Neurocognitive performance in family-based and case-control studies of schizophrenia

Abstract

Background

Neurocognitive deficits in schizophrenia (SZ) are established and the Consortium on the Genetics of Schizophrenia (COGS) investigated such measures as endophenotypes in family-based (COGS-1) and case-control (COGS-2) studies. By requiring family participation, family-based sampling may result in samples that vary demographically and perform better on neurocognitive measures.

Methods

The Penn computerized neurocognitive battery (CNB) evaluates accuracy and speed of performance for several domains and was administered across sites in COGS-1 and COGS-2. Most tests were included in both studies. COGS-1 included 328 patients with SZ and 497 healthy comparison subjects (HCS) and COGS-2 included 1195 patients and 1009 HCS.

Results

Demographically, COGS-1 participants were younger, more educated, with more educated parents and higher estimated IQ compared to COGS-2 participants. After controlling for demographics, the two samples produced very similar performance profiles compared to their respective controls. As expected, performance was better and with smaller effect sizes compared to controls in COGS-1 relative to COGS-2. Better performance was most pronounced for spatial processing while emotion identification had large effect sizes for both accuracy and speed in both samples. Performance was positively correlated with functioning and negatively with negative and positive symptoms in both samples, but correlations were attenuated in COGS-2, especially with positive symptoms.

Conclusions

Patients ascertained through family-based design have more favorable demographics and better performance on some neurocognitive domains. Thus, studies that use case-control ascertainment may tap into populations with more severe forms of illness that are exposed to less favorable factors compared to those ascertained with family-based designs.

Introduction

Methods of ascertainment are pivotal across biomedical research and are an important consideration in the research design. In genetic studies, the utility and statistical approach of family-based and unrelated case-controls studies has been discussed (e. g. Hiekkalinna et al., 2012). The incorporation of endophenotypes to genetic investigations of schizophrenia (SZ) has grown significantly with neurocognitive measures (Gur et al., 2007a, Gur et al., 2007b, Lee et al., 2015--in this issue, Nuechterlein et al., 2015--in this issue, Stone et al., 2015--in this issue) and neurophysiological measures (Swerdlow et al., 2014, Light et al., 2015--in this issue, Turetsky et al., 2015--in this issue) playing key roles. Family-based designs enable testing the endophenotype criteria (Braff et al., 2007, Braff, 2015--in this issue, Gottesman and Gould, 2003) and, when sufficiently powered, allow for the examination of heritability, association with the disease phenotype and co-segregation within families (Glahn et al., 2014, Greenwood et al., 2007, Greenwood et al., 2011, Greenwood et al., 2013).

Several meta-analyses have reported that adult relatives of probands with SZ show intermediate deficits in neurocognitive measures including executive functions, such as working memory and attention, verbal fluency and sensori-motor speed (Faraone et al., 2001, Kremen and Hoff, 2004, Sitskoorn et al., 2004, Snitz et al., 2006). Similar deficits have also been observed in younger relatives (Niemi et al., 2003, Seidman et al., 2006, Keshavan et al., 2010, Agnew-Blais and Siedman, 2013). The neurocognitive domains implicated in family-based studies are similar to deficits observed in case-control studies (Gur et al., 2001b). Yet, direct evaluation of these complementary ascertainment strategies applying the same measures has not been conducted. The Penn computerized neurocognitive battery (CNB) used in the Consortium on the Genetics of Schizophrenia (COGS) provides a unique opportunity to evaluate effects of ascertainment methods—family-based (COGS-1) vs. case control (COGS-2)—with the same neurocognitive battery across the participating sites.

The CNB, developed in concert with functional neuroimaging studies (Gur et al., 2010), has been validated in healthy participants and people with SZ (Gur et al., 2001a, Gur et al., 2001b) and is sensitive to the effects of age and sex (Gur et al., 2012, Irani et al., 2012). The battery, which provides measures of performance accuracy and response time, was applied in three independent large-scale family-based genetic studies. The Multiplex Multigenerational Investigation of Schizophrenia (MGI; Gur et al., 2007a) reported that probands demonstrated greatest impairment relative to healthy controls, with intermediate performance of family members. Liability for SZ affected the speed–accuracy tradeoff differently for specific neurocognitive domains. Significant heritability estimates were obtained for accuracy of verbal, facial, and spatial memory and spatial and emotion processing. For speed, estimates of heritability were significant for abstraction and mental flexibility, attention, face memory, and spatial and sensorimotor processing. The results of the Project among African-Americans to Explore Risks for Schizophrenia (PAARTNERS) revealed that patients with SZ exhibited less accuracy and speed in most neurocognitive domains than their relatives, who were impaired relative to HCS in most domains. Significant heritabilities were observed for most neurocognitive domains, with the highest for accuracy of abstraction and mental flexibility, verbal memory, face memory, spatial processing, and emotion processing and for speed of attention (Calkins et al., 2010).

In COGS-1 all of the measures applied from the Penn CNB (Abstraction and Mental Flexibility, Face Memory, Spatial Memory, Spatial Processing, Sensorimotor Dexterity, and Emotion Recognition) were significantly heritable with heritability estimates ranging from 24% for Spatial Memory to 55% for Spatial Processing (Greenwood et al., 2007). These heritabilities are in the same range as the heritability of SZ itself in the COGS-1 families (Light et al., in press). Furthermore, we noted sex differences in familiality effects with male probands' performance predictive of performance of their unaffected relatives (Calkins et al., 2013). The subsequent application of the CNB in the case-control design of COGS-2 enabled evaluation of the pattern of performance of individuals with SZ, compared to HCS, ascertained in family-based and case-control designs. We noted that in some endophenotypic measures in COGS-1 probands were less impaired than observed in other samples of patients with SZ (Greenwood et al., 2007). The major ascertainment difference between the samples is that patients recruited for COGS-1 required the availability of parents and siblings while COGS-2 permitted participation of patients regardless of family availability (Swerdlow et al., 2015--in this issue). This difference likely affects multiple demographic characteristics related to age, education, socioeconomic status as well as severity of illness, favoring COGS-1. We hypothesized that while the profile of impairment would be similar, probands in the COGS-1 family-based ascertainment would perform better than those ascertained as cases in COGS-2.