Strategies for secondary use of real-world clinical and administrative data for outcome ascertainment in pragmatic clinical trials.

BACKGROUND: Pragmatic trials are gaining popularity as a cost-effective way to examine treatment effectiveness and generate timely comparative evidence. Incorporating supplementary real-world data is recommended for robust outcome monitoring. However, detailed operational guidelines are needed to inform effective use and integration of heterogeneous databases. OBJECTIVE: Lessons learned from the Veterans Affairs (VA) Diuretic Comparison Project (DCP) are reviewed, providing adaptable recommendations to capture clinical outcomes from real-world data. METHODS: Non-cancer deaths and major cardiovascular (CV) outcomes were determined using VA, Medicare, and National Death Index (NDI) data. Multiple ascertainment strategies were applied, including claims-based algorithms, natural language processing, and systematic chart review. RESULTS: During a mean follow-up of 2.4 (SD = 1.4) years, 907 CV events were identified within the VA healthcare system. Slight delays (∼1 year) were expected in obtaining Medicare data. An additional 298 patients were found having a CV event outside of the VA in 2016 - 2021, increasing the CV event rate from 3.5 % to 5.7 % (770 of 13,523 randomized). NDI data required âˆ¼2 years waiting period. Such inclusion did not increase the number of deaths identified (all 894 deaths were captured by VA data) but enhanced the accuracy in determining cause of death. CONCLUSION: Our experience supports the recommendation of integrating multiple data sources to improve clinical outcome ascertainment. While this approach is promising, hierarchical data aggregation is required when facing different acquisition timelines, information availability/completeness, coding practice, and system configurations. It may not be feasible to implement comparable applications and solutions to studies conducted under different constraints and practice. The recommendations provide guidance and possible action plans for researchers who are interested in applying cross-source data to ascertain all study outcomes.

Ascertainment of stroke from administrative data to support a pragmatic embedded clinical trial.

The goal of this observational study was to identify stroke hospitalizations using International Classification of Disease (ICD)-10 codes and use these codes to develop an ascertainment algorithm for use in pragmatic clinical trials, reducing or eliminating the need for manual chart adjudication in future. Using VA (Veterans Affairs) electronic medical records, 9959 patient charts with ICD-10 codes indicating stroke were screened and a sample of 304 were adjudicated by three clinical reviewers. Hospitalizations were categorized as stroke or non-stroke and positive predictive value (PPV) was calculated for each ICD-10 code that was sampled. The adjudicated codes were categorized for use in a decision tool for identifying stroke in a clinical trial. Of the 304 hospitalizations adjudicated, 192 met the definition of stroke. Of the ICD-10 codes evaluated, I61 yielded the highest PPV (100%) while I63.x yielded the 2nd highest PPV (90%) with a false discovery rate of 10%. A relatively high PPV of ≥80% was associated with codes I60.1-7, I61, I62.9 and I63, which accounted for nearly half of all cases reviewed. Hospitalizations associated with these codes were categorized at positive stroke cases. The incorporation of large administrative datasets, and elimination of trial specific data collection, increases efficiencies, while reducing costs. Accurate algorithms must be developed to allow for identification of clinical endpoints from administrative databases to offer a reliable alternative to study-specific case report form completion. This study demonstrates an example of how to apply medical record data to a decision tool for clinical trial outcomes. CSP597 or clinicaltrials.gov NCT02185417.

ß-Blocker Use and Cardiovascular Outcomes in Hemodialysis: A Systematic Review.

Rationale & Objective: There is conflicting evidence regarding the type of ß-blockers to use in dialysis patients. This systematic review seeks to determine whether highly dialyzable ß-blockers are associated with higher rates of cardiovascular events and mortality in hemodialysis patients than poorly dialyzable ß-blockers. Study Design: A systematic review of the existing literature was conducted. A meta-analysis was performed using data from the selected studies. Setting & Study Populations: Participants were from the United States, Canada, and Taiwan. The mean ages of participants ranged from 55.9-75.7 years. Selection Criteria for Studies: We searched the Ovid MEDLINE database from 1990 to September 2020. Studies without adult hemodialysis participants and without comparisons of at least 2 ß-blockers of different dialyzability were excluded. Data Extraction: Baseline and adjusted outcome data were extracted from each study. Analytical Approach: Random-effects models were used to calculate pooled risk ratios using fully adjusted models from individual studies. Results: Four cohort studies were included. Pooling fully adjusted models, highly dialyzable ß-blockers did not influence mortality (HR, 0.94; 95% CI, 0.81-1.08; I2 = 0.84) compared with poorly dialyzable ß-blockers but were associated with a reduction in cardiovascular events (HR, 0.88; 95% CI, 0.83-0.93). There was significant heterogeneity between studies (I2 = 0.35). Only 1 study reported on adverse events. Intradialytic hypotension was more common in those on carvedilol (a poorly dialyzable ß-blocker) compared with those on metoprolol (a highly dialyzable ß-blocker; adjusted incidence rate ratio, 1.10; 95% CI, 1.09-1.11). Limitations: No randomized controlled trials were identified. Each study used different analytic methods and different definitions for outcomes. Classifications of ß-blockers varied. Only 1 study reported on adverse events. Conclusions: Pooled data suggest highly dialyzable ß-blockers are associated with similar mortality events and fewer cardiovascular events compared with poorly dialyzable ß-blockers.

Identification of Acute Decompensated Heart Failure Hospitalizations Using Administrative Data.

Hospitalization for acute decompensated heart failure (ADHF) is an important outcome in clinical trials and heart failure registries; however, the optimal strategy to identify these hospitalizations using International Classification of Diseases, Ninth Revision (ICD-9) codes is uncertain. We sought to identify diagnostic codes that improve ascertainment of ADHF hospitalizations. Heart failure-related ICD-9 principal discharge codes were used to identify 2,202 hospitalizations within the Minneapolis Veterans Affairs Medical Center from 2009 to 2014. Two independent reviewers adjudicated 447 of these hospitalizations to determine the accuracy of each code. We then applied our findings to an unadjusted nationwide sample containing the same ICD-9 codes of interest, from which overall positive predictive value (PPV), sensitivity, and accuracy were calculated. Use of 428.x alone resulted in a PPV of 91.3% (95% confidence interval [CI] 91.0 to 91.7), sensitivity of 97.5% (95% CI 97.3 to 97.6), and accuracy of 89.7% (95% CI 89.4 to 90.0). Combining 428.x with 402.x1, 404.x1, 415, and 518.4 resulted in improved sensitivity (99.2%; 95% CI 99.0 to 99.3) and accuracy (90.7%; 95% CI 90.4 to 91.1) while maintaining a PPV of 91.1% (95% CI 90.7 to 91.4). Excluding chronic heart failure codes (428.22, 428.32, and 428.42) from the proposed strategy resulted in an improvement of PPV to 92.3% (95% CI 92.0 to 92.6), although sensitivity and accuracy decreased to 96.6% (95% CI 96.3 to 96.8) and 90.0% (95% CI 89.6 to 90.3), respectively. In conclusion, a combination of codes including 428.x, 402.x1, 404.x1, 415, and 518.4 improves sensitivity and overall accuracy in ascertaining ADHF events compared with 428.x alone. This strategy could be further improved by manual adjudication of chronic heart failure codes.

Incidental melanomas detected in veterans referred to dermatology.

BACKGROUND: Early detection of melanoma is integral to preventing morbidity and mortality. OBJECTIVE: We sought to characterize and compare incidental versus consult melanomas detected in veterans referred to the Minneapolis, MN, Department of Veterans Affairs Medical Center dermatology clinic. METHODS: We retrospectively reviewed charts of all dermatology consults between January 2004 and March 2012. RESULTS: Of the 28,405 consults sent during the study period, 17,174 met inclusion criteria. There were 231 melanomas identified in 221 patients. In all, 144 melanomas were identified on the consult and 87 melanomas were discovered incidentally. The incidental melanoma detection rate was 0.5% (84/17,174). Consult melanomas were more likely to be invasive than incidental melanomas (relative risk 1.51, 95% confidence interval 1.23-1.86, P < .0001) and less likely to have a Breslow depth of less than 1.00 mm (relative risk 0.73, 95% confidence interval 0.61-0.88, P = .0036). Incidental melanomas were smaller than consult melanomas (mean diameter 0.98 vs 1.3 cm, respectively) and thinner (mean Breslow depth 0.64 vs 1.74 mm). Consult melanomas were more likely to be detected on the head/neck (relative risk 1.25, 95% confidence interval 1.03-1.52, P = .0295). LIMITATIONS: Nondiverse patient population is a limitation. CONCLUSION: Melanomas detected during an in-person skin examination by a dermatologist were more likely to be detected at an earlier stage of disease.

Incidental lesions found in veterans referred to dermatology: the value of a dermatologic examination.

BACKGROUND: Few studies have evaluated the detection of incidental skin cancers. OBJECTIVE: We sought to evaluate the rate of incidental cutaneous malignancies in routine dermatology consults. METHODS: This was a retrospective chart review of all dermatology consults at the Minneapolis Department of Veterans Affairs Medical Center over 8.25 years. Inclusion criteria included an in-person clinic visit within 18 months of the initial consult date. Patients with an in-person skin examination by a dermatologist in the 18 months before consult date were excluded. RESULTS: Of 28,405 consults sent during the study period, 17,174 met inclusion criteria. In all, 2257 (13.1%) patients had 1 or more biopsied incidental lesions. Half (50.3%; n = 1674) of the 3328 biopsied incidental lesions were malignant, which included 1187 patients. The per-person detection rate for an incidental malignant lesion was 6.9% (1187/17,174). There were 87 incidental melanomas identified in 84 patients. The per-person detection rate for an incidental melanoma was 0.5% (84/17,174). The most frequent anatomical location for biopsied incidental malignancies was the head and neck (53.9%). Incidental melanomas were most frequently located on the back (33.3%). LIMITATIONS: Nondiverse patient population and conservative detection rate estimates are limitations. CONCLUSION: An in-person skin examination by a trained dermatologist is important for detection of skin malignancies. This may have implications for teledermatology.

Adverse reactions to sunscreen agents: epidemiology, responsible irritants and allergens, clinical characteristics, and management.

Sunscreen is a key component in the preventive measures recommended by dermatologists and public health campaigns aimed at reducing sunburn, early skin aging, and skin cancer. To maximize compliance, adverse reactions to sunscreens should be minimized. Although inactive ingredients cause many of these reactions, it is important for dermatologists to be aware of reactions to active ultraviolet filters. There are approximately 120 chemicals that can function as ultraviolet (UV) filters. This review focuses on the 36 most common filters in commercial and historical use. Of these, 16 are approved for use by the US Food and Drug Administration. The benzophenones and dibenzoylmethanes are the most commonly implicated UV filters causing allergic and photoallergic contact dermatitis (PACD) reactions; benzophenone-3 is the leading allergen and photoallergen within this class. When clinically indicated, patch and photopatch testing should be performed to common UV filters.

Benzophenones.

Benzophenones are ultraviolet light filters that have been documented to cause a myriad of adverse cutaneous reactions, including contact and photocontact dermatitis, contact and photocontact urticaria, and anaphylaxis. In recent years, they have become particularly well known for their ability to induce allergy and photoallergy. Topical sunscreens and other cosmetics are the sources of these allergens in most patients, but reports of reactions secondary to use of industrial products also exist. Benzophenones as a group have been named the American Contact Dermatitis Society's Allergen of the Year for 2014 to raise awareness of both allergy and photoallergy to these ubiquitous agents.

Concomitant patch test reactions to mercapto mix and mercaptobenzothiazole: retrospective analysis from the North American Contact Dermatitis Group, 1994-2008.

BACKGROUND: Mercaptobenzothiazole (MBT) and mercapto compounds are primarily used in rubber products. OBJECTIVE: This study aimed to examine concomitant-positive rates of MBT (1% pet) and the 4-part mercapto mix (MM) (1% pet). DESIGN: This is a retrospective cross-sectional data from the North American Contact Dermatitis Group. RESULTS: A total of 30,880 patients were patch tested to MM and MBT. There were 333 positive reactions to MM and 427 positive reactions to MBT. Ninety-eight patients were positive to MM alone, 192 to MBT alone, and 235 reacted to both. Forty-five percent (192/427) of MBT reactions would have been missed by only testing to MM, and 29% (98/333) of MM reactions would have been missed by testing to MBT alone. Most of these "missed" reactions, however, were doubtful (+/-) or mild (+) (MBT, 65%; MM, 78%), whereas most reactions in patients who reacted to both were moderate (++) and/or strong (+++) (52.3%). Gloves were the most common source. CONCLUSIONS: Mercaptobenzothiazole is the preferential screening allergen for mercapto compounds because of the following: (1) greater proportion of missed reactions with MM; (2) greater proportion of doubtful/mild reactions in the missed group for MM; and (3) in the group positive to both, the low rate (2%) of moderate/strong reactions to MM and doubtful/mild reactions to MBT as compared with the converse (21%). Mercapto mix may be useful in an auxiliary rubber series.

Positive patch test reactions to carba mix and iodopropynyl butylcarbamate: data from the North American Contact Dermatitis Group, 1998-2008.

BACKGROUND: Carba mix (CM) contains 3 chemicals used as accelerators in manufacturing of rubber products and agricultural chemicals. Iodopropynyl butylcarbamate (IPBC) is a preservative used in industrial and personal care products. Potential cross-reactivity between these allergens is unclear. OBJECTIVE: This study aimed to determine concomitant reaction rates between CM (3% petrolatum [pet]) and IPBC (0.1% pet and/or 0.5% pet). DESIGN: A retrospective cross-sectional analysis of data from the North American Contact Dermatitis Group from 1998 to 2008 was conducted. Frequencies of positive reactions, strength of reactions, and concomitant reaction rates were calculated. RESULTS: A total of 25,435 patients were tested. There were 1131 allergic reactions to CM and 346 positive reactions to IPBC (either 0.1% pet and/or 0.5% pet). Fifty-two patients reacted to both allergens. Most reactions (>69%) were doubtful/weakly positive, and of those who reacted to both, most (58%) had doubtful and/or weakly positive reactions. There was a statistically significant association of concomitant reactions between CM and IPBC; formaldehyde positivity was used as control and showed statistically significant concomitant reactions. CONCLUSIONS: Overall, concomitant reactions to CM and IPBC were low, and rates varied by strength of reaction. True cross-reactivity is unlikely; statistical association is likely due to frequent low-grade reactions to irritant patch test preparations.

Clinical course outcomes for store and forward teledermatology versus conventional consultation: a randomized trial.

We assessed the clinical course of patients after store and forward teledermatology in comparison with conventional consultations. Patients being referred from primary care to dermatology clinics were randomly assigned to teledermatology or a conventional consultation. A total of 392 patients were randomized; 261 patients completed the study and were included in the analysis. Their clinical course was rated on a five-point scale by a panel of three dermatologists, blinded to study assignment, who reviewed serial digital image sets. The clinical course was assessed by comparing images sets between baseline and first clinic visit (if one occurred) and between baseline and nine months. There was no evidence to suggest a difference between the two groups in either clinical course between baseline and nine months post-referral (P = 0.88) or between baseline and the first dermatology clinic visit (P = 0.65). Among teledermatology referrals, subsequent presentation for an in-person dermatology clinic visit was significantly correlated with clinical course (P = 0.023). Store and forward teledermatology did not result in a significant difference in clinical course at either of two post-referral time periods.

Effect of store and forward teledermatology on quality of life: a randomized controlled trial.

IMPORTANCE: Although research on quality of life and dermatologic conditions is well represented in the literature, information on teledermatology's effect on quality of life is virtually absent. OBJECTIVE: To determine the effect of store and forward teledermatology on quality of life. DESIGN: Two-site, parallel-group, superiority randomized controlled trial. SETTING: Dermatology clinics and affiliated sites of primary care at 2 US Department of Veterans Affairs medical facilities. PARTICIPANTS: Patients being referred to a dermatology clinic were randomly assigned, stratified by site, to teledermatology or the conventional consultation process. Among the 392 patients who met the inclusion criteria and were randomized, 326 completed the allocated intervention and were included in the analysis. INTERVENTIONS: Store and forward teledermatology (digital images and a standardized history) or conventional text-based consultation processes were used to manage the dermatology consultations. Patients were followed up for 9 months. MAIN OUTCOME MEASURES: The primary end point was change in Skindex-16 scores, a skin-specific quality-of-life instrument, between baseline and 9 months. A secondary end point was change in Skindex-16 scores between baseline and 3 months. RESULTS: Patients in both randomization groups demonstrated a clinically significant improvement in Skindex-16 scores between baseline and 9 months with no significant difference by randomization group (P = .66, composite score). No significant difference in Skindex-16 scores by randomization group between baseline and 3 months was found (P = .39, composite score). CONCLUSIONS: Compared with the conventional consultation process, store and forward teledermatology did not result in a statistically significant difference in skin-related quality of life at 3 or 9 months after referral. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00488293.

Positive patch test reactions in older individuals: retrospective analysis from the North American Contact Dermatitis Group, 1994-2008.

BACKGROUND: Relatively little is known about the epidemiology of allergic contact dermatitis in older individuals. OBJECTIVES: We sought to determine the frequency of positive and clinically relevant patch test reactions in older individuals (≥ 65 years old) referred for patch testing, and to compare these results with those of adults (≤ 64-19 years) and children (<18 years). DESIGN: This was a retrospective cross-sectional analysis of North American Contact Dermatitis Group data from 1994 to 2008. RESULTS: A total of 31,942 patients (older n = 5306; adults n = 25,028; children n = 1608) were patch tested. The overall frequency of at least one allergic reaction in older individuals was 67.3% as compared with 66.9% for adults (P = .5938) and 47% for children (P = .0011). Reaction rates that were statistically higher in older individuals as compared with both adults and children included: Myroxylon pereirae, fragrance mix I, quaternium-15, formaldehyde, imidazolidinyl urea, diazolidinyl urea, neomycin, bacitracin, methyldibromo glutaronitrile, methyldibromo glutaronitrile/phenoxyethanol, ethyleneurea melamine formaldehyde mix, and carba mix (P values < .0004). Patch test reaction rates that were significantly lower in older individuals than both comparison groups included: nickel, thimerosal, and cobalt (P values < .0001). LIMITATIONS: Referral population was a limitation. CONCLUSIONS: Older individuals were more likely to have at least one positive patch test reaction as compared with children, but had similar rates to adults. The frequency of positive reactions to specific allergens differed by age group, most likely as a result of exposures.