Right or Wrong?

On the Difficult Relationship Between Epidemiologists and Handedness

Abstract

The declining prevalence of left-handers with age has resulted in the hypothesis that sinistrality, being the result of a developmental insult, may be associated with a reduced life span. While it is plausible that some individuals become left-handed as a consequence of neurologic impairment, the literature on handedness itself appears to suffer from a number of problems. These include the ease with which information on handedness can be collected in the absence of prior hypotheses, the failure to address heterogeneity among left-handers, and the selective publication of positive results. Even if individual contributions, including one published in this issue of Epidemiology, are of reasonable quality, all the above problems conspire to lower the credibility of this area of research.

Dextrals, also known as right-handers, know that they can’t be wrong. So, while a dexterous left hand is, technically, an oxymoron, for a minority it is a reality attracting too much attention. For centuries, prejudice and superstition have stigmatized left-handers, and several languages hint at this history by openly indicating that there is something sinister about favoring one’s left. Only recently, and only in some cultures, have left-handers become accepted, but their woes are not over yet.

Numerous reports have associated left-handedness with various disorders and, generally, a shorter life span. The latter notion, specifically, originates from the observation that the prevalence of left-handers declines with age.¹ Overall, prevalence of left-handedness is approximately 10%, with wide geographic variations.² However, within a population, consistently more young left-handers than older ones are observed. Some left-handers may switch during their lifetime¹ and, since many were “corrected” as children, especially in former times,^3,4 some may report their acquired handedness rather than the innate one. Research into handedness and mortality has been spurred, however, by the hypothesis that left-handedness is the result of an insult suffered during early development, which ultimately leads to the premature demise of left-handers.¹

In this issue of Epidemiology, Ramadhani and colleagues⁵ contribute to this debate by presenting results from a cohort of middle-aged Dutch women followed for approximately 13 years. They report elevated colorectal cancer mortality among sinistrals compared with dextrals. Mortality for cerebrovascular disease was also increased. Breast cancer mortality, although higher, did not reach statistical significance, but incidence of premenopausal breast cancer was elevated among left-handers in this cohort.⁶ The analysis was careful, although the study was based on small numbers of deaths in each category.

At this point I should disclose that I am left-handed, and having successfully dodged a number of disorders, I doubt that my left hand is prematurely pulling me toward my grave. However, I am not alone in thinking that the literature on handedness suffers from a number of ills, irrespective of the putative illnesses suffered by left-handers.

Perhaps the problem from which all others follow is that it is simply too easy to include one or more questions about handedness in any questionnaire.⁷ That the question is easy to ask, however, does not mean that it will be answered accurately. As previously mentioned, older left-handers may classify themselves as right-handers, with the consequence that the average age of current left-handers will be younger than that of the apparent right-handers. This mechanism has led at least one deeply flawed study to conclude that left-handers’ life span was, on average, 9 years shorter than that of right-handers, thus making left-handedness as dangerous as smoking.⁸ Since then, several studies have addressed this topic, as reviewed by Ramadhani et al,⁵ with both positive and negative findings, and the question remains unresolved.

One source of confusion is that handedness is inconsistently determined across studies. Many assess handedness by asking hand preference in specified tasks,^1,3 which translates into a degree of sidedness. Since the score usually ends up being dichotomized, this approach may be prone to posthoc manipulation of cut-offs to obtain an association.⁷ Others consider that the hand with which one would “naturally” write should define handedness,² as very few are ambidextrous for writing, and few switch their writing hand over a lifetime unless forced to do so. Ramadhani and colleagues⁵ used a longitudinal design with comparable age of left- and right-handers at the beginning of follow-up. They analyzed self-reported innate handedness, which may have been reported inaccurately but is extremely unlikely to have been differentially misclassified.

Physiologically healthy left-handers may in fact end up being less successful or less healthy than right-handers, for a variety of reasons. Perelle and Ehrman² report a study in which teachers perceived left-handed children as having poor speech and writing, even though this was not apparent when the children were tested. Perhaps some left-handers, especially among the older generations, have been successfully persuaded that they are aberrant and slow, leading to reduced performance, lower socioeconomic status, and poorer health. It is also possible that being forced to switch to right-hand writing results in slower overall performance and, ultimately, poorer health. Social class of left- and right-handers was similar in Ramadhani and colleagues’ study,⁵ although the variable used may have missed subtle differences.

One consequence of the ease with which handedness can be determined is that heterogeneity among left-handers is rarely addressed.² The causes of handedness are unknown. Right-handedness is probably related to left-hemisphere dominance for speech. More than 90% of right-handers have left-hemisphere language activation,^3,9,10 but this is also true of approximately 75% of left-handers, whereas 14–16% of left-handers have symmetric activation, and the remaining right-side activation.^9,11,12 Among healthy volunteers with “atypical” (nonleft) language lateralization, no significant differences were seen with respect to verbal fluency, academic achievements, and other performance indicators.¹³ Individuals with “weak” lateralization showed reduced disruption in language after experimentally-induced transient lesions on either side, compared with individuals with marked lateralization.¹⁴ Left-handers with aphasic may have a better prognosis than right-handers, especially if from families of left-handers,⁹ although the evidence is inconsistent.¹⁵

Why do so many left-handers have left-hemisphere dominance for language and, in general, higher variability in brain lateralization? The most likely answer is that not all left-handers are born equal. Perelle and Ehrman² suggest that there are 3 types of left-handers. First are the “pathologic” ones, ie, those who would have likely been right-handed had they not suffered some damage to their left hemisphere. These would account for the higher proportion of left-handers among those with mental retardation and other neurologic disorders.² The second group is the “natural” left-handers, who are the mirror image of right-handers and none the worse for that. The third group is the “learned” left-handers, who have left-hemisphere dominance but, early in life, start using their left hand by chance and perpetuate this behavior. If they learn to write with the left hand, they may suffer a slight delay due to impulses having to cross the corpus callosum from the left hemisphere, (processing language), to the right hemisphere, (controlling the hand). Some may then compensate by developing verbal processing areas also in the right hemisphere, which may be related to the higher-than-expected fraction of left-handers among those scoring highest in the verbal and mathematical portions of the Scholastic Attitude Test.²

In general, if an insult to the left cerebral hemisphere ends up leading to left-handedness, the influx of these “forced” left-handers into the group of “normal” ones will be substantial, purely by virtue of the sheer number of those destined to be right-handed. Ramadhani et al⁵ acknowledge this, although not in so many words. Too often, however the entirety of left-handers is labeled as one developmentally-disrupted entity, generally ignoring the fact that, in all the conditions putatively associated with sinistrality, dextrals retain a substantial majority.

Beyond recognizing that there are differences among left-handers, can these differences be better characterized? Hemisphere dominance cannot easily be determined in population-based studies, but attempts may be made to assess functional markers. If individuals with signs of neurologic impairment could be identified, the focus would shift from handedness to a more specific “syndrome,” which would result in the double benefit of increasing the likelihood of identifying early exposures that might be associated with a meaningful end point, while taking the pressure off left-handers in general. Another option may be to collect information about handedness in relatives and assess whether outcomes differ between sporadic versus familial left-handers. Sensitivity will be poor, however, and left-handers with no family history would still constitute a heterogeneous group.

Genetics of left-handedness is another unresolved issue. Having one left-handed parent increases one’s chance of being left-handed from 10% to 20%. Still, even 2 left-handed parents have about a 75% chance of having a right-handed child. Hand discordance in monozygotic twins is about 20%,³ although no genes for handedness have been identified. In McManus’ proposed genetic model for handedness,³ one allele, C, in double dose would give a 50% chance of being sinistral and a 50% chance of being dextral. Another allele, D, would always produce dextrals when in double dose. The D and C alleles would act additively, and the DC genotype would thus result in 75% dextrals and 25% sinistrals.

Annett’s model¹⁶ proposes that inheritance of a “right-shift” gene would handicap speech-related activities in the right hemisphere and, incidentally, weaken the left hand. Those with no copy of the gene would have random and independent brain and hand asymmetry. The model implies heterozygote advantage, as homozygotes would be excessively lateralized. Annett also hypothesizes a mutation causing the gene to handicap one hemisphere at random, which could result in impairment of both hemispheres and, potentially, schizophrenia or autism.¹⁶ According to this model, reduced asymmetry will occur because neither hemisphere is impaired, or because both are.¹⁶ Over two-thirds of right-handers are “strong” dextrals, but only about one third of left-handers are “strong” sinistrals.³ This may be explained by left-handers having to live their life (however short) in a right-handers’ world. It is also compatible with the higher heterogeneity for hemisphere dominance in left-handers.

While sinistrality may share a common etiology with neurologic disorders (and, perhaps, cerebrovascular mortality), it is unclear why left-handedness would be associated with colorectal cancer mortality. This brings us to another consequence of an exposure that is too easy to assess: the frequent lack of prior hypotheses between handedness and outcome. Ramadani et al⁵ do not suggest a mechanism for colorectal cancer, although they speculate that prenatal exposure to sex hormones may be at the root of the association with breast cancer, as previously suggested.¹⁷ That steroid hormones, particularly testosterone, may affect handedness has been hypothesized from the excess of males among left-handers. However, males are generally more vulnerable to developmental disruptions than females, and they are also more prone to some neurologic disorders, such as reading disabilities and autism-spectrum disorders.^18,19 Boys, but not girls, whose mothers were exposed to prenatal ultrasounds were found to be more frequently left-handed,²⁰ and recent findings suggest that exposure to ultrasound may interfere with neuronal migration in mouse fetuses,²¹ although these findings may not apply to humans. Coren¹ reports that left-handedness is inherited more frequently from mothers than from fathers, which—if true—would fit with more males becoming left-handed as the result of nongenetic causes. While the study in this issue⁵ is restricted to females, the authors discuss the notion that sinistrals may have more frequently suffered developmental disruptions resulting in increased susceptibility to some diseases.⁵ However, the lack of a specific mechanism for colorectal cancer mortality is probably the weakest point of this report.

Ramadhani and colleagues recognize that theirs might be a chance finding,⁵ which takes me to the final, and most problematic, item in my list of shortcomings in the literature: publication bias. The availability of handedness and the possibility of correlating it with any outcome, pose a difficult challenge to reviewers and editors. Positive studies, of good and not-so-good quality, are more likely to be published than good negative studies, which only stand a chance of being published after the positive ones have made their appearance and, sometimes, the news. This leaves the readers with the task of guessing how many unwritten or unpublished negative ones are out there for every positive finding, at least until someone produces a funnel plot that may—or may not—provide a credible estimate. Meanwhile, life goes on, even for left-handers.

ABOUT THE AUTHOR

Born and educated in Italy, OLGA BASSO has worked for several years at the Danish Epidemiology Science Centre in Denmark and is currently employed at the National Institute of Environmental Health Sciences in North Carolina. Her main interest is in reproductive and perinatal epidemiology, but she also has longstanding fascination with sources of bias in epidemiology.