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Evaluating proposed phenotypic predictors of recurrence risk in unaffected individuals with a family history of isolated cleft lip with or without cleft palate

Skinner, Charlotte (2019) Evaluating proposed phenotypic predictors of recurrence risk in unaffected individuals with a family history of isolated cleft lip with or without cleft palate. Master's Thesis, University of Pittsburgh. (Unpublished)

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Cleft lip ± cleft palate (CL/P) is a common birth defect and public health concern, with significant, long-term health impacts, which require many healthcare resources and increase costs of care. The majority (>70%) of cases are isolated and non-syndromic (NSCL/P). Single-gene syndromes, chromosome anomalies, or teratogens account for the remainder. There is a strong genetic component in NSCL/P; individuals with a positive family history are more likely to have an affected child. The complex, multifactorial nature of NSCL/P complicates recurrence risk assessment. Currently, genetic counseling for NSCL/P is based on empiric recurrence risk figures from large cohort studies. Thus, risk assessment cannot be personalized. Developing predictive models based on established risk factors could refine estimates. Several subtle phenotypic differences have been identified among unaffected relatives of an individual with NSCL/P, compared to individuals with no family history. Phenotypes consistently associated with NSCL/P may be useful as markers of recurrence risk. The present study investigated the effect of seven such traits, on the odds of participants’ case versus control family status. Three models were built using logistic regression. Model 1 included orbicularis oris muscle defects and velopharyngeal dysfunction, and achieved an area under the receiver operating curve (AUC) of 0.63. Model 2 included maximum facial and intercanthal width, upper and lower facial height, and midface depth measurements, and achieved an AUC of 0.64. Model 3 included all variables from Models 1 and 2, and achieved an AUC of 0.72. AUC values below 0.7 indicate poor model discrimination. Models 1 and 2 had poor predictive performance, while Model 3 had fair performance. The public health significance of this work is that it adds to the body of research on risk factors and recurrence risk assessment in NSCL/P. It also works towards creating risk models. Reliable risk models allow for the identification of high-risk individuals, therefore making it possible to design and/or implement primary and secondary prevention interventions.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Skinner, Charlotteche24@pitt.eduche24
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairMarizita,
Committee MemberAndrea,
Committee MemberJohn,
Committee MemberSeth,
Date: 25 July 2019
Date Type: Publication
Defense Date: 10 June 2019
Approval Date: 25 July 2019
Submission Date: 19 June 2019
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 155
Institution: University of Pittsburgh
Schools and Programs: School of Public Health > Genetic Counseling
Degree: MS - Master of Science
Thesis Type: Master's Thesis
Refereed: Yes
Uncontrolled Keywords: cleft lip, cleft palate, orofacial cleft, recurrence risk, risk modeling, predicting risk, predictive modeling, phenotypic risk factor
Date Deposited: 25 Jul 2019 14:00
Last Modified: 25 Jul 2019 14:00


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