Date of Award

5-2026

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Healthcare Genetics

Committee Chair/Advisor

Tracy B. Lowe, Ph.D., M.S., R.N

Committee Member

Sara M. Sarasua, Ph.D.

Committee Member

Christopher L. Farrell, Ph.D.

Committee Member

Melanie Gillingham, Ph.D., R.D., L.D.

Abstract

Inborn errors of metabolism (IEMs) are a group of rare genetic disorders in which individuals cannot properly process specific dietary nutrients due to an insufficient or absent enzyme. Many IEMs, including phenylketonuria (PKU), require lifelong dietary management to limit substrate buildup and prevent neurological or other health complications associated with the untreated disease.

Within IEMs, metabolic biomarkers are used to guide treatment decisions, assess metabolic control, and evaluate clinical outcomes. For example, in PKU, blood phenylalanine (Phe) levels are used to adjust dietary intake as well as monitor for treatment adherence. More recently, pharmaceutical therapeutics have been developed, or are currently in development, for several IEMs. When a therapy is under investigation, the same biomarkers used to monitor clinical and dietary management are also used to determine drug efficacy. This creates a challenge, as dietary intake affects the laboratory values used to evaluate therapeutic response. Without prior characterization of natural dietary and biomarker variability, interpretation of treatment effects may be complicated by changes unrelated to the intervention itself. The objective of this dissertation was to evaluate how dietary intake is addressed within clinical trials for nutrition-related disorders and to quantify natural variability in dietary intake and key biomarkers, with particular attention to how dietary changes influence biomarker response.

This work included two reviews conducted using a systematic process and an original data-based analysis. The first review examined phase 2 and 3 clinical trials in weight loss, diabetes, and PKU to evaluate how dietary intake was measured, controlled, and reported when diet could influence primary outcomes. The second review focused on clinical trials across IEMs to assess how dietary management was incorporated into study design and to compare current practices with relevant U.S. Food and Drug Administration (FDA) dietary management guidance and established clinical research practices.

Across both reviews, dietary intake was inconsistently measured and reported despite its direct influence on primary endpoints. Trials in weight loss and diabetes frequently did not report detailed dietary intake during study periods. Trials in PKU and other IEMs were more likely to include dietary monitoring; however, they often did not clearly define acceptable dietary variability, specify allowable deviations from usual intake, or describe how dietary changes were considered when interpreting laboratory outcomes. Comparison with FDA guidance indicated that although dietary stability is emphasized, operational definitions and reporting practices vary substantially across studies, with many trials not addressing key elements of existing guidance.

The original research study utilized a multi-center, longitudinal dataset of individuals with PKU that included repeated three-day diet records and blood Phe measurements collected over multiple years across genotype and pharmacotherapy subgroups. Both intra- and inter-individual variability in dietary intake, as well as variability in blood Phe levels, were evaluated to characterize natural fluctuations under routine clinical care. Longitudinal analyses and mixed-effects modeling were used to assess associations between dietary intake and blood Phe levels, including temporally paired diet and biomarker measurements.

Substantial variability was observed in both dietary intake and blood Phe levels over time, with blood Phe variability often exceeding variability in dietary intake. Variability patterns differed by genotype severity and medication status, with pharmacologic therapy altering variability structure. Among individuals with classic PKU managed with diet alone, short-term changes in natural protein intake were closely associated with corresponding changes in blood Phe. These findings demonstrate that natural dietary fluctuations can meaningfully influence primary biomarkers in the absence of pharmacologic intervention.

Collectively, this dissertation highlights the importance of applying sound nutritional research principles, including attention to precision, reproducibility, and validity, when designing and interpreting clinical trials for PKU and other nutrition-dependent disorders. Clearer definitions of dietary stability, improved characterization of baseline biomarker variability, and more consistent reporting of dietary intake are necessary to strengthen interpretation of treatment effects. By quantifying natural dietary and biomarker variability and examining how diet is incorporated into current trial designs, this work provides a framework for improving methodological rigor and interpretability in clinical trials for IEMs and other conditions in which diet directly influences laboratory outcomes.

Author ORCID Identifier

0000-0002-6205-283X

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