Utilization of Positive and Negative Controls to Examine Comorbid Associations in Observational Database Studies.

BACKGROUND: Opportunities to leverage observational data for precision medicine research are hampered by underlying sources of bias and paucity of methods to handle resulting uncertainty. We outline an approach to account for bias in identifying comorbid associations between 2 rare genetic disorders and type 2 diabetes (T2D) by applying a positive and negative control disease paradigm. RESEARCH DESIGN: Association between 10 common and 2 rare genetic disorders [Hereditary Fructose Intolerance (HFI) and α-1 antitrypsin deficiency] and T2D was compared with the association between T2D and 7 negative control diseases with no established relationship with T2D in 4 observational databases. Negative controls were used to estimate how much bias and variance existed in datasets when no effect should be observed. RESULTS: Unadjusted association for common and rare genetic disorders and T2D was positive and variable in magnitude and distribution in all 4 databases. However, association between negative controls and T2D was 200% greater than expected indicating the magnitude and confidence intervals for comorbid associations are sensitive to systematic bias. A meta-analysis using this method demonstrated a significant association between HFI and T2D but not for α-1 antitrypsin deficiency. CONCLUSIONS: For observational studies, when covariate data are limited or ambiguous, positive and negative controls provide a method to account for the broadest level of systematic bias, heterogeneity, and uncertainty. This provides greater confidence in assessing associations between diseases and comorbidities. Using this approach we were able to demonstrate an association between HFI and T2D. Leveraging real-world databases is a promising approach to identify and corroborate potential targets for precision medicine therapies.

A case report of Poland Syndrome with Absent Limb Anomalies.

INTRODUCTION: Poland Syndrome(PS) is a rare congenital condition associated with the absence of unilateral chest wall muscles and sometimes ipsilateral symbrachydactyly (abnormally short and webbed fingers). The condition typically presents with unilateral absence of the sternal portion of the pectoralis major muscle which may or may not be associated with a hypoplasia of the breast, an ipsilateral webbing of the fingers (cutaneous syndactyly) and agenesis of 2, 3, 4, and 5 ipsilateral costal cartilages, and athelia. CASE REPORT: We report a 13-year-old patient with an atypical variant of PS without any limb anomalies. In view of the good function of the upper limb, no surgical treatment was offered, and the patient and his family were counseled regarding the condition. A follow-up of the patient at 2 years revealed that the patient is still asymptomatic with good functional status of the upper limb. CONCLUSION: It is hoped that this paper will further improve our understanding of this rare syndrome and its atypical presentations.

Creation and implementation of a historical controls database from randomized clinical trials.

BACKGROUND: Ethical concerns about randomly assigning patients to suboptimal or placebo arms and the paucity of willing participants for randomization into control and experimental groups have renewed focus on the use of historical controls in clinical trials. Although databases of historical controls have been advocated, no published reports have described the technical and informatics issues involved in their creation. OBJECTIVE: To create a historical controls database by leveraging internal clinical trial data at Pfizer, focusing on patients who received only placebo in randomized controlled trials. METHODS: We transformed disparate clinical data sources by indexing, developing, and integrating clinical data within internal databases and archives. We focused primarily on trials mapped into a consistent standard and trials in the pain therapeutic area as a pilot. RESULTS: Of the more than 20,000 internal Pfizer clinical trials, 2404 completed placebo controlled studies with a parallel design were identified. Due to challenges with informed consent and data standards used in older clinical trials, studies completed before 2000 were excluded, yielding 1134 studies from which placebo subjects and associated clinical data were extracted. CONCLUSIONS: It is technically feasible to pool portions of placebo populations through a stratification and segmentation approach for a historical placebo group database. A sufficiently large placebo controls database would enable previous distribution calculations on representative populations to supplement, not eliminate, the placebo arm of future clinical trials. Creation of an industry-wide placebo controls database, utilizing a universal standard, beyond the borders of Pfizer would add significant efficiencies to the clinical trial and drug development process.