer this. Choice B is an epidemiological question – ‘how many in a population have a particular condition?’ A cross-sectional survey could answer this question. Choice C refers to a prognostic question – how long will it take for schizoaffective relapse following lithium discontinuation? A prospective cohort (or a RCT if ethically approved) is the most appropriate design for this question. Choice D requires a clinical audit, which is often closer to a cross-sectional survey in design. Choice E refers to defined cases and controls being compared for a possible exposure or risk factor that might have occurred in the past. Hence the case– control design is best suited to answer this question. Please note that it is possible to design a prospective cohort study by observing for a long time those with academic failure to detect development of depression.
A 50-year-old man sustained significant memory loss following near-fatal carbon monoxide poisoning. Following discussion he agreed to take part in a double-blinded trial of donepezil vs placebo administered in six separate 4-week modules with a 2-week washout period in between. Neuropsychological measures were obtained at regular pre-planned intervals to monitor changes. He was the sole subject on the trial and the randomization sequence was generated and maintained by the pharmacy.
This study design could be best described as:
B. N-of-1 trials are randomized double-blind multiple crossover comparisons of an active drug against placebo in a single patient. The design uses a series of pairs of treatment periods called modules. Within each module the patient receives active treatment during one period and either an accepted standard treatment or placebo in the other. Random allocation determines the order of the two treatment periods within each pair and both clinician and patient are blinded for the intervention. This design is mostly suited for chronic recurrent conditions for which long-term interventions exist that are not curative. Interventions with rapid onset and offset of effects are best suited for n-of-1 trials. This allows shorter treatment periods wherein multiple modules of intervention and placebo/standard treatment can be compared, increasing the chance of achieving a statistically significant result. It is also necessary that the interventions tested must be cleared from the patient’s system within a fi nite washout period.
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