I do not think it is an unfair comparison since Sequel has both basic parts on the same level as PDO, and then implements the more advanced features on top of these basic parts. The basic parts of Sequel has superior usability and safety to PDO.

Sequel's right way:

    user = db['SELECT name FROM users WHERE id = ?', id].first

Sequel's wrong way:

    user = db["SELECT name FROM users WHERE id = #{id}"].first

PDO's right way:

    $stmt = $db->prepare('SELECT name FROM users WHERE id = ?');
    $stmt->execute([$id]);
    $user = $stmt->fecth();

PDO's wrong way:

    $user = $db->query("SELECT name FROM users WHERE id = $id")->fetch();

As you can see PDO is optimized for doing things easily the unsafe way while Sequel has the safe way as the normal way of running queries which is just as easy to use as the unsafe way.

> Just like any other template language (thinking of something like ColdFusion or ASP), of course one unescaped variable is going to be a headache.

That is simply not true. Look at Twig which by default escapes everything automatically, or Rails's patched ERB which keeps track of escaped an unescaped strings based on data types and makes sure everything is automatically escaped in the end. In those template languages you need the explicitly do something unsafe to get an unescaped value. While in PHP you need to audit all places where echo can be called directly or indirectly.