Colorado Family Reading Study. Our first attempt to investigate the etiology of a learning disability was the Colorado Family Reading Study, initiated in 1973 by a grant from the Spencer Foundation.  The primary objectives of that study were as follows: (1) to construct a short battery of tests that differentiates children with a diagnosed reading disability from matched controls; (2) to assess possible deficits in parents and siblings of affected children; and (3) to study the transmission of reading disability in families of affected children. Children with reading difficulties were ascertained by referral from local school districts and matched to control children on the basis of age, gender, grade, school, and home neighborhood.

Between October 1, 1973, and July 30, 1976, 133 reading-disabled children, their parents and siblings (7.5 to 18 years of age), and members of 125 control families were administered an extensive test battery.  On measures of both reading performance and symbol-processing speed, siblings and parents of probands manifested substantial and highly significant deficits (DeFries, Singer, Foch, & Lewitter, 1978).  During the next several years these family data were subjected to various genetic analyses including tests for sex-influenced polygenic inheritance and both X-chromosome and autosomal major-gene effects (for reviews, see DeFries & Decker, 1982; DeFries, Vogler, & LaBuda, 1986).  Subsequently, results obtained from a complex segregation analysis of these data by Center co-investigators (Pennington et al., 1991) provided evidence for a dominant major-gene effect with sex-dependent penetrance.

Colorado Reading Project.  In order to obtain data from reading-disabled and control children on a broader array of measures, a program project application (Differential Diagnosis in Reading Disability, 5 P01 HD11681) was funded on July 1, 1979.  During the 01-03 project periods, a test battery that included measures of cognitive abilities, reading and language processes, and electrophysiological activity was developed and administered to a sample of 140 reading-disabled children and 140 matched controls.  Because approximately half of these children were previously tested in the Colorado Family Reading Study, the resulting data set facilitated longitudinal analyses, as well as risk and typological analyses (e.g., DeFries, 1983, 1988; Vogler, Baker, Decker, DeFries, & Huizinga, 1989; Vogler, DeFries, & Decker, 1985_ENREF_41).

A twin study of reading disability was initiated during project periods 04-06.  During this period, the test battery was administered to 30 identical and 30 fraternal twin pairs in which at least one member of each pair had reading difficulties, to an equal number of control twins, to 50 nontwin reading-disabled and 50 nontwin control children who were tested during project periods 01-03, and to the parents and siblings of these children.  Results obtained from analyses of these data were reported at an NICHD conference on "Biobehavioral Measures of Dyslexia." (Decker & Vandenberg, 1985; DeFries, 1985; Olson, 1985; Schucard, Cummins, Gay, Lairsmith, & Welanko, 1985).

During project periods 07-09, we proposed to enlarge the sample to include additional twin pairs and members of nuclear families in which one or more children were reading disabled.  However, during this period we developed a new multiple regression analysis of twin data that is highly versatile and statistically more powerful than alternative methods (DeFries & Fulker, 1985, 1988). Thus, additional resources were devoted to the recruitment and testing of twins during subsequent project periods.

Because of its special relevance to the specific aims of the program project, a new component (Linkage Analysis) was added during budget periods 07-09.  During budget periods 07-12, Drs. Shelley Smith and Bruce Pennington selected program project families who manifested apparent autosomal dominance for reading disability and then attempted to replicate their previous finding of linkage to chromosome 15 (Smith, Kimberling, Pennington, & Lubs, 1983) using genetic markers that included DNA restriction fragment length polymorphisms.  In addition, a new component directed by Dr. Pennington (Epidemiology of Immunological Differences) was added during budget periods 10-12.

Because our application for the Colorado Learning Disabilities Research Center was funded for five years beginning September 30, 1990, we did not apply for competitive renewal of the program project. As indicated below, applications for competitive renewal of the Colorado Learning Disabilities Research Center were subsequently funded for the budget periods of 04/01/96 - 11/30/2000, 12/01/2000 – 11/30/2005, and the current budget period of 12/01/2005 – 11/30/2010, The current budget period was lengthened through ARRA supplement funding to 11/30/2011 in order to align the funding cycle of the CLDRC to be consistent with the other LD Centers.

Colorado Learning Disabilities Research Center (CLDRC).  A major goal of the co-investigators of the CLDRC is to assess the genetic and environmental etiologies of reading disabilities, ADHD and their comorbidity, as well as their covariation with measures of reading, language and perceptual processes, executive functions, and other psychopathology. (Changes in CLDRC focus across the different budget periods are described in the following paragraphs.) To accomplish this goal, Administrative Core Unit staff ascertain and schedule twin pairs and siblings that are tested in each of the individual research projects.  During budget periods 01-05, test batteries that included measures of cognitive abilities (Research Project I, DeFries and Fulker), reading and language processes (Research Project II, Olson), and ADHD and executive functions (Research Project III, Pennington) were administered to 100 pairs of identical twins and 100 pairs of fraternal twins (both same-sex and opposite-sex) in which at least one member of each pair had a substantial deficit in reading and/or mathematics, to a comparison group of 50 pairs of identical twins and 50 pairs of fraternal twins with a school history of no significant deficit in either reading or mathematics, and to the siblings of all twins.  In order to map quantitative trait loci that may influence learning disabilities, blood samples or buccal swabs were obtained from families of all twin pairs and analyzed by staff of Research Project IV (Smith).  Average yearly direct costs during budget periods 1-5 of the CLDRC were $680,492.

The CLDRC application for budget periods 6 – 10 included continued testing of twins and siblings as in budget periods 1 – 5, and continued analyses of their DNA. In addition to a new sample of 50 pairs of identical twins and 50 pairs of fraternal twins in which at least one member of each pair has reading deficits, a new selection procedure was added to identify an independent sample of 50 pairs of identical twins and 50 pairs of fraternal twins in which at least one member of each pair manifested symptoms of ADHD. As in budget periods 01-05, we also tested a comparison sample of 50 pairs of identical twins and 50 pairs of fraternal twins with no school history of learning disabilities or ADHD.  The application for budget periods 06-10 also included funding for continued studies of computer-based remediation of reading disabilities in the schools that had previously been funded exclusively through separate R01 grants (Olson, PI). These studies were quite successful for improving word reading and spelling skills in the early grades, and they yielded important information about developmental changes in the optimal balance of instruction, concentrating on phonological awareness and decoding in grades 2 and 3, and on computer-supported accurate reading in grades 4-5 (Wise, Ring, & Olson, 1999, 2000). The intervention study was not continued into the following funding cycle because of the high cost of personnel needed to support the computer programs and small-group instruction in the schools. Average yearly direct costs during budget periods 6-10 of the CLDRC were $850,738.

The CLDRC application for the 2000 – 2005 budget period included two new projects that were responsive to that RFA. They included a major expansion of Project II, with a subcontract to Janice Keenan at the University of Denver to focus on reading and listening comprehension, and Project V with a subcontract to Brian Byrne in Australia to support a longitudinal twin study (beginning in preschool) that ran parallel to an R01 funded longitudinal study in Colorado (Olson, P.I.) . The increased emphasis on reading comprehension in Project II was based on evidence that while deficits in phonological decoding and word recognition were important in most reading disabilities, they were not the only factors constraining the ultimate goal of reading, comprehension. Average yearly direct costs during budget periods 11-15 were $1,114,640.

Our expanded assessment of comprehension led us to discover that genetic influences underlying comprehension were distinct from those for word reading (Keenan, Betjemann, Wadsworth, DeFries, & Olson, 2006) and thus supported the view that distinctly different deficits can underlie different learning disabilities. Thus, for the current 2005 -2011 funding period we continued our emphasis on reading and listening comprehension and expanded it to include fluency and writing. In addition, the computer-based intervention programs that were run in the schools during budget periods 6 – 10 were revised and adapted to run more independently for children with reading disabilities in the early grades (Wise, P.I.). We also continued longitudinal research on reading with separate R01 funding for both the study starting with preschoolers (Olson, P.I.) and the reassessment of adolescent twins that were tested earlier in the CLDRC (Wadsworth, PI). For the continuing molecular studies we switched to much more stable saliva sampling and were awarded ARRA funds to substantially increase our sample size, allowing us to expand our molecular genetic collaborations in important new directions (described in more detail in Project IV and Service Core B). Average yearly direct costs during budget periods 16-20 of the CLDRC, including the current ARRA supplement year 21 were $1,162,080.

In conclusion, the CLDRC projects have evolved across the Center funding cycles to be responsive to emerging knowledge and changing emphases in the Center RFAs. With the present Center application, we look forward to developing new knowledge about the etiologies of disabilities in reading and listening comprehension and reading fluency, writing, mathematics, and their comorbidities with each other and with ADHD, all within a behavioral- and molecular-genetic design. In addition, Center investigators plan to continue their longitudinal behavior-genetic studies of early and later reading development in a new Project VI (Wadsworth, P.I.) and in conjunction with separately-funded longitudinal studies (Willcutt, P.I., Hewitt, P.I.). We do not propose to continue the computer-based intervention study that is currently being conducted in the schools (Wise, P.I.). That project has been supplemented with substantial separate funding from the Institute for Educational Science, which is no longer available. Given the LD centers’ funding cap, there are not sufficient resources for continued support of this costly intervention study. The specific aims of the research in each of the six proposed Center projects, and the progress that has been achieved to date, are summarized in their individual Research Project Descriptions.