Case study: Development and validation of PHTS specific neurobehavioural evaluation tools

Key facts

Research category: Clinical outcomes measures

Project 1: Lead researchers: Dr Mirko Uljarevic1 and Professor Antonio Hardan2

Institution: 1Melbourne School of Psychological Sciences, University of Melbourne, Australia; 2Stanford University Medical Center, California, USA

Project start: January 2021           Expected completion: Completed

Project 2: Lead researcher: Professor Thomas Frazier

Institution: John Carroll University, Ohio, USA 

Project start: February 2021           Expected completion: July 2024

Project goals

Dr Uljarevic, Professor Hardan and Professor Frazier are collaborating on two projects, both focussed on the development of validated clinical evaluation tools to characterise and quantify symptoms of neurodevelopmental delay in people with PHTS, and to track longitudinal changes in response to treatment.


Currently, there is a lack of measures specifically developed and tailored for the PHTS population. The high prevalence of neurodevelopmental and neuropsychiatric symptoms in this clinically diverse population, together with the significant negative impact on affected individuals and their families, makes this particular manifestation a key target for the development of improved clinical measures. New tools should be optimised for screening, diagnosis, treatment outcome monitoring and neurobiological investigations in this population. An additional challenge for rare conditions, such as PHTS, is that people with the condition are often very distant from specialist research centres, so remote tools are highly desirable.

Study design

The first project, at the University of Melbourne, is conducting a rigorous psychometric evaluation of currently available assessment instruments to clarify the symptom structure in children and young adults with PTEN mutations. Learnings will then be used to modify and improve those instruments and take initial steps towards the development of dedicated PHTS assessments.

This project will examine a comprehensive battery of instruments that were designed to capture key clinical domains of interest, including social and communication functioning, restricted and repetitive behaviours, motor skills, executive functioning, and neuropsychiatric and behavioural problems.

The second project, at John Carroll University, will develop, pilot, test and validate a web-based, neurobehavioural evaluation tool designed specifically for people with PHTS. It will include caregiver-administered survey scales and, as an exploratory objective, assess the use of webcam-collected performance measures to facilitate remote capture of key neurobehavioural information. Once feasibility is established and pilot testing is complete, baseline data will be collected from at least 200 patient-caregiver pair groups, including individuals who have PHTS with or without neurobehavioural development delay (NDD), and control groups, with longitudinal follow-up.

Recruitment of families for the survey scale and webcam-collected performance measures took place in the USA and UK (NCT05671107) and has now been completed. The development of the survey scale has been published in The American Journal of Medical Genetics Part A (doi:10.1002/ajmg.a.63195) and the webcam performance measure in The American Journal of Medical Genetics Part C (doi:10.1002/ajmg.c.32058).

Anticipated outcomes of this work

Validated clinical outcomes tools will be critical for the efficacy assessment of investigational medications in PHTS clinical trials, and thus form an important step in the pathway to developing new targeted treatments. Furthermore, clinical management of individuals may benefit from having simple tools to track the progression of symptoms over time and inform when interventions are needed, as well as their impact.