Publications by authors named "Rupa Makadia"

11 Publications

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Characterizing the incidence of adverse events of special interest for COVID-19 vaccines across eight countries: a multinational network cohort study.

medRxiv 2021 Mar 28. Epub 2021 Mar 28.

Background: As large-scale immunization programs against COVID-19 proceed around the world, safety signals will emerge that need rapid evaluation. We report population-based, age- and sex- specific background incidence rates of potential adverse events of special interest (AESI) in eight countries using thirteen databases.

Methods: This multi-national network cohort study included eight electronic medical record and five administrative claims databases from Australia, France, Germany, Japan, Netherlands, Spain, the United Kingdom, and the United States, mapped to a common data model. People observed for at least 365 days before 1 January 2017, 2018, or 2019 were included. We based study outcomes on lists published by regulators: acute myocardial infarction, anaphylaxis, appendicitis, Bell's palsy, deep vein thrombosis, disseminated intravascular coagulation, encephalomyelitis, Guillain-Barre syndrome, hemorrhagic and non-hemorrhagic stroke, immune thrombocytopenia, myocarditis/pericarditis, narcolepsy, pulmonary embolism, and transverse myelitis. We calculated incidence rates stratified by age, sex, and database. We pooled rates across databases using random effects meta-analyses. We classified meta-analytic estimates into Council of International Organizations of Medical Sciences categories: very common, common, uncommon, rare, or very rare.

Findings: We analysed 126,661,070 people. Rates varied greatly between databases and by age and sex. Some AESI (e.g., myocardial infarction, Guillain-Barre syndrome) increased with age, while others (e.g., anaphylaxis, appendicitis) were more common in young people. As a result, AESI were classified differently according to age. For example, myocardial infarction was very rare in children, rare in women aged 35-54 years, uncommon in men and women aged 55-84 years, and common in those aged ≥85 years.

Interpretation: We report robust baseline rates of prioritised AESI across 13 databases. Age, sex, and variation between databases should be considered if background AESI rates are compared to event rates observed with COVID-19 vaccines.
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http://dx.doi.org/10.1101/2021.03.25.21254315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010764PMC
March 2021

Understanding patient journey in ulcerative colitis prior to biologic initiation: a 5-year exploration.

BMC Gastroenterol 2021 Mar 17;21(1):121. Epub 2021 Mar 17.

Janssen Global Services, LLC, Raritan, 08869, NJ, USA.

Background: There has been a more pronounced shift toward earlier, more aggressive therapies in Crohn's disease than in ulcerative colitis (UC). The aim of this study was to describe the pre-biologic treatment and health care experience, including co-morbidities and overall health care utilization, for UC patients who initiated biologic therapies, in the 5 years prior to the initiation of the first biologic agent.

Methods: UC patients who initiated a biologic agent approved for UC between 9/15/2005 and 1/30/2018 were identified from the IBM® MarketScan® Commercial Database, a large US database. The date of the first recorded UC biologic exposure was defined as the index date, and ≥ 5 years of pre-index records were required to evaluate patients' treatment, disease progression and overall health care utilization prior to initiating biologic agents.

Results: Among the 1891 eligible patients, treatment with oral corticosteroids, 5-aminosalicylates, and other non-biologic immunomodulators, all increased progressively across the 5 years prior to the index. From within year-five to within year-one prior to the index, the median duration of oral corticosteroid treatment increased from 34 to 88 days per year and the proportion of patients who experienced more extensive/pancolitis disease increased from 16 to 59%. Overall, the frequency of all-cause health care visits also increased.

Conclusions: Patients with UC experienced increasing morbidity and treatment burden in the 5 years prior to initiating biologic therapy. To achieve reduced corticosteroids in UC management, better risk stratification is needed to help identify patients for more timely biologic treatment.
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http://dx.doi.org/10.1186/s12876-021-01708-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7967955PMC
March 2021

Understanding patient journey in ulcerative colitis prior to biologic initiation: a 5-year exploration.

BMC Gastroenterol 2021 Mar 17;21(1):121. Epub 2021 Mar 17.

Janssen Global Services, LLC, Raritan, 08869, NJ, USA.

Background: There has been a more pronounced shift toward earlier, more aggressive therapies in Crohn's disease than in ulcerative colitis (UC). The aim of this study was to describe the pre-biologic treatment and health care experience, including co-morbidities and overall health care utilization, for UC patients who initiated biologic therapies, in the 5 years prior to the initiation of the first biologic agent.

Methods: UC patients who initiated a biologic agent approved for UC between 9/15/2005 and 1/30/2018 were identified from the IBM® MarketScan® Commercial Database, a large US database. The date of the first recorded UC biologic exposure was defined as the index date, and ≥ 5 years of pre-index records were required to evaluate patients' treatment, disease progression and overall health care utilization prior to initiating biologic agents.

Results: Among the 1891 eligible patients, treatment with oral corticosteroids, 5-aminosalicylates, and other non-biologic immunomodulators, all increased progressively across the 5 years prior to the index. From within year-five to within year-one prior to the index, the median duration of oral corticosteroid treatment increased from 34 to 88 days per year and the proportion of patients who experienced more extensive/pancolitis disease increased from 16 to 59%. Overall, the frequency of all-cause health care visits also increased.

Conclusions: Patients with UC experienced increasing morbidity and treatment burden in the 5 years prior to initiating biologic therapy. To achieve reduced corticosteroids in UC management, better risk stratification is needed to help identify patients for more timely biologic treatment.
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http://dx.doi.org/10.1186/s12876-021-01708-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7967955PMC
March 2021

Deep phenotyping of 34,128 adult patients hospitalised with COVID-19 in an international network study.

Nat Commun 2020 10 6;11(1):5009. Epub 2020 Oct 6.

Clinical Pharmacology Unit, Zealand University Hospital, Køge, Denmark.

Comorbid conditions appear to be common among individuals hospitalised with coronavirus disease 2019 (COVID-19) but estimates of prevalence vary and little is known about the prior medication use of patients. Here, we describe the characteristics of adults hospitalised with COVID-19 and compare them with influenza patients. We include 34,128 (US: 8362, South Korea: 7341, Spain: 18,425) COVID-19 patients, summarising between 4811 and 11,643 unique aggregate characteristics. COVID-19 patients have been majority male in the US and Spain, but predominantly female in South Korea. Age profiles vary across data sources. Compared to 84,585 individuals hospitalised with influenza in 2014-19, COVID-19 patients have more typically been male, younger, and with fewer comorbidities and lower medication use. While protecting groups vulnerable to influenza is likely a useful starting point in the response to COVID-19, strategies will likely need to be broadened to reflect the particular characteristics of individuals being hospitalised with COVID-19.
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http://dx.doi.org/10.1038/s41467-020-18849-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7538555PMC
October 2020

Risk of hydroxychloroquine alone and in combination with azithromycin in the treatment of rheumatoid arthritis: a multinational, retrospective study.

Lancet Rheumatol 2020 Nov 21;2(11):e698-e711. Epub 2020 Aug 21.

Janssen Research and Development, Titusville, NJ, USA.

Background: Hydroxychloroquine, a drug commonly used in the treatment of rheumatoid arthritis, has received much negative publicity for adverse events associated with its authorisation for emergency use to treat patients with COVID-19 pneumonia. We studied the safety of hydroxychloroquine, alone and in combination with azithromycin, to determine the risk associated with its use in routine care in patients with rheumatoid arthritis.

Methods: In this multinational, retrospective study, new user cohort studies in patients with rheumatoid arthritis aged 18 years or older and initiating hydroxychloroquine were compared with those initiating sulfasalazine and followed up over 30 days, with 16 severe adverse events studied. Self-controlled case series were done to further establish safety in wider populations, and included all users of hydroxychloroquine regardless of rheumatoid arthritis status or indication. Separately, severe adverse events associated with hydroxychloroquine plus azithromycin (compared with hydroxychloroquine plus amoxicillin) were studied. Data comprised 14 sources of claims data or electronic medical records from Germany, Japan, the Netherlands, Spain, the UK, and the USA. Propensity score stratification and calibration using negative control outcomes were used to address confounding. Cox models were fitted to estimate calibrated hazard ratios (HRs) according to drug use. Estimates were pooled where the value was less than 0·4.

Findings: The study included 956 374 users of hydroxychloroquine, 310 350 users of sulfasalazine, 323 122 users of hydroxychloroquine plus azithromycin, and 351 956 users of hydroxychloroquine plus amoxicillin. No excess risk of severe adverse events was identified when 30-day hydroxychloroquine and sulfasalazine use were compared. Self-controlled case series confirmed these findings. However, long-term use of hydroxychloroquine appeared to be associated with increased cardiovascular mortality (calibrated HR 1·65 [95% CI 1·12-2·44]). Addition of azithromycin appeared to be associated with an increased risk of 30-day cardiovascular mortality (calibrated HR 2·19 [95% CI 1·22-3·95]), chest pain or angina (1·15 [1·05-1·26]), and heart failure (1·22 [1·02-1·45]).

Interpretation: Hydroxychloroquine treatment appears to have no increased risk in the short term among patients with rheumatoid arthritis, but in the long term it appears to be associated with excess cardiovascular mortality. The addition of azithromycin increases the risk of heart failure and cardiovascular mortality even in the short term. We call for careful consideration of the benefit-risk trade-off when counselling those on hydroxychloroquine treatment.

Funding: National Institute for Health Research (NIHR) Oxford Biomedical Research Centre, NIHR Senior Research Fellowship programme, US National Institutes of Health, US Department of Veterans Affairs, Janssen Research and Development, IQVIA, Korea Health Industry Development Institute through the Ministry of Health and Welfare Republic of Korea, Versus Arthritis, UK Medical Research Council Doctoral Training Partnership, Foundation Alfonso Martin Escudero, Innovation Fund Denmark, Novo Nordisk Foundation, Singapore Ministry of Health's National Medical Research Council Open Fund Large Collaborative Grant, VINCI, Innovative Medicines Initiative 2 Joint Undertaking, EU's Horizon 2020 research and innovation programme, and European Federation of Pharmaceutical Industries and Associations.
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http://dx.doi.org/10.1016/S2665-9913(20)30276-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7442425PMC
November 2020

An international characterisation of patients hospitalised with COVID-19 and a comparison with those previously hospitalised with influenza.

medRxiv 2020 Apr 25. Epub 2020 Apr 25.

Science Policy and Research, National Institute for Health and Care Excellence, UK.

Background: To better understand the profile of individuals with severe coronavirus disease 2019 (COVID-19), we characterised individuals hospitalised with COVID-19 and compared them to individuals previously hospitalised with influenza.

Methods: We report the characteristics (demographics, prior conditions and medication use) of patients hospitalised with COVID-19 between December 2019 and April 2020 in the US (Columbia University Irving Medical Center [CUIMC], STAnford Medicine Research data Repository [STARR-OMOP], and the Department of Veterans Affairs [VA OMOP]) and Health Insurance Review & Assessment [HIRA] of South Korea. Patients hospitalised with COVID-19 were compared with patients previously hospitalised with influenza in 2014-19.

Results: 6,806 (US: 1,634, South Korea: 5,172) individuals hospitalised with COVID-19 were included. Patients in the US were majority male (VA OMOP: 94%, STARR-OMOP: 57%, CUIMC: 52%), but were majority female in HIRA (56%). Age profiles varied across data sources. Prevalence of asthma ranged from 7% to 14%, diabetes from 18% to 43%, and hypertensive disorder from 22% to 70% across data sources, while between 9% and 39% were taking drugs acting on the renin-angiotensin system in the 30 days prior to their hospitalisation. Compared to 52,422 individuals hospitalised with influenza, patients admitted with COVID-19 were more likely male, younger, and, in the US, had fewer comorbidities and lower medication use.

Conclusions: Rates of comorbidities and medication use are high among individuals hospitalised with COVID-19. However, COVID-19 patients are more likely to be male and appear to be younger and, in the US, generally healthier than those typically admitted with influenza.
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http://dx.doi.org/10.1101/2020.04.22.20074336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7239064PMC
April 2020

Criteria2Query: a natural language interface to clinical databases for cohort definition.

J Am Med Inform Assoc 2019 04;26(4):294-305

Department of Biomedical Informatics, Columbia University, New York, New York, USA.

Objective: Cohort definition is a bottleneck for conducting clinical research and depends on subjective decisions by domain experts. Data-driven cohort definition is appealing but requires substantial knowledge of terminologies and clinical data models. Criteria2Query is a natural language interface that facilitates human-computer collaboration for cohort definition and execution using clinical databases.

Materials And Methods: Criteria2Query uses a hybrid information extraction pipeline combining machine learning and rule-based methods to systematically parse eligibility criteria text, transforms it first into a structured criteria representation and next into sharable and executable clinical data queries represented as SQL queries conforming to the OMOP Common Data Model. Users can interactively review, refine, and execute queries in the ATLAS web application. To test effectiveness, we evaluated 125 criteria across different disease domains from ClinicalTrials.gov and 52 user-entered criteria. We evaluated F1 score and accuracy against 2 domain experts and calculated the average computation time for fully automated query formulation. We conducted an anonymous survey evaluating usability.

Results: Criteria2Query achieved 0.795 and 0.805 F1 score for entity recognition and relation extraction, respectively. Accuracies for negation detection, logic detection, entity normalization, and attribute normalization were 0.984, 0.864, 0.514 and 0.793, respectively. Fully automatic query formulation took 1.22 seconds/criterion. More than 80% (11+ of 13) of users would use Criteria2Query in their future cohort definition tasks.

Conclusions: We contribute a novel natural language interface to clinical databases. It is open source and supports fully automated and interactive modes for autonomous data-driven cohort definition by researchers with minimal human effort. We demonstrate its promising user friendliness and usability.
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http://dx.doi.org/10.1093/jamia/ocy178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6402359PMC
April 2019

Depression Is Associated With High Levels of C-Reactive Protein and Low Levels of Fractional Exhaled Nitric Oxide: Results From the 2007-2012 National Health and Nutrition Examination Surveys.

J Clin Psychiatry 2016 Dec;77(12):1666-1671

Department of Epidemiology, Janssen Research & Development, LLC, Titusville, New Jersey, USA.

Objective: Major depressive disorder may be due to psychoneuroimmunological dysfunction, as studies have documented increased levels of a variety of inflammatory mediators in depressed subjects. Nitric oxide (NO) is marker of inflammation, and fractional exhaled NO (FeNO) is a marker of airway inflammation. Plasma NO and FeNO levels have been shown to be lower in subjects with depression in small studies. We sought to assess the association of depression with C-reactive protein (CRP) and FeNO levels in a large and representative sample of the US population.

Methods: Population-based cross-sectional study using data from the National Health and Nutrition Examination Survey (NHANES). NHANES collects health information about the US population through interviews, medical examinations, and laboratory tests. We included subjects ≥ 20 years old who participated in NHANES in 2007 to 2012, responded to the depression questions, and had CRP values or ≥ 2 reproducible FeNO measures. Depression was measured using the 9-item Patient Health Questionnaire (PHQ-9). Subjects were classified as depressed if PHQ-9 scores were ≥ 10. FeNO and CRP levels were log transformed. Unadjusted and adjusted regression analyses were conducted.

Results: A total of 14,276 subjects responded to the PHQ-9, and 7.73% had depressive symptoms. Of these subjects, 10,036 had CRP values and 12,513 had FeNO measurements. Subjects with depressive symptoms had, after adjustment, CRP levels that were 31% higher (95% confidence interval [CI], 14% to 50%) and FeNO levels that were 10.7% lower (95% CI, -2.5% to -17.1%) than in subjects with no depressive symptoms.

Conclusions: Depression is associated with high CRP levels and low FeNO levels. Of importance, this study (1) assesses the association of depression with CRP and exhaled NO levels in a large and representative sample of the US population, (2) contributes to the neuroimmunological dimension of depression, (3) confirms the association of depression with high levels of CRP, and (4) assesses, for the first time, the association of depression with peripheral NO in more than 10,000 subjects from the general population.
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http://dx.doi.org/10.4088/JCP.15m10267DOI Listing
December 2016

Incidence of ischemic stroke or transient ischemic attack in patients with multiple risk factors with or without atrial fibrillation: a retrospective cohort study.

Curr Med Res Opin 2015 6;31(7):1257-66. Epub 2015 May 6.

Janssen Research & Development LLC , Titusville, NJ , USA.

Background: The risk of stroke in atrial fibrillation (AF) increases with number of risk factors (RFs). However, the combined effect from multiple RFs on the incidence of ischemic stroke and transient ischemic attack (TIA) among US patients without AF has not been fully examined.

Methods And Results: Truven MarketScan Medicare Supplemental database was used to establish cohorts of patients ≥65 years old with and without AF. Index date was first occurrence of AF diagnosis (AF patients) or first medical encounter (non-AF patients) during the inception period from 2010 through 2011. Incidences of ischemic stroke/TIA in relation to number of baseline RFs (congestive heart failure, hypertension, advanced age, diabetes, and prior stroke/TIA, myocardial infarction) were determined during the follow-up period from the index date through March 2013. A total of 158,199 patients were included in the AF cohort and 1,181,273 patients in the non-AF cohort. Approximately 51% of AF patients had ≥3 RFs versus 18% in non-AF patients. Ischemic stroke/TIA were observed in 24,680 and 104,154 patients in the AF and non-AF cohorts, yielding incidence rate (SD) of 7.3 (0.05) and 3.2 (0.01) per 100 person-years, respectively. In the AF cohort, incidence rate of ischemic stroke/TIA was 2.3, 4.9, 9.4, and 16.9 per 100-person years for 0, 1-2, 3-4, and 5-6 RFs, respectively, compared with the corresponding rate of 1.3, 2.8, 6.4, and 12.3 per 100 person-years for the non-AF cohort. This positive association between the number of risk factors and incidence rates within each cohort was consistently observed in sensitivity analyses.

Conclusion: In a large cohort of elderly patients without AF, the risk of ischemic stroke/TIA increased substantially in the presence of multiple RFs, highlighting potentially unmet medical needs. This observation implies that future studies may be warranted to investigate the effect of prophylactic anticoagulation in high risk non-AF patients.
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http://dx.doi.org/10.1185/03007995.2015.1041469DOI Listing
February 2016

Feasibility and utility of applications of the common data model to multiple, disparate observational health databases.

J Am Med Inform Assoc 2015 May 10;22(3):553-64. Epub 2015 Feb 10.

Epidemiology Analytics, Janssen Research & Development, Titusville, New Jersey, USA.

Objectives: To evaluate the utility of applying the Observational Medical Outcomes Partnership (OMOP) Common Data Model (CDM) across multiple observational databases within an organization and to apply standardized analytics tools for conducting observational research.

Materials And Methods: Six deidentified patient-level datasets were transformed to the OMOP CDM. We evaluated the extent of information loss that occurred through the standardization process. We developed a standardized analytic tool to replicate the cohort construction process from a published epidemiology protocol and applied the analysis to all 6 databases to assess time-to-execution and comparability of results.

Results: Transformation to the CDM resulted in minimal information loss across all 6 databases. Patients and observations excluded were due to identified data quality issues in the source system, 96% to 99% of condition records and 90% to 99% of drug records were successfully mapped into the CDM using the standard vocabulary. The full cohort replication and descriptive baseline summary was executed for 2 cohorts in 6 databases in less than 1 hour.

Discussion: The standardization process improved data quality, increased efficiency, and facilitated cross-database comparisons to support a more systematic approach to observational research. Comparisons across data sources showed consistency in the impact of inclusion criteria, using the protocol and identified differences in patient characteristics and coding practices across databases.

Conclusion: Standardizing data structure (through a CDM), content (through a standard vocabulary with source code mappings), and analytics can enable an institution to apply a network-based approach to observational research across multiple, disparate observational health databases.
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http://dx.doi.org/10.1093/jamia/ocu023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4457111PMC
May 2015

Transforming the Premier Perspective Hospital Database into the Observational Medical Outcomes Partnership (OMOP) Common Data Model.

EGEMS (Wash DC) 2014 11;2(1):1110. Epub 2014 Nov 11.

Janssen Research & Development.

Background: The Observational Medical Outcomes Partnership (OMOP) Common Data Model (CDM) has been implemented on various claims and electronic health record (EHR) databases, but has not been applied to a hospital transactional database. This study addresses the implementation of the OMOP CDM on the U.S. Premier Hospital database.

Methods: We designed and implemented an extract, transform, load (ETL) process to convert the Premier hospital database into the OMOP CDM. Standard charge codes in Premier were mapped between the OMOP version 4.0 Vocabulary and standard charge descriptions. Visit logic was added to impute the visit dates. We tested the conversion by replicating a published study using the raw and transformed databases. The Premier hospital database was compared to a claims database, in regard to prevalence of disease.

Findings: The data transformed into the CDM resulted in 1% of the data being discarded due to data errors in the raw data. A total of 91.4% of Premier standard charge codes were mapped successfully to a standard vocabulary. The results of the replication study resulted in a similar distribution of patient characteristics. The comparison to the claims data yields notable similarities and differences amongst conditions represented in both databases.

Discussion: The transformation of the Premier database into the OMOP CDM version 4.0 adds value in conducting analyses due to successful mapping of the drugs and procedures. The addition of visit logic gives ordinality to drugs and procedures that wasn't present prior to the transformation. Comparing conditions in Premier against a claims database can provide an understanding about Premier's potential use in pharmacoepidemiology studies that are traditionally conducted via claims databases.

Conclusion And Next Steps: The conversion of the Premier database into the OMOP CDM 4.0 was completed successfully. The next steps include refinement of vocabularies and mappings and continual maintenance of the transformed CDM.
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http://dx.doi.org/10.13063/2327-9214.1110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4371500PMC
April 2015