Michael K. McCormack

New measures to capture end of life concerns in Huntington disease: Meaning and Purpose and Concern with Death and Dying from HDQLIFE (a patient-reported outcomes measurement system).

PurposeHuntington disease (HD) is an incurable terminal disease. Thus, end of life (EOL) concerns are common in these individuals. A quantitative measure of EOL concerns in HD would enable a better understanding of how these concerns impact health-related quality of life. Therefore, we developed new measures of EOL for use in HD.MethodsAn EOL item pool of 45 items was field tested in 507 individuals with prodromal or manifest HD. Exploratory and confirmatory factor analyses (EFA and CFA, respectively) were conducted to establish unidimensional item pools. Item response theory (IRT) and differential item functioning analyses were applied to the identified unidimensional item pools to select the final items.ResultsEFA and CFA supported two separate unidimensional sets of items: Concern with Death and Dying (16 items), and Meaning and Purpose (14 items). IRT and DIF supported the retention of 12 Concern with Death and Dying items and 4 Meaning and Purpose items. IRT data supported the development of both a computer adaptive test (CAT) and a 6-item, static short form for Concern with Death and Dying.ConclusionThe HDQLIFE Concern with Death and Dying CAT and corresponding 6-item short form, and the 4-item calibrated HDQLIFE Meaning and Purpose scale demonstrate excellent psychometric properties. These new measures have the potential to provide clinically meaningful information about end-of-life preferences and concerns to clinicians and researchers working with individuals with HD. In addition, these measures may also be relevant and useful for other terminal conditions.

Multiple chromosome aberrations in an infant with acute monoblastic leukemia

A male infant was diagnosed at age 16 months with acute monoblastic leukemia. At diagnosis, studies of bone marrow revealed multiple chromosome aberrations: 48,XY,+8,+19,t(4;11). Chromosome studies have been repeated at remission and relapse over the course of his disease. To our knowledge, this combination of chromosome abnormalities has not been previously reported.

A psychometric study of children at‐risk for Huntington disease

Huntington disease (HD) is an autosomal dominant disorder of the central nervous system with an average age of onset between 35 and 45 years and symptoms progressing slowly over the next 10 to 20 years. Research in the past few years has focused on the hypothesis that a presymptomatic or prodromal phase for HD is detectable at least 10 years prior to chronic symptoms. This study attempts to identify possible signs of a prodromal phase for HD in children who are at primary (50%) and secondary (25%) risk for HD using a screening battery of psychometric tests. The children tested were between the ages of 5 1/2 and 15 years and the tests used were the WISC‐R, the PPVT‐R, and the VMI. Results from this study indicated performance on the WISC‐R Digit Span and to a lesser extent Coding subtests might be useful in assessing a possible memory dysfunction in children at‐risk for HD.

CAG nucleotide repeat profiles in persons with schizophrenia or schizoaffective disorders with and without tardive dyskinesia: Pilot study

Tardive dyskinesia (TD) is a drug‐induced syndrome of involuntary movements often associated with neuroleptic treatment of psychiatric conditions. Huntingtons disease (HD) and other neurological conditions are caused by CAG nucleotide repeat expansions in specific genes. We, therefore, explore the hypothesis that TD may be related to CAG repeat expansion by using the repeat expansion detection (RED) method as a measure of CAG content without knowledge of the location of the responsible gene. The number of CAG repeats ([CAG]n) from persons with schizophrenia or schizoaffective disorders with (n = 10) and without (n = 9) TD are determined. A comparison of [CAG]n in persons with (56.90 ± 23.45 repeats) and without (57.00 ± 19.35 repeats) TD was not statistically different. The total [CAG]n was determined by combining [CAG]n for both groups. The median of 45 repeats was used to divide the total into two groups (SG1 and SG2 with smaller and larger [CAG]n fragments, respectively) and a means analysis of the two subgroups based on [CAG]n demonstrated that SG1 (n = 10 samples at 45 repeats per sample, mean [CAG]n = 45.00 ± 0.00) was significantly smaller than SG2 (n = 9, ranging from 48 to 120 repeats, mean = 70.22 ± 24.83; P < 0.005). Thus, this lends support to the idea of CAG repeat expansions in the study population. Results are encouraging that a larger population and a more structured subject selection process may yield more meaningful information about the relationship between CAG repeat expansion and TD.

Risk factors associated with neural tube defects.

Spina bifida represents a broad category of neural tube defects (NTD) which affects approximately 1–4/1,000 live births. Since effective prenatal diagnostic testing for 90 % of NTD is available through measurement of alpha‐fetoprotein (AFP) in amniotic fluid, ascertainment of high risk factors associated with the occurrence of NTD would be both desirable and important. At the present time, generally, the major indication for prenatal testing for NTD is the presence of a first‐degree relative with some form of NTD. To date, few other factors have been utilized to identify a family as “at risk”.

Agreement between clinician-rated versus patient-reported outcomes in Huntington disease

BackgroundClinician-rated measures of functioning are often used as primary endpoints in clinical trials and other behavioral research in Huntington disease. As study costs for clinician-rated assessments are not always feasible, there is a question of whether patient self-report of commonly used clinician-rated measures may serve as acceptable alternatives in low risk behavioral trials.AimThe purpose of this paper was to determine the level of agreement between self-report and clinician-ratings of commonly used functional assessment measures in Huntington disease.Design486 participants with premanifest or manifest Huntington disease were examined. Total Functional Capacity, Functional Assessment, and Independence Scale assessments from the Unified Huntington Disease Rating scale were completed by clinicians; a self-report version was also completed by individuals with Huntington disease. Cronbach’s α was used to examine internal consistency, one-way analysis of variance was used to examine group differences, and paired t tests, kappa agreement coefficients, and intra-class correlations were calculated to determine agreement between raters.ResultsInternal consistency for self-reported ratings of functional capacity and ability were good. There were significant differences between those with premanifest, early-, and late-stage disease; those with later-stage disease reported less ability and independence than the other clinical groups. Although self-report ratings were not a perfect match with associated clinician-rated measures, differences were small. Cutoffs for achieving specified levels of agreement are provided.ConclusionsDepending on the acceptable margin of error in a study, self-reported administration of these functional assessments may be appropriate when clinician-related assessments are not feasible.

Evaluating cognition in individuals with Huntington disease: Neuro-QoL cognitive functioning measures

PurposeCognitive functioning impacts health-related quality of life (HRQOL) for individuals with Huntington disease (HD). The Neuro-QoL includes two patient-reported outcome (PRO) measures of cognition—Executive Function (EF) and General Concerns (GC). These measures have not previously been validated for use in HD. The purpose of this analysis is to evaluate the reliability and validity of the Neuro-QoL Cognitive Function measures for use in HD.MethodsFive hundred ten individuals with prodromal or manifest HD completed the Neuro-QoL Cognition measures, two other PRO measures of HRQOL (WHODAS 2.0 and EQ5D), and a depression measure (PROMIS Depression). Measures of functioning The Total Functional Capacity and behavior (Problem Behaviors Assessment) were completed by clinician interview. Objective measures of cognition were obtained using clinician-administered Symbol Digit Modalities Test and the Stroop Test (Word, Color, and Interference). Self-rated, clinician-rated, and objective composite scores were developed. We examined the Neuro-QoL measures for reliability, convergent validity, discriminant validity, and known-groups validity.ResultsExcellent reliabilities (Cronbach’s alphas ≥ 0.94) were found. Convergent validity was supported, with strong relationships between self-reported measures of cognition. Discriminant validity was supported by less robust correlations between self-reported cognition and other constructs. Prodromal participants reported fewer cognitive problems than manifest groups, and early-stage HD participants reported fewer problems than late-stage HD participants.ConclusionsThe Neuro-QoL Cognition measures provide reliable and valid assessments of self-reported cognitive functioning for individuals with HD. Findings support the utility of these measures for assessing self-reported cognition.

Relationships Among Apathy, Health-Related Quality of Life, and Function in Huntington’s Disease

Up to 90% of individuals with Huntingtons disease (HD)-a progressive, inherited neurodegenerative disorder-experience apathy. Apathy is particularly debilitating because it is marked by a reduction in goal-directed behaviors, including self-care, social interactions, and mobility. The objective of this study was to examine relationships between variables of apathy, functional status, physical function, cognitive function, behavioral status/emotional function, and health-related quality of life. Clinician-rated measures of physical, cognitive, and behavioral function, including one clinician-rated item on apathy, and self-reported measures of physical function, health-related quality of life, and emotional, cognitive, and social function were collected in a single session from 487 persons with the HD mutation (prodromal, N=193; early-stage manifest, N=186; late-stage manifest, N=108). Multiple linear regression models were used to examine which outcomes best predicted clinician-rated apathy after controlling for disease stage. Greater apathy related to less independence, increased motor impairment, and more clinician-rated behavioral problems (i.e., anger, irritability, depression). Similarly, poorer self-reported health-related quality of life; greater chorea; greater upper- and lower-extremity dysfunction; greater speech and swallowing dysfunction; worse anxiety, depression, and behavioral dyscontrol; worse cognitive function; and less satisfaction with social roles related to greater apathy. In conclusion, apathy related to physical, cognitive, and behavioral dysfunction across disease stages. Future work should explore whether clinical interventions targeting different functional domains may have the potential to reduce apathy in this patient population.

Factors Associated With End-of-Life Planning in Huntington Disease

Objective: Knowledge of one’s gene status for adult onset conditions provides opportunity to make advance end-of-life (EOL) plans. The purposes of these analyses were to (1) determine the prevalence of EOL plans, including advance directives (ADs) among persons across 3 stages of Huntington disease (HD) and (2) examine factors associated with having ADs in this sample. Methods: Data are from 503 participants in the HD Quality of Life study. Participants completed an online health-related quality-of-life survey that included questions regarding EOL planning and self-reported HD symptoms. Frequencies were calculated for EOL planning by the HD stage. Bivariate analysis and logistic regression were used to identify variables associated with having ADs. Results: A total of 38.2% of participants stated they had ADs and fewer than half had other EOL plans. Being older, increased HD stage, more years of education, lower anxiety, more swallowing symptoms, and higher meaning and purpose were associated with having ADs. Conclusion: The prevalence of ADs in our sample is comparable to the general US population, but surprisingly low, considering the severity and long disease course of HD. Practice Implications: Health-care providers should develop specific interventions early in the disease process to increase ADs in this population.

Reliability and Validity of the HD-PRO-TriadTM, a Health-Related Quality of Life Measure Designed to Assess the Symptom Triad of Huntington's Disease

BACKGROUND Huntingtons disease (HD), is a neurodegenerative disorder that is associated with cognitive, behavioral, and motor impairments that diminish health related quality of life (HRQOL). The HD-PRO-TRIADTM is a quality of life measure that assesses health concerns specific to individuals with HD. Preliminary psychometric characterization was limited to a convenience sample of HD participants who completed measures at home so clinician-ratings were unavailable. OBJECTIVES The current study evaluates the reliability and validity of the HD-PRO-TRIADTM in a well-characterized sample of individuals with HD. METHODS Four-hundred and eighty-two individuals with HD (n = 192 prodromal, n = 193 early, and n = 97 late) completed the HD-PRO-TRIADTM questionnaire. Clinician-rated assessments from the Unified Huntington Disease Rating Scales, the short Problem Behaviors Assessment, and three generic measures of HRQOL (WHODAS 2.0, RAND-12, and EQ-5D) were also examined. RESULTS Internal reliability for all domains and the total HD-PRO-TRIADTM was excellent (all Cronbachs α >0.93). Convergent and discriminant validity were supported by significant associations between the HD-PRO-TRIADTM domains, and other patient reported outcome measures as well as clinician-rated measures. Known groups validity was supported as the HD-PRO-TRIADTM differentiated between stages of the disease. Floor and ceiling effects were generally within acceptable limits. There were small effect sizes for 12-month change over time and moderate effect sizes for 24-month change over time. CONCLUSIONS Findings support excellent internal reliability, convergent and discriminant validity, known groups validity, and responsiveness to change over time. The current study supports the clinical efficacy of the HD-PRO-TRIADTM. Future research is needed to assess the test-retest reliability of this measure.