A common critique of biologists, and scientists in general, concerns their occasionally overenthusiastic tendency to find patterns in nature – especially when the pattern is a straight line. It is certainly notable how, confronted with a cloud of noisy data, scientists often manage to draw a straight line through it and announce that the result is “statistically significant”.
Straight lines have many pleasing properties, both in architecture and in science. If a time series follows a straight line, for example, it is pretty easy to forecast how it should evolve in the near future – just assume that the line continues (note: doesn’t always work).
However this fondness for straightness doesn’t always hold; indeed there are cases where scientists prefer to opt for a more complicated solution. An example is the modelling of tumour growth in cancer biology.
Tumour growth is caused by the proliferation of dividing cells. For example if cells have a cell cycle length td, then the total number of cells will double every td hours, which according to theory should result in exponential growth. In the 1950s (see Collins et al., 1956) it was therefore decided that the growth rate could be measured using the cell doubling time.
In practice, however, it is found that tumours grow more slowly as time goes on, so this exponential curve needed to be modified. One variant is the Gompertz curve, which was originally derived as a model for human lifespans by the British actuary Benjamin Gompertz in 1825, but was adapted for modelling tumour growth in the 1960s (Laird, 1964). This curve gives a tapered growth rate, at the expense of extra parameters, and has remained highly popular as a means of modelling a variety of tumour types.
However, it has often been observed empirically that tumour diameters, as opposed to volumes, appear to grow in a roughly linear fashion. Indeed, this has been known since at least the 1930s. As Mayneord wrote in 1932: “The rather surprising fact emerges that the increase in long diameter of the implanted tumour follows a linear law.” Furthermore, he noted, there was “a simple explanation of the approximate linearity in terms of the structure of the sarcoma. On cutting open the tumour it is often apparent that not the whole of the mass is in a state of active growth, but only a thin capsule (sometimes not more than 1 cm thick) enclosing the necrotic centre of the tumour.”
Because only this outer layer contains dividing cells, the rate of increase for the volume depends on the doubling time multiplied by the volume of the outer layer. If the thickness of the growing layer is small compared to the total tumour radius, then it is easily seen that the radius grows at a constant rate which is equal to the doubling time multiplied by the thickness of the growing layer. The result is a linear growth in radius. This translates to cubic growth in volume, which of course grows more slowly than an exponential curve at longer times – just as the data suggests.
In other words, rather than use a modified exponential curve to fit volume growth, it may be better to use a linear equation to model diameter. This idea that tumour growth is driven by an outer layer of proliferating cells, surrounding a quiescent or necrotic core, has been featured in a number of mathematical models (see e.g. Checkley et al., 2015, and our own CellCycler model). The linear growth law can also be used to analyse tumour data, as in the draft paper: “Analysing within and between patient patient tumour heterogenity via imaging: Vemurafenib, Dabrafenib and Trametinib.” The linear growth equation will of course not be a perfect fit for the growth of all tumours (no simple model is), but it is based on a consistent and empirically verified model of tumour growth, and can be easily parameterised and fit to data.
So why hasn’t this linear growth law caught on more widely? The reason is that what scientists see in data often depends on their mental model of what is going on.
I first encountered this phenomenon in the late 1990s when doing my D.Phil. in the prediction of nonlinear systems, with applications to weather forecasting. The dominant theory at the time said that forecast error was due to sensitivity to initial condition, aka the butterfly effect. As I described in The Future of Everything, researchers insisted that forecast errors showed the exponential growth characteristic of chaos, even though plots showed they clearly grew with slightly negative curvature, which was characteristic of model error.
A similar effect in cancer biology has again changed the way scientists interpret data. Sometimes, a straight line really is the best solution.
Collins, V. P., Loeffler, R. K. & Tivey, H. Observations on growth rates of human tumors. The American journal of roentgenology, radium therapy, and nuclear medicine 76, 988-1000 (1956).
Laird A. K. Dynamics of tumor growth. Br J of Cancer 18 (3): 490–502 (1964).
W. V. Mayneord. On a Law of Growth of Jensen’s Rat Sarcoma. Am J Cancer 16, 841-846 (1932).
Stephen Checkley, Linda MacCallum, James Yates, Paul Jasper, Haobin Luo, John Tolsma, Claus Bendtsen. Bridging the gap between in vitro and in vivo: Dose and schedule predictions for the ATR inhibitor AZD6738. Scientific Reports, 5(3)13545 (2015).
Yorke, E. D., Fuks, Z., Norton, L., Whitmore, W. & Ling, C. C. Modeling the Development of Metastases from Primary and Locally Recurrent Tumors: Comparison with a Clinical Data Base for Prostatic Cancer. Cancer Research 53, 2987-2993 (1993).
Hitesh Mistry, David Orrell, and Raluca Eftimie. Analysing within and between patient patient tumour heterogenity via imaging: Vemurafenib, Dabrafenib and Trametinib. (Working paper)