Ratio Sequence Research Articles

Evaluating the Associated Hyperuricemia Risk with Sodium-Glucose Cotransporter 2 Inhibitors: A Sequence Symmetry Analysis Using the Japanese Administrative Claims Database.

Hyperuricemia is defined as high uric acid levels within the bloodstream and is commonly associated with gout, type 2 diabetes mellitus, and kidney disease. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are novel drugs that prevent glucose reabsorption; additionally, this drug has shown promising results in patients at risk of developing cardiovascular or renal complications by lowering uric acid levels. This study aimed to investigate the association between SGLT2i and hyperuricemia. Here, a self-controlled sequence symmetry analysis using the JMDC administrative claims database (January 2005 to September 2022) consisting of 12396 patients, who were newly prescribed both SGLT2i and hypouricemic agents, was conducted. Trend-adjusted sequence ratios (SR) at intervals of 6, 12, 18, and 24 months were calculated. Significant inverse signals across all intervals were observed between SGLT2i and hypouricemic agents, with the strongest effect observed in the 24-month interval [adjusted SR 0.52 (95% CI 0.49-0.55)]. Significant inverse signals were observed for each of the six types of SGLT2i across all intervals. This indicates that SGLT2i initiation may be associated with a decreased risk of hyperuricemia. Further investigation of the efficacy of SGLT2i is needed in hypothesis-testing designs such as cohort studies.

Signal detection of drugs associated with obstructive and central sleep apnoea

We aim to discover new safety signals of drug-induced sleep apnoea (SA), a global health problem affecting approximately 1 billion people worldwide.We first conducted a series of sequence symmetry analyses (SSA) in a cohort composed from all patients who received a first SA diagnosis or treatment between 2006 and 2018 in the Echantillon Généraliste des Bénéficaires (EGB), a random sample of the French healthcare database. We used two primary outcomes to estimate the sequence ratio (SR) for all drug classes available in France: a sensitive one (diagnosis or treatment of SA) and a specific one (Positive Airway Pressure (PAP) therapy). We then performed disproportionality analyses using the “Bayesian neural network method” on all cases of sleep apnoea (MedDRA high level term) reported up to November 2023 in the World Health Organisation (WHO) pharmacovigilance database.Among the 728,167 individuals, 46,193 had an incident diagnosis or treatment for SA and 17,080 had started an incident treatment by PAP therapy. Fifty-eight drug classes had a significant SR, with 7 considered highly plausible: opium alkaloids and derivatives, benzodiazepine derivatives, other centrally acting agents, other anxiolytics, carbamic acid esters, quinine and derivatives and antivertigo preparations; with consistent signals found for the first 3 drug classes in the disproportionality analysis.In this signal detection study, we found that opioids, benzodiazepines (but not Z-drugs) and myorelaxing agents are associated with the onset or aggravation of SA. Moreover, a new safety signal for antivertigo preparations such as betahistine emerged and needs to be further explored.

Is the sequence ratio an unbiased estimate of the incidence rate ratio? A simulation study.

We aimed to evaluate the conditions under which the sequence ratio (SR) obtained from a sequence symmetry analysis is an unbiased estimate of the true incidence rate ratio (IRR). We simulated cohorts of 1 million individuals who could initiate an exposure drug and experience a very rare, rare, common, or frequent outcome of interest. The outcome rate among exposed individuals was modified by a true incidence rate ratio of 0.2, 0.5, 1.0, 2.0, and 5.0. We further evaluated scenarios where the outcome was fatal and led to immediate censoring or the outcome reduced the rate of initiation of the exposure drug. We found the SR to be close to unbiased for rare, common, and frequent events, except when the true IRR was 5.0 (mean SR 4.94 and 3.74 for common and frequent events). The SR was slightly biased when the outcome was very rare. When the outcome was potentially fatal, the SR was increasingly biased with an increasing probability of death. Likewise, when the outcome reduced the probability of future exposure, the SR was upwards biased. The SR is a biased estimate of the incidence rate ratio, when the true IRR is high, the outcome has a high mortality, or when the outcome reduces the probability of future exposure.

Abstract P106: High-throughput Sequence Symmetry Analysis To Detect Angiotensin-receptor Blockers (arb) Induced Prescribing Cascades.

Introduction: ARBs are considered first-line antiHTN therapy, but side effects may prompt additional therapy resulting in prescribing cascades. We sought to screen for potential ARB-induced prescribing cascades during real-world use via high-throughput sequence symmetry analysis. Methods: Using claims from 5% (2011-15) and 15% (2016-20) samples of Medicare fee-for-service beneficiaries we identified new ARB users aged ≥66 years who had continuous enrollment for ≥360 days pre- and ≥180 days post-ARB initiation. We screened for initiation of 446 other ‘marker’ drug classes (based on WHO Anatomical Therapeutic Classification level 4 codes) within ±90 days of ARB initiation, generating sequence ratios (SRs) representing proportions of ARB initiators starting the marker class after, compared to before, the ARB. Adjusted SRs (aSRs), accounting for prescribing trends over time, were calculated with 95% CIs >1 considered statistically significant. Results: We identified 278,586 ARB initiators (mean ± SD age, 76.3 ± 7.3 years; 63% women, 92% hypertension). Of 446 ‘marker’ classes studied, and excluding other antihypertensive classes, we discovered 49 statistically significant signals indicative of potential prescribing cascades. The 30 strongest prescribing cascade signals by aSR are summarized (Figure), and included iron trivalent medications and H. pylori treatments. Conclusion: We identified potential prescribing cascade signals reflecting known as well as potentially underrecognized ARB adverse events in this Medicare cohort. Future work is needed to assess biologic plausibility and determine impact of these cascades on patient outcomes.

Abstract P105: High-throughput Sequence Symmetry Analysis To Detect Angiotensin-converting Enzyme Inhibitors (acei) Induced Prescribing Cascades.

Introduction: ACEIs are the most commonly prescribed antiHTN drugs, but side effects may prompt additional therapy resulting in a prescribing cascade. We aimed to identify potential ACEI-induced prescribing cascades using high throughput sequence symmetry analysis. Methods: Using claims from 5% (2011-15) and 15% (2016-20) national samples of Medicare FFS beneficiaries, we identified new ACEI users aged ≥66 y with continuous enrollment for ≥360 days pre- and ≥180 days post-ACEI initiation. We screened for initiation of 446 other ‘marker’ drug classes (based on WHO Anatomical Therapeutic Classification level 4 codes) within ±90 days of ACE initiation, generating sequence ratios (SRs) representing the proportions of ACEI initiators starting the marker class after, vs before, the ACEI. Adjusted SRs (aSRs), accounting for prescribing trends over time, were calculated with 95% CIs >1 considered statistically significant. Results: We identified 297,410 ACEI initiators (mean ± SD age, 76.1 ± 7.5 y; 59% women, 88% HTN). Of 446 ‘marker’ classes studied, and excluding other antiHTN classes, we identified 110 statistically significant signals indicative of potential prescribing cascades. The 30 strongest prescribing cascade signals (by aSR) are summarized (Figure) and included decongestant nasal preparations and monoamine oxidase B inhibitors. Conclusion: We identified potential prescribing cascade signals reflecting known and possibly underrecognized ACEI adverse events in this Medicare cohort. Additional research is needed to determine impact of these cascades on patient outcomes.

Abstract P107: High-throughput Screening Detects Thiazide-induced Prescribing Cascades.

Introduction: Thiazide diuretics are effective but can cause adverse effects that prompt the use of additional therapy, i.e., a prescribing cascade. We aimed to identify potential thiazide-induced prescribing cascades using high throughput sequence symmetry analysis. Methods: Using claims from 5% (2011-15) and 15% (2016-20) samples of Medicare fee-for-service beneficiaries we identified new thiazide users aged ≥66 years who had continuous enrollment for ≥360 days pre- and ≥180 days post-thiazide initiation. We screened for the initiation of 446 other ‘marker’ drug classes (based on WHO Anatomical Therapeutic Classification level 4 codes) within ±90 days of thiazide initiation, generating sequence ratios (SRs) representing the proportion of thiazide initiators starting the marker class after, compared to before, the thiazide. Adjusted SRs (aSRs), accounting for prescribing trends over time, were calculated with 95% CIs >1 suggesting a prescribing cascade signal. Results: We identified unique 189,971 thiazide initiators (mean ± SD age 76.2 ± 7.4 years, 66% women, 90% with hypertension). Among 446 ‘marker’ classes analyzed, we identified 21 statistically significant prescribing cascade signals (Figure). The 2 strongest prescribing cascade signals were carbohydrates and electrolyte solutions. Conclusion: Among 446 classes, we identified 21 possible prescribing cascades in our Medicare population, which may impact patient care outcomes. Further investigation is required to determine the biological plausibility of these signals.

Detecting Suspected Prescribing Cascades by Prescription Sequence Symmetry Analysis of Nationwide Real-World Data

A prescription cascade is a subsequent event that occurs when an adverse drug event is misinterpreted as a new medical condition, resulting in the prescription of a potentially unnecessary medication to treat this new condition. This study was designed to test the hypothesis of whether prescribing cascades exist and their magnitude among older individuals by using prescription sequence symmetry analysis (PSSA). A retrospective population-based cohort study based on data from Taiwan's National Health Insurance Research Database (NHIRD), a nationwide claims-based database that covers 99% of the population in Taiwan. Patients receiving newly initiated index and marker drugs in the outpatient setting between 2014 and 2016 were included. Those who received index and marker drugs on the same date were excluded. PSSA measures the propensity for a marker drug (eg, thyroxine) to be prescribed after an index drug (eg, amiodarone) has been initiated, where the index drug is suspected of inducing a side effect (eg, hypothyroidism) and the marker drug is used to treat the side effect. We evaluated 14 PSSA sets as potential prescription cascade-related drug pairs (index and marker drug), including 2 confirmatory analyses (eg, amiodarone and thyroxin), to check the validity of the PSSA results and 12 exploratory analyses of cardiovascular medication-related prescribing cascades (eg, statins and antidepressants). The observation periods for sequences of incident marker drug use were 1year before and 1year after the use of the incident index drug, and the symmetry of prescriptions filled for the 2 periods was examined. The results of the PSSA were performed as the crude sequence ratio (SR), defined as the ratio of patients initiating the marker drug after the index drug (causal group) to those initiating the marker drug before the index drug (noncausal group), and the adjusted SR (aSR) with 95% confidence intervals (CIs). Among 12 potential prescription cascade-related drug pairs in exploratory analysis, 9 of them reached statistical significance, and aSR ranged from 1.02 to 1.46. Dihydropyridine calcium channel blocker-induced edema showed the highest aSR (1.46, 95% CI 1.45-1.48), and statin-induced muscle pain showed the lowest aSR (1.02, 95% CI 1.02-1.03). Our study supported the application of PSSA in detecting prescribing cascades using a nationwide claims database. Nevertheless, most previously reported prescribing cascades among cardiovascular medications were shown to have a low effect size of sequence ratios among older individuals.

Repurposing haloperidol for the treatment of rheumatoid arthritis: an integrative approach using data mining techniques

Introduction:Treatment of rheumatoid arthritis (RA) has advanced with the introduction of biological disease-modifying antirheumatic drugs. However, more than 20% of patients with RA still have moderate or severe disease activity. Hence, novel antirheumatic drugs are required. Recently, drug repurposing, a process of identifying new indications for existing drugs, has received great attention. Furthermore, a few reports have shown that antipsychotics are capable of affecting several cytokines that are also modulated by existing antirheumatic drugs. Therefore, we investigated the association between antipsychotics and RA by data mining using real-world data and bioinformatics databases.Methods:Disproportionality and sequence symmetry analyses were employed to identify the associations between the investigational drugs and RA using the US Food and Drug Administration Adverse Event Reporting System (2004–2016) and JMDC administrative claims database (January 2005–April 2017; JMDC Inc., Tokyo, Japan), respectively. The reporting odds ratio (ROR) and information component (IC) were used in the disproportionality analysis to indicate a signal. The adjusted sequence ratio (SR) was used in the sequence symmetry analysis to indicate a signal. The bioinformatics analysis suite, BaseSpace Correlation Engine (Illumina, CA, USA) was employed to explore the molecular mechanisms associated with the potential candidates identified by the drug-repurposing approach.Results:A potential inverse association between the antipsychotic haloperidol and RA, which exhibited significant inverse signals with ROR, IC, and adjusted SR, was found. Furthermore, the results suggested that haloperidol may exert antirheumatic effects by modulating various signaling pathways, including cytokine and chemokine signaling, major histocompatibility complex class-II antigen presentation, and Toll-like receptor cascade pathways.Conclusion:Our drug-repurposing approach using data mining techniques identified haloperidol as a potential antirheumatic drug candidate.

Metabolic events associated with the use of antipsychotics in children, adolescents and young adults: a multinational sequence symmetry study.

It is known that younger patients treated with antipsychotics are at increased risk of metabolic events; however, it is unknown how this risk varies according to ethnicity, the class of antipsychotic and the specific product used, and by age group. We conducted a multinational sequence symmetry study in Asian populations (Hong Kong, Japan, Korea, Taiwan and Thailand) and non-Asian populations (Australia and Denmark) to evaluate the metabolic events associated with antipsychotics in both Asian and non-Asian populations, for typical and atypical antipsychotics, and by the subgroups of children and adolescents, and young adults. Patients aged 6-30years newly initiating oral antipsychotic drugs were included. We defined a composite outcome for metabolic events which included dyslipidemia, hypertension and hyperglycemia. We calculated the sequence ratio (SR) by dividing the number of people for whom a medicine for one of the outcome events was initiated within a 12-month period after antipsychotic initiation by the number before antipsychotic initiation. This study included 346,904 antipsychotic initiators across seven countries. Antipsychotic use was associated with an increased risk of composite metabolic events with a pooled adjusted SR (ASR) of 1.22 (95% CI 1.00-1.50). Pooled ASRs were similar between Asian (ASR, 1.22; 95% CI 0.88-1.70) and non-Asian populations (ASR, 1.22; 95% CI 1.04-1.43). The pooled ASR for typical and atypical antipsychotics was 0.98 (95% CI 0.85-1.12) and 1.24 (95% CI 0.97-1.59), respectively. No difference was observed in the relative effect in children and adolescents compared to young adults. The risk of metabolic events associated with antipsychotics use was similar in magnitude in Asian and non-Asian populations despite the marked difference in drug utilization patterns.

Association Between Antipsychotics and Osteoporosis Based on Real-World Data.

Osteoporosis, which is a major public health concern, has been known to reduce health-related quality of life. Some studies have suggested that antipsychotics could perhaps cause osteoporosis by increasing serum prolactin levels. However, the association between antipsychotics and the risk for developing osteoporosis has been controversial. The present study aimed to assess the association between antipsychotic use and onset of osteoporosis in real-world settings. A multimethod data-mining approach using different algorithms and databases was used. First, disproportionality analysis was conducted using the US Food and Drug Administration Adverse Event Reporting System (FAERS) database (2004-2017) with reporting odds ratio (ROR) and information component (IC) being used to indicate a signal. Furthermore, a sequence symmetry analysis using data from a large Japanese administrative claims database (2005-2017; JMDC Inc, Japan) was conducted. Short-term intervals (ie, 12, 24, and 36 months) were set to investigate the association between antipsychotic use and onset of osteoporosis using the adjusted sequence ratio (SR) to indicate a signal. No potential association between osteoporosis and all antipsychotics was observed in the FAERS database, except for perphenazine, which exhibited significant signals using both ROR and IC. Moreover, no potential association between osteoporosis and antipsychotics was observed in the JMDC claims database, except for sulpiride and aripiprazole. None of the antipsychotics indicated significant signals using all analyzed items (ROR, IC, and adjusted SR). Real-world data show no association between antipsychotic use and the onset of osteoporosis. Further pharmacoepidemiological studies are needed for causality assessment.

Selective serotonin reuptake inhibitors and the risk of restless legs syndrome: a symmetry analysis.

Largely based on case series, several drugs have been implicated in drug-induced restless legs syndrome (RLS) including selective serotonin reuptake inhibitors (SSRI). We aimed to assess the association between initiation of SSRIs and RLS in a self-controlled design. We conducted a symmetry analysis, including Danish adults who filled in their first prescription of an SSRI in the period of 1997-2017 and initiated an RLS drug (quinine, ropinirole, pramipexole or rotigotine) 1year prior to or after this date. A symmetrical distribution of prescriptions before and after SSRI initiation is expected if there is no association between SSRI and RLS (a sequence ratio (SR) of 1.0). The symmetry analysis design is robust to confounders that are stable over time. Subgroup analyses were conducted, restricting the population on sex, age, selected diagnoses and concurrent medication. A total of 10,875 patients filled in their first-ever prescription of both an SSRI and an RLS drug within a 1-year interval; 5341 patients filled their prescription of SSRI prior to their prescription of an RLS drug, and 5534 patients redeemed their prescriptions in the opposite order (SR 0.97, 95% CI 0.93-1.00). Restricting the outcome to dopamine agonist initiation revealed a slightly increased sequence ratio (SR 1.34, 95% CI 1.24-1.46), which was reduced when adjusting for trends in prescription (adjusted SR 1.21, 95% CI 1.12-1.32). Restricting the outcome to quinine initiation showed no association. We found no association between the initiation of an SSRI and the development of RLS assessed by the prescription of an RLS drug.

Association between oral anticoagulants and osteoporosis: Real-world data mining using a multi-methodological approach.

Introduction: Warfarin and direct oral anticoagulants (DOACs) have been widely used in antithrombotic therapy. Although warfarin use has been suspected to be associated with osteoporosis risk, several studies have shown otherwise. Conversely, a few reports have found an association between DOACs and osteoporosis. This study therefore clarifies the association between oral anticoagulants and osteoporosis by analyzing real-world data using different methodologies, algorithms, and databases.Methods: Real-world data from the US Food and Drug Administration Adverse Event Reporting System (FAERS; 2004-2016) and Japanese administrative claims database (2005-2017; JMDC Inc., Tokyo) were used. Reporting odds ratio (ROR) and information component (IC) were calculated through disproportionality analysis (DPA) using reports recorded in the FAERS. Sequence symmetry analysis (SSA) was employed to calculate the adjusted sequence ratio (SR) using the JMDC Claims Database. For the adjusted SR and ROR, a significant signal was detected when the lower limit of the two-sided 95% confidence interval (CI) was more than 1. For the IC, a significant signal was detected when the lower limit of the 95% CI was more than 0.Results: DPA for warfarin found significant signals for osteoporosis in ROR (1.43, 95% CI: 1.32-1.54) and IC (0.50, 95% CI: 0.39-0.61). SSA showed a significant association between warfarin use and osteoporosis or bisphosphonate use. Moreover, a significant association was observed in males and females, albeit only for warfarin.Conclusion: Multi-methodological data mining revealed that warfarin use, not DOACs, is significantly associated with osteoporosis regardless of sex difference.

Signal Detection Between Fluoroquinolone Use and the Risk of Rhegmatogenous Retinal Detachment: Sequence Symmetry Analysis Using Nationwide South Korean Healthcare Database Between 2004 and 2015

The association between fluoroquinolone and rhegmatogenous retinal detachment (RRD) has been controversial as a result of inconsistent findings. We set out to detect a possible association of fluoroquinolone use and risk of RRD, using sequence symmetry analysis (SSA). We conducted an SSA, case-only design, using a Korean nationwide healthcare database between 2004 and 2015. Exposure was defined as new fluoroquinolone use and outcome as an incident RRD, defined by a diagnosis of RRD (ICD-10: "H33.0") or surgery for RRD. Pairs of exposure and RRD within a 1-year time-window were included. The sequence ratio (SR) was calculated by the ratio of the number of patients prescribed with exposure first and diagnosed with RRD second divided by the number of patients diagnosed with RRD first and prescribed with exposure second. SR was adjusted (aSR) for underlying trends and 95% confidence intervals (CIs) were calculated. In order to observe whether the estimated ratio stabilized over time, we did repeated time-sequential analyses with the cumulative data starting from the 3-year period 2004-2006 to 2015. Fluoroquinolone use had a greater association with RRD as compared with other antibiotics [fluoroquinolone: 5234 pairs; aSR = 1.70 (95% CI 1.61-1.80), first-generation cephalosporin: 4139 pairs; aSR = 1.39 (95% CI 1.31-1.80), second-generation cephalosporin: 5914 pairs; aSR = 1.31 (95% CI 1.24-1.38), third-generation cephalosporin: 3650 pairs; aSR = 0.88 (95% CI 0.83-0.95), extended-spectrum penicillin: 4823 pairs; aSR = 1.29 (95% CI 1.31-1.47), macrolides: 4115 pairs; aSR = 1.31 (95% CI 1.24-1.39)]. Time-sequential analyses supported the association between fluoroquinolone and RRD. Our detection suggests a possible association between fluoroquinolone use and RRD. However, possible overestimation and reverse causality bias may have influenced our findings due to the limitation of an SSA design.

The Uncertainty of the Association Between Proton Pump Inhibitor Use and the Risk of Dementia: Prescription Sequence Symmetry Analysis Using a Korean Healthcare Database Between 2002 and 2013.

Studies have found an association between the use of proton pump inhibitors (PPIs) and dementia, but these findings may have been confounded by selection biases. We used prescription sequence symmetry analysis (PSSA) to estimate the sequence ratio (SR) between PPI use and dementia compared with an active comparator, the use of histamine-2 receptor antagonists (H2RAs). We conducted a PSSA on a nationwide South Korean database between 2002 and 2013. Exposure was defined as new PPI users, and outcome was defined as a new dementia diagnosis (International Statistical Classification of Diseases and Related Health Problems, 10th revision [ICD-10] codes F00-03, F05.1, G30, G31.1, G31.9, G31.82). In this study, we applied the 3-year time window. So the patients who initiated PPIs 3 years before or after their first diagnosis of dementia were included. The pairs with the time window <6 months were excluded to minimize the potential protopathic bias. The SR was calculated as the number of patients first diagnosed with dementia after initiating PPI (causal group) divided by the number of patients first diagnosed with dementia before the initiation of PPI (non-causal group). The SR was adjusted (aSR) to avoid the distortion of results due to underlying trends in PPI use and dementia diagnosis over time. We calculated 95% confidence intervals (CIs) for the aSR. The analysis was repeated for initiators of H2RAs. Sensitivity analyses were conducted using 1-, 2-, and 6-year time windows and using the initiation of medication for dementia treatment (Anatomical Therapeutic Chemical code: N06D). Our results showed that the aSR of dementia and PPIs (7342 pairs, aSR 1.21 [95% CI 1.16-1.27]) was not higher than that for dementia and H2RAs (6170 pairs, aSR 1.91 [95% CI 1.80-2.02]). When we used various time windows and restricted the findings to the use of medication for treating dementia, the results were consistent with the main results. The risk of PPIs being associated with dementia may be overestimated. Further pharmacoepidemiological studies are needed to identify the risk of dementia with PPI use.

Is combined use of SSRIs and NSAIDs associated with an increased risk of starting peptic ulcer treatment?

De Jong et al. [1] reported that the combined use of nonsteroidal anti-inflammatory drugs (NSAIDs) with selective serotonin reuptake inhibitors (SSRIs) synergistically increased the risk of initiating a treatment course with peptic ulcer drugs as a proxy for gastrointestinal adverse effects. In an attempt to limit confounding by indication, tricyclic antidepressant (TCA) users were used as a control group. As the observed association was not adjusted for potential differences between TCA and SSRI users [1], unmeasured confounding may have affected the estimation of the adverse effects. We therefore addressed the association using another pharmacoepidemiological study design, a so-called prescription sequence symmetry design [2]. The main advantage of this design is that it controls for time-invariant (unmeasured) confounding, because the patient population serves as its own control group. We used data from the same pharmacy prescription database (IADB; http://www.IADB.nl) that de Jong et al. [1] used and applied similar inclusion and exclusion criteria. When assessing the association between initiating treatment A and B, the sequence ratio (SR) is calculated by dividing the number of individuals starting treatment A first and treatment B second by the number of individuals starting treatment B first and treatment A second. For the primary analysis, only patients with a time span between both incident prescriptions between 2 and 28 days were included to limit time-variant confounding. We adjusted for prescription time trends by dividing the crude SR by a null ratio, i.e. the SR obtained assuming no association between both drugs, based on overall prescription rates of both drugs in the total IADB population. We estimated 95% confidence intervals (CIs) of SRs using exact confidence intervals for binomial distributions using STATA 12 software (StataCorp LP, College Station, TX, USA). In total, 50 350 adult patients who initiated SSRI treatment were identified between July 1994 and December 2011. A peptic ulcer drug treatment course was started in 277 of them within a 4 week period of SSRI therapy initiation; 126 (45%) started SSRI therapy prior to peptic ulcer drug treatment, while 151 (55%) patients first started peptic ulcer drug treatment [adjusted (a)SR, 0.83; 95% CI, 0.65–1.06; Table ​Table1].1]. Concurrent use of SSRIs and NSAIDs was associated with a statistically nonsignificant increase in the risk of starting peptic ulcer drug treatment (aSR, 1.48; 95% CI, 0.90–2.49), which did not exceed the risk estimated for NSAID treatment alone (aSR, 2.50; 95% CI, 2.27–2.76). Similar results were obtained for TCA treatment alone and concurrent use of TCAs and NSAIDs (Table ​(Table11). Table 1 Symmetry analysis of selected drug therapy initiation within 4 weeks of peptic ulcer drug therapy initiation using a drug-free run-in period of half a year Given that we used the same database and similar inclusion and exclusion criteria as de Jong et al. [1], the main difference between their study and ours is that we used an alternative design that reduces time-invariant (unmeasured) confounding. In accordance with our results, Dall et al., who applied a case–control design in which they controlled for various potential confounders including alcohol abuse, did not observe an increased risk of uncomplicated peptic ulcers associated with combined use of SSRIs and NSAIDs [3]. As we restricted our analyses to relatively short time spans to reduce the potential influence of time-variant confounding, we could not detect a risk that develops later in the course of treatment. However, de Jong et al. found an increased risk for concomitant use of SSRIs and NSAIDs during an average follow-up of 21 days [1]. In addition, Dall et al. found that the risk of uncomplicated peptic ulcers is greatest during the first 30 days of SSRI treatment [3], indicating that our time span of 4 weeks should be long enough to capture potential drug-related increases in peptic ulcer drug prescribing. We could not capture peptic ulcer drug courses prescribed during hospitalization, measure gastrointestinal adverse effects that required hospitalization or measure over-the-counter NSAID and peptic ulcer drug use. However, de Jong et al. did previously find an increased risk in patients concurrently using SSRIs and NSAIDs, while coping with the same limitations [1]. Therefore, the lack of an increased risk associated with SSRI use, whether used concurrently with NSAIDs or not, is likely not to be related to these potential limitations. In conclusion, our results suggest that the observations reported by de Jong et al. [1] might, at least partly, be attributed to unmeasured confounding. Although comparison with a drug that is used to treat the same indication does limit confounding, it does not eliminate all potential confounders. Therefore, when limited data on potential confounders are available, a self-controlled design can have added value, because it eliminates all time-invariant confounders [4].

Inhaled Corticosteroids and the Occurrence of Oral Candidiasis: A Prescription Sequence Symmetry Analysis

The primary aim of the study was to gain insight into the relative risk of clinically relevant oral candidiasis following inhaled corticosteroid (ICS) initiation over time. A secondary aim was to analyse the influence of patient characteristics and co-medication on the occurrence of this adverse effect. Drug prescription data from 1994 to 2011 were retrieved from the IADB.nl database. To study the influence of ICS use on occurrence of oral candidiasis, a prescription symmetry analysis was used, including patients using medication for oral candidiasis up to 1year before or after ICS initiation. The relative risk was calculated by dividing the number of patients receiving medication for oral candidiasis after ICS initiation by the number of patients receiving the same medication before ICS initiation. Sub-analyses were conducted to compare the relative risks at several time points after ICS initiation and to account for therapy persistence by only including chronic users of ICS. A multivariate logistic regression model was used to identify predictive factors. A total of 52,279 incident users of ICS therapy were identified, of which 1,081 received medication for oral candidiasis up to 1year before or after ICS initiation. A total of 701 patients received medication for oral candidiasis after ICS initiation, while 361 received these medications in the reversed sequence, resulting in a sequence ratio (SR) of 1.94 (95% CI 1.71-2.21). In the first 3months after ICS initiation, the SR was 2.72 (95% CI 2.19-3.38) and then decreased to 1.47 (95% CI 1.11-1.95) 9-12months after ICS initiation. Predictive factors were higher daily dose of ICS and concomitant use of oral corticosteroids. This study found a significant and clinically relevant increased number of patients receiving medication for oral candidiasis in the first year after therapy initiation with ICS. Relative risk is highest in the first 3months, but remains increased up to at least 1year after ICS initiation. This study stresses the need for patient education and inhalation instruction.

Bisection hardly ever converges linearly

For real functions that cross the unit interval, the method of bisection converges linearly if, but only if, the point of crossing is a diadic number where the function does not vanish, or, except for finitely many digits, its binary expansion coincides with that of one third or two thirds. Otherwise, the order of convergence remains undefined. If the point of crossing is one of Borel's normal real numbers (Lebesgue's measure of all of which equals one), then the sequence of ratios of two consecutive errors accumulates simultaneously at zero, one half, and negative infinity. Thus, in every finite sequence of estimates from the bisection, the last estimate need not be more accurate than the first one.