Recommendations on the calculation of confidence intervals for sequence symmetry analyses

Lund, Lars Christian; Hallas, Jesper

doi:10.1002/pds.5578

Cited by 2 publications

(4 citation statements)

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“…21,23,33 Next, we calculated an adjusted sequence ratio (aSR) with 95% confidence intervals (CIs) by dividing the cSR by the null-effect ratio. 34 To estimate the incidence rate of the gabapentin-LD prescribing cascade among all older adults initiating a gabapentinoid with PSSA, we calculated the difference in the number of patients between those initiating a LD after gabapentinoid initiation and those initiating a LD before gabapentinoid initiation and divided the result by the number of patients initiating a gabapentinoid between 2013 and 2019. We adjusted the estimated incidence rate by the length of the exposure window and presented it in terms of person-years.…”

Section: Discussionmentioning

confidence: 99%

“…The null‐effect sequence ratio has been previously described and represents an expected sequence ratio based on the probability of the sequencing of initiation of marker drugs after index drugs in the absence of a causal association 21,23,33 . Next, we calculated an adjusted sequence ratio (aSR) with 95% confidence intervals (CIs) by dividing the cSR by the null‐effect ratio 34 . To estimate the incidence rate of the gabapentin–LD prescribing cascade among all older adults initiating a gabapentinoid with PSSA, we calculated the difference in the number of patients between those initiating a LD after gabapentinoid initiation and those initiating a LD before gabapentinoid initiation and divided the result by the number of patients initiating a gabapentinoid between 2013 and 2019.…”

Section: Methodsmentioning

confidence: 99%

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Which older adults are at highest risk of prescribing cascades? A national study of the gabapentinoid–loop diuretic cascade

Growdon,

Jing,

Morris

et al. 2024

J American Geriatrics Society

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BackgroundPrescribing cascades are important contributors to polypharmacy. Little is known about which older adults are at highest risk of experiencing prescribing cascades. We explored which older veterans are at highest risk of the gabapentinoid (including gabapentin and pregabalin)–loop diuretic (LD) cascade, given the dramatic increase in gabapentinoid prescribing in recent years.MethodsUsing Veterans Affairs and Medicare claims data (2010–2019), we performed a prescription sequence symmetry analysis (PSSA) to assess loop diuretic initiation before and after gabapentinoid initiation among older veterans (≥66 years). To identify the cascade, we calculated the adjusted sequence ratio (aSR), which assesses the temporality of LD relative to gabapentinoid initiation. To explore high‐risk groups, we used multivariable logistic regression with prescribing order modeled as a binary dependent variable. We calculated adjusted odds ratios (aORs), measuring the extent to which factors are associated with one prescribing order versus another.ResultsOf 151,442 veterans who initiated a gabapentinoid, there were 1,981 patients who initiated a LD within 6 months after initiating a gabapentinoid compared to 1,599 patients who initiated a LD within 6 months before initiating a gabapentinoid. In the gabapentinoid–LD group, the mean age was 73 years, 98% were male, 13% were Black, 5% were Hispanic, and 80% were White. Patients in each group were similar across patient and health utilization factors (standardized mean difference <0.10 for all comparisons). The aSR was 1.23 (95% CI: 1.13, 1.34), strongly suggesting the cascade's presence. People age ≥85 years were less likely to have the cascade (compared to 66–74 years; aOR 0.74, 95% CI: 0.56–0.96), and people taking ≥10 medications were more likely to have the cascade (compared to 0–4 drugs; aOR 1.39, 95% CI: 1.07–1.82).ConclusionsAmong older adults, those who are younger and taking many medications may be at higher risk of the gabapentinoid–LD cascade, contributing to worsening polypharmacy and potential drug‐related harms. We did not identify strong predictors of this cascade, suggesting that prescribing cascade prevention efforts should be widespread rather than focused on specific subgroups.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Which older adults are at highest risk of prescribing cascades? A national study of the gabapentinoid–loop diuretic cascade

Growdon,

Jing,

Morris

et al. 2024

J American Geriatrics Society

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show abstract

“…We obtained 95% confidence intervals based on Jeffrey's interval for binomial proportions. 9 As the exposure-anchored SSA is susceptible to temporal prescribing trends for the outcome drug, we adjusted for such trends using null-effect SR adjustment. 10 As a sensitivity analysis, and to evaluate the robustness of our results, we repeated the analysis with shortened time windows of 90 and 180 days.…”

Section: Methodsmentioning

confidence: 99%

“…The SR estimates an incidence rate ratio, and ratios below one can be interpreted as protective effects. We obtained 95% confidence intervals based on Jeffrey's interval for binomial proportions 9 . As the exposure‐anchored SSA is susceptible to temporal prescribing trends for the outcome drug, we adjusted for such trends using null‐effect SR adjustment 10 .…”

Section: Methodsmentioning

confidence: 99%

A case for screening real‐world data for collateral drug benefits: Glucagon‐like peptide 1 receptor agonists and bile acid diarrhea

Rahbek

Lund

Hallas

2023

Pharmacoepidemiology and Drug

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PurposeCollateral drug benefits are hitherto unknown beneficial effects that might lead to repurposing of already marketed drugs. A randomized controlled trial has found liraglutide to be non‐inferior to colesevelam in reducing bile acid diarrhea. We hypothesized that this collateral drug benefit of liraglutide could have been detected using observational data.MethodsWe performed a sequence symmetry analysis (SSA). In the SSA, we indexed individuals on the date of the first prescription of GLP1‐RA and restricted the analysis to all individuals who had a first prescription of bile acid sequestrants between 365 days prior to until 365 days after the index date. Sequence ratios (SR), that is, the ratio between counts of persons initiating GLP1‐RA first versus last, were calculated, and 95% confidence intervals were obtained. We adjusted for prescribing trends using null‐effect SR adjustment.ResultsWe included 158 individuals, with a median age of 58 years. The trend‐adjusted SR was 0.96 (95% confidence interval 0.70–1.31). When stratifying on the type of GLP1‐RA (liraglutide or semaglutide), we found results compatible with the previous trial (SRliraglutide 0.75, 0.51–1.10 and SRsemagltuide 1.23, 0.80–1.89). Since BAS also can be used as a cholesterol lowering drug, we repeated the main analysis while excluded statin users, resulting in a stronger association (SR 0.56, 0.33–0.96).ConclusionUsing the SSA methodology, we obtained estimates of a collateral drug benefit that were compatible with trial results. These results support the use of epidemiological analyses of observational data as instrument for detecting collateral drug benefits.

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Recommendations on the calculation of confidence intervals for sequence symmetry analyses

Cited by 2 publications

References 15 publications

Which older adults are at highest risk of prescribing cascades? A national study of the gabapentinoid–loop diuretic cascade

Which older adults are at highest risk of prescribing cascades? A national study of the gabapentinoid–loop diuretic cascade

A case for screening real‐world data for collateral drug benefits: Glucagon‐like peptide 1 receptor agonists and bile acid diarrhea

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