Missing Values in Longitudinal Proteome Dynamics Studies: Making a Case for Data Multiple Imputation.

Temporal proteomics data sets are often confounded by the challenges of missing values. These missing data points, in a time-series context, can lead to fluctuations in measurements or the omission of critical events, thus hindering the ability to fully comprehend the underlying biomedical processes. We introduce a Data Multiple Imputation (DMI) pipeline designed to address this challenge in temporal data set turnover rate quantifications, enabling robust downstream analysis to gain novel discoveries. To demonstrate its utility and generalizability, we applied this pipeline to two use cases: a murine cardiac temporal proteomics data set and a human plasma temporal proteomics data set, both aimed at examining protein turnover rates. This DMI pipeline significantly enhanced the detection of protein turnover rate in both data sets, and furthermore, the imputed data sets captured new representation of proteins, leading to an augmented view of biological pathways, protein complex dynamics, as well as biomarker-disease associations. Importantly, DMI exhibited superior performance in benchmark data sets compared to single imputation methods (DSI). In summary, we have demonstrated that this DMI pipeline is effective at overcoming challenges introduced by missing values in temporal proteome dynamics studies.

Development and validation of a computable phenotype for Turner syndrome utilizing electronic health records from a national pediatric network.

Turner syndrome (TS) is a genetic condition occurring in ~1 in 2000 females characterized by the complete or partial absence of the second sex chromosome. TS research faces similar challenges to many other pediatric rare disease conditions, with homogenous, single-center, underpowered studies. Secondary data analyses utilizing electronic health record (EHR) have the potential to address these limitations; however, an algorithm to accurately identify TS cases in EHR data is needed. We developed a computable phenotype to identify patients with TS using PEDSnet, a pediatric research network. This computable phenotype was validated through chart review; true positives and negatives and false positives and negatives were used to assess accuracy at both primary and external validation sites. The optimal algorithm consisted of the following criteria: female sex, ≥1 outpatient encounter, and ≥3 encounters with a diagnosis code that maps to TS, yielding an average sensitivity of 0.97, specificity of 0.88, and C-statistic of 0.93 across all sites. The accuracy of any estradiol prescriptions yielded an average C-statistic of 0.91 across sites and 0.80 for transdermal and oral formulations separately. PEDSnet and computable phenotyping are powerful tools in providing large, diverse samples to pragmatically study rare pediatric conditions like TS.

Exploring the role of digital tools in rare disease management: An interview-based study.

While digital tools, such as the Internet, smartphones, and social media, are an important part of modern society, little is known about the specific role they play in the healthcare management of individuals and caregivers affected by rare disease. Collectively, rare diseases directly affect up to 10% of the global population, suggesting that a significant number of individuals might benefit from the use of digital tools. The purpose of this qualitative interview-based study was to explore: (a) the ways in which digital tools help the rare disease community; (b) the healthcare gaps not addressed by current digital tools; and (c) recommended digital tool features. Individuals and caregivers affected by rare disease who were comfortable using a smartphone and at least 18 years old were eligible to participate. We recruited from rare disease organizations using purposive sampling in order to achieve a diverse and information rich sample. Interviews took place over Zoom and reflexive thematic analysis was utilized to conceptualize themes. Eight semistructured interviews took place with four individuals and four caregivers. Three themes were conceptualized which elucidated key aspects of how digital tools were utilized in disease management: (1) digital tools should lessen the burden of managing a rare disease condition; (2) digital tools should foster community building and promote trust; and (3) digital tools should provide trusted and personalized information to understand the condition and what the future may hold. These results suggest that digital tools play a central role in the lives of individuals with rare disease and their caregivers. Digital tools that centralize trustworthy information, and that bring the relevant community together to interact and promote trust are needed. Genetic counselors can consider these ideal attributes of digital tools when providing resources to individuals and caretakers of rare disease.

Development and Validation of a Computable Phenotype for Turner Syndrome Utilizing Electronic Health Records from a National Pediatric Network.

Turner syndrome (TS) is a genetic condition occurring in ~1 in 2,000 females characterized by the complete or partial absence of the second sex chromosome. TS research faces similar challenges to many other pediatric rare disease conditions, with homogenous, single-center, underpowered studies. Secondary data analyses utilizing Electronic Health Record (EHR) have the potential to address these limitations, however, an algorithm to accurately identify TS cases in EHR data is needed. We developed a computable phenotype to identify patients with TS using PEDSnet, a pediatric research network. This computable phenotype was validated through chart review; true positives and negatives and false positives and negatives were used to assess accuracy at both primary and external validation sites. The optimal algorithm consisted of the following criteria: female sex, ≥1 outpatient encounter, and ≥3 encounters with a diagnosis code that maps to TS, yielding average sensitivity 0.97, specificity 0.88, and C-statistic 0.93 across all sites. The accuracy of any estradiol prescriptions yielded an average C-statistic of 0.91 across sites and 0.80 for transdermal and oral formulations separately. PEDSnet and computable phenotyping are powerful tools in providing large, diverse samples to pragmatically study rare pediatric conditions like TS.