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The Department of Computational Biology has had a long history of association with biological statisticians, tracing back to the very first uses of computers in performing statistical analysis.  The earliest roots trace to the Biometrics Unit within the Department of Plant Breeding, founded in 1947. In 1948 Walter T. Federer was hired as its first faculty along with a secretary and a technical assistant; they were provided with (at that time) state-of-the-art Monroe and Marchant desk calculators.

The department continued to grow from the mid 1950's through the 1960's, increasing both the number of faculty and the scope of its research. In 1966, the status of the Biometrics Unit was recognized in the renamed Department of Plant Breeding and Biometry and in 1998, the Unit became the Department of Biometrics, affiliated with the Department of Statistical Science, with seven full-time faculty.

The Biometrics Unit and later the Department of Biometrics had a distinguished record in research, including Walter Federer, Shayle Searle, Charles McCulloch and George Casella as faculty. A report on the first 40 years of the unit lists 1041 technical reports, 546 papers, 21 books and 132 theses written. From the very beginning, the Unit had a strong service element providing statistical consulting to faculty and graduate students throughout Cornell University; this tradition continues to this day.

In 2000, the Department of Biometry was reformulated as the Department of Biological Statistics and Computational Biology in order to incorporate the new and rapidly expanding field of quantitative and evolutionary genomics. As of 2008, four new faculty have joined the department in the graduate field of Computational Biology and have established links with the Weill Medical School, the New Life Sciences Initiative and the Institute for Cell Biology.  In 2019, the department lost its statisticians to the new Department of Statistics and Data Science, retaining some members as joint faculty, and of course retaining a vibrant set of active collaborations.  At this same time, the Department of Computational Biology was formed, with promise to grow in exciting new directions.